AACR Annual Meeting 2019

ATLANTA – Adding intratumoral talimogene laherparepvec (TVEC) to neoadjuvant chemotherapy appears to improve response rates in patients with nonmetastatic triple-negative breast cancer, according to findings from a phase 1 trial.

The pathologic complete response rate (pCR) in nine patients aged 18-70 years with stage T2-T3NO-2 disease who were enrolled in the single-center trial was 55%, whereas the expected rate with neoadjuvant chemotherapy alone was 30%, Hatem Soliman, MD, reported at the annual meeting of the American Association for Cancer Research.

“Even in the patients with residual disease, they had almost complete obliteration of their tumors, as well,” said Dr. Soliman of Moffitt Cancer Center, Tampa, Fla., adding that preliminary analyses of T cell subtypes indicated that CD45RO+ cells, which are associated with activated memory effector phenotype cells, were found in higher percentages in tumor specimens from patients who had pCR vs. those who did not.

“This could be an emerging marker that could be associated with pCR from TVEC,” he said, stressing, however, that “this is preliminary data [that] needs to be borne out in subsequent studies.”

Of the nine participants, six had stage II disease and three had stage III disease, and tumor size was greater than 5 cm in 2 patients, and 2-5 cm in 7 patients. Three received 10⁶ plaque-forming units (PFUs) x 5 injections (dose level 1), and 6 received 10⁶ PFUs for the first injection then 10⁸ PFUs for 4 additional injections. Patients also received neoadjuvant paclitaxel followed by doxorubicin/cyclophosphamide chemotherapy.

They then went on to surgery and were evaluated for pCR.

No dose-limiting toxicities occurred, therefore the maximum-tolerated dose was dose level 2, Dr. Soliman noted.

The most common toxicities due to TVEC were fevers, chills, and injection site reactions, and “these are considered expected side effects of TVEC administration and were manageable,” he said.

Two serious adverse events occurred in the trial: a pulmonary embolism and a postoperative case of severe bradycardia thought to be a vasovagal episode; there were no deaths or any sequelae from these adverse events and they completely resolved.

One latent genital wild type herpes simplex 1 virus (HSV1) reactivation event occurred and was treated with a topical agent.


Early-stage triple-negative breast cancer is associated with a higher risk of early relapse, but attaining a pCR after neoadjuvant chemotherapy is associated with improved prognosis, Dr. Soliman said.

“Historically, standard regimens used for triple-negative breast cancer include an anthracycline and a taxane, and the rates of pCR in those patients hover around 30%,” he said. “Others have looked at the relationship of increased tumor infiltrating lymphocytes (TILs] in triple-negative breast cancers and other breast cancers, and found that those tumors that did have a higher de novo TIL infiltrate, either at the beginning of treatment or acquired during treatment, seemed to have a higher rate of pCR and also seemed to have improved prognosis.”

This suggested that these TIL infiltrates may be both a predictive and prognostic biologic marker for the biology of the disease, he noted.

Further, promising prior research on the role of oncolytic viruses as a potential treatment modality for cancer led to interest in their use during neoadjuvant chemotherapy “with the idea that we could potentially improve pathologic complete response rates both through direct tumor cell lysis of treated tumors, but also through recruitment of a robust antitumor immune response caused by the viruses’ mechanism of action,” he said, adding that “this could be beneficial, particularly in those immunologically ‘cold’ tumors.”

This led to the incorporation of TVEC, a genetically engineered oncolytic HSV1 currently approved for the treatment of melanoma, in this neoadjuvant trial. TVEC preferentially lyses tumor cells over normal tissue to release tumor associated antigens, produces granulocyte-macrophage colony-stimulating factor to activate dendritic cells, and stimulates T cells to provoke an adaptive immune response, he explained.

“[This] then can not only potentially attack tumor cells at the primary site, but then may potentially spread around the body to improve host surveillance and try to eradicate micrometastatic disease, as well,” he said.

The current findings show that adding TVEC to neoadjuvant chemotherapy is feasible at the full Food and Drug Administration–approved dose and has manageable toxicity, he concluded, noting that “a phase 2 single-arm trial of this regimen is ongoing, and we are actively accruing patients to further evaluate the efficacy signal and formally test the hypothesis along with immune correlates.”

Dr. Soliman reported relationships with Eli Lilly, Pfizer, Celgene, AstraZeneca, PUMA, Novartis, Eisai, and Amgen.

SOURCE: Soliman H et al. AACR 2019, Abstract CT040.

ATLANTA – Adding intratumoral talimogene laherparepvec (TVEC) to neoadjuvant chemotherapy appears to improve response rates in patients with nonmetastatic triple-negative breast cancer, according to findings from a phase 1 trial.

The pathologic complete response rate (pCR) in nine patients aged 18-70 years with stage T2-T3NO-2 disease who were enrolled in the single-center trial was 55%, whereas the expected rate with neoadjuvant chemotherapy alone was 30%, Hatem Soliman, MD, reported at the annual meeting of the American Association for Cancer Research.

“Even in the patients with residual disease, they had almost complete obliteration of their tumors, as well,” said Dr. Soliman of Moffitt Cancer Center, Tampa, Fla., adding that preliminary analyses of T cell subtypes indicated that CD45RO+ cells, which are associated with activated memory effector phenotype cells, were found in higher percentages in tumor specimens from patients who had pCR vs. those who did not.

“This could be an emerging marker that could be associated with pCR from TVEC,” he said, stressing, however, that “this is preliminary data [that] needs to be borne out in subsequent studies.”

Of the nine participants, six had stage II disease and three had stage III disease, and tumor size was greater than 5 cm in 2 patients, and 2-5 cm in 7 patients. Three received 10⁶ plaque-forming units (PFUs) x 5 injections (dose level 1), and 6 received 10⁶ PFUs for the first injection then 10⁸ PFUs for 4 additional injections. Patients also received neoadjuvant paclitaxel followed by doxorubicin/cyclophosphamide chemotherapy.

They then went on to surgery and were evaluated for pCR.

No dose-limiting toxicities occurred, therefore the maximum-tolerated dose was dose level 2, Dr. Soliman noted.

The most common toxicities due to TVEC were fevers, chills, and injection site reactions, and “these are considered expected side effects of TVEC administration and were manageable,” he said.

Two serious adverse events occurred in the trial: a pulmonary embolism and a postoperative case of severe bradycardia thought to be a vasovagal episode; there were no deaths or any sequelae from these adverse events and they completely resolved.

One latent genital wild type herpes simplex 1 virus (HSV1) reactivation event occurred and was treated with a topical agent.


Early-stage triple-negative breast cancer is associated with a higher risk of early relapse, but attaining a pCR after neoadjuvant chemotherapy is associated with improved prognosis, Dr. Soliman said.

“Historically, standard regimens used for triple-negative breast cancer include an anthracycline and a taxane, and the rates of pCR in those patients hover around 30%,” he said. “Others have looked at the relationship of increased tumor infiltrating lymphocytes (TILs] in triple-negative breast cancers and other breast cancers, and found that those tumors that did have a higher de novo TIL infiltrate, either at the beginning of treatment or acquired during treatment, seemed to have a higher rate of pCR and also seemed to have improved prognosis.”

This suggested that these TIL infiltrates may be both a predictive and prognostic biologic marker for the biology of the disease, he noted.

Further, promising prior research on the role of oncolytic viruses as a potential treatment modality for cancer led to interest in their use during neoadjuvant chemotherapy “with the idea that we could potentially improve pathologic complete response rates both through direct tumor cell lysis of treated tumors, but also through recruitment of a robust antitumor immune response caused by the viruses’ mechanism of action,” he said, adding that “this could be beneficial, particularly in those immunologically ‘cold’ tumors.”

This led to the incorporation of TVEC, a genetically engineered oncolytic HSV1 currently approved for the treatment of melanoma, in this neoadjuvant trial. TVEC preferentially lyses tumor cells over normal tissue to release tumor associated antigens, produces granulocyte-macrophage colony-stimulating factor to activate dendritic cells, and stimulates T cells to provoke an adaptive immune response, he explained.

“[This] then can not only potentially attack tumor cells at the primary site, but then may potentially spread around the body to improve host surveillance and try to eradicate micrometastatic disease, as well,” he said.

The current findings show that adding TVEC to neoadjuvant chemotherapy is feasible at the full Food and Drug Administration–approved dose and has manageable toxicity, he concluded, noting that “a phase 2 single-arm trial of this regimen is ongoing, and we are actively accruing patients to further evaluate the efficacy signal and formally test the hypothesis along with immune correlates.”

Dr. Soliman reported relationships with Eli Lilly, Pfizer, Celgene, AstraZeneca, PUMA, Novartis, Eisai, and Amgen.

SOURCE: Soliman H et al. AACR 2019, Abstract CT040.

ATLANTA – Adding intratumoral talimogene laherparepvec (TVEC) to neoadjuvant chemotherapy appears to improve response rates in patients with nonmetastatic triple-negative breast cancer, according to findings from a phase 1 trial.

The pathologic complete response rate (pCR) in nine patients aged 18-70 years with stage T2-T3NO-2 disease who were enrolled in the single-center trial was 55%, whereas the expected rate with neoadjuvant chemotherapy alone was 30%, Hatem Soliman, MD, reported at the annual meeting of the American Association for Cancer Research.

“Even in the patients with residual disease, they had almost complete obliteration of their tumors, as well,” said Dr. Soliman of Moffitt Cancer Center, Tampa, Fla., adding that preliminary analyses of T cell subtypes indicated that CD45RO+ cells, which are associated with activated memory effector phenotype cells, were found in higher percentages in tumor specimens from patients who had pCR vs. those who did not.

“This could be an emerging marker that could be associated with pCR from TVEC,” he said, stressing, however, that “this is preliminary data [that] needs to be borne out in subsequent studies.”

Of the nine participants, six had stage II disease and three had stage III disease, and tumor size was greater than 5 cm in 2 patients, and 2-5 cm in 7 patients. Three received 10⁶ plaque-forming units (PFUs) x 5 injections (dose level 1), and 6 received 10⁶ PFUs for the first injection then 10⁸ PFUs for 4 additional injections. Patients also received neoadjuvant paclitaxel followed by doxorubicin/cyclophosphamide chemotherapy.

They then went on to surgery and were evaluated for pCR.

No dose-limiting toxicities occurred, therefore the maximum-tolerated dose was dose level 2, Dr. Soliman noted.

The most common toxicities due to TVEC were fevers, chills, and injection site reactions, and “these are considered expected side effects of TVEC administration and were manageable,” he said.

Two serious adverse events occurred in the trial: a pulmonary embolism and a postoperative case of severe bradycardia thought to be a vasovagal episode; there were no deaths or any sequelae from these adverse events and they completely resolved.

One latent genital wild type herpes simplex 1 virus (HSV1) reactivation event occurred and was treated with a topical agent.


Early-stage triple-negative breast cancer is associated with a higher risk of early relapse, but attaining a pCR after neoadjuvant chemotherapy is associated with improved prognosis, Dr. Soliman said.

“Historically, standard regimens used for triple-negative breast cancer include an anthracycline and a taxane, and the rates of pCR in those patients hover around 30%,” he said. “Others have looked at the relationship of increased tumor infiltrating lymphocytes (TILs] in triple-negative breast cancers and other breast cancers, and found that those tumors that did have a higher de novo TIL infiltrate, either at the beginning of treatment or acquired during treatment, seemed to have a higher rate of pCR and also seemed to have improved prognosis.”

This suggested that these TIL infiltrates may be both a predictive and prognostic biologic marker for the biology of the disease, he noted.

Further, promising prior research on the role of oncolytic viruses as a potential treatment modality for cancer led to interest in their use during neoadjuvant chemotherapy “with the idea that we could potentially improve pathologic complete response rates both through direct tumor cell lysis of treated tumors, but also through recruitment of a robust antitumor immune response caused by the viruses’ mechanism of action,” he said, adding that “this could be beneficial, particularly in those immunologically ‘cold’ tumors.”

This led to the incorporation of TVEC, a genetically engineered oncolytic HSV1 currently approved for the treatment of melanoma, in this neoadjuvant trial. TVEC preferentially lyses tumor cells over normal tissue to release tumor associated antigens, produces granulocyte-macrophage colony-stimulating factor to activate dendritic cells, and stimulates T cells to provoke an adaptive immune response, he explained.

“[This] then can not only potentially attack tumor cells at the primary site, but then may potentially spread around the body to improve host surveillance and try to eradicate micrometastatic disease, as well,” he said.

The current findings show that adding TVEC to neoadjuvant chemotherapy is feasible at the full Food and Drug Administration–approved dose and has manageable toxicity, he concluded, noting that “a phase 2 single-arm trial of this regimen is ongoing, and we are actively accruing patients to further evaluate the efficacy signal and formally test the hypothesis along with immune correlates.”

Dr. Soliman reported relationships with Eli Lilly, Pfizer, Celgene, AstraZeneca, PUMA, Novartis, Eisai, and Amgen.

SOURCE: Soliman H et al. AACR 2019, Abstract CT040.

ATLANTA – Combination entinostat and pembrolizumab showed promising activity in a phase 2 study of non–small cell lung cancer patients who progressed on or after anti-programmed death-ligand 1 (PD-L1) therapy, and new analyses have identified gene signatures associated with treatment response.

Gene set analysis in tumors from 43 of the patients – 4 responders and 39 nonresponders – who participated in the open-label ENCORE-601 study revealed that Myc gene signaling was enriched in responders vs. nonresponders, Suresh S. Ramalingam, MD, said at the annual meeting of the American Association for Cancer Research.

High Myc gene activity is known from previous studies to be associated with response to immune checkpoint inhibition, and this has been attributed to high PD-L1 expression, decrease in interferon signatures, and exclusion of lymphocytes, he noted.

“And we know from other publications that entinostat is known to decrease Myc activity,” he said. “Therefore, our putative hypothesis at this time – albeit on a small set of patients – is that for patients with baseline high Myc activity, when they have developed resistance to PD-1 or PD-L1 inhibition ... giving them entinostat drives down the Myc activity and results in a change in the tumor microenvironment to one where immune checkpoint inhibition could be rendered effective.”


Patients from ENCORE-601 also were evaluated by baseline circulating classical monocyte levels as prior findings showed improved overall survival and progression-free survival (PFS) in melanoma patients with higher vs. lower counts, Dr. Ramalingam explained.

The overall response rate (ORR) in those with baseline levels above the median (MHi, 11 patients) was 21.1% vs. 6.5% in those with levels below the median (MLo, 32 patients); median PFS was 4.7 vs. 2.7 months in the MHi and MLo groups, respectively, said Dr. Ramalingam of Winship Cancer Institute, Emory University, Atlanta.

ENCORE-601 included 76 subjects who received entinostat at a dose of 5 mg per week plus intravenous pembrolizumab at 200 mg every 3 weeks. The confirmed ORR with treatment in 72 efficacy-evaluable patients was 10%, with an additional 50% of patients having stable disease. The median duration of response was 8 months, and median PFS was 2.8 months.

Top-line results from the study, which was undertaken based in part on preclinical data showing synergy between the oral class 1-selective histone deacetylase inhibitor entinostat and anti-PD-1 inhibition, were presented at the 2018 World Conference on Lung Cancer, and the current findings represent secondary outcome measures involving analyses in pretreatment tumor samples from patients with sufficient RNA yield for analysis.


The data may provide a mechanistic basis for the responses seen with entinostat and pembrolizumab in ENCORE-601, Dr. Ramalingam said.

“Now we acknowledge that this is a relatively small dataset, and therefore further studies are warranted using these biomarkers to further understand whether they can be used as predictive biomarkers for treatment,” he said, noting that one such clinical trial is currently in the discussion phase.

The ENCORE-601 findings are important given that “with the movement of checkpoint inhibitors to the front-line setting, there is now an unmet need in the second-line [setting] where patients have already received a checkpoint inhibitor and have developed disease progression,” he noted, adding that “while chemotherapy remains central to this group of patients, development of novel agents is an unmet need.”

Dr. Ramalingam disclosed ties to AbbVie, Advaxis, Amgen, Astra Zeneca, Bristol-Myers Squibb, Genentech/Roche, Loxo, Merck, Nektar, Takeda, and Syndax.

sworcester@mdedge.com

SOURCE: Ramalingam S et al. AACR 2019, Abstract CT041.

ATLANTA – Combination entinostat and pembrolizumab showed promising activity in a phase 2 study of non–small cell lung cancer patients who progressed on or after anti-programmed death-ligand 1 (PD-L1) therapy, and new analyses have identified gene signatures associated with treatment response.

Gene set analysis in tumors from 43 of the patients – 4 responders and 39 nonresponders – who participated in the open-label ENCORE-601 study revealed that Myc gene signaling was enriched in responders vs. nonresponders, Suresh S. Ramalingam, MD, said at the annual meeting of the American Association for Cancer Research.

High Myc gene activity is known from previous studies to be associated with response to immune checkpoint inhibition, and this has been attributed to high PD-L1 expression, decrease in interferon signatures, and exclusion of lymphocytes, he noted.

“And we know from other publications that entinostat is known to decrease Myc activity,” he said. “Therefore, our putative hypothesis at this time – albeit on a small set of patients – is that for patients with baseline high Myc activity, when they have developed resistance to PD-1 or PD-L1 inhibition ... giving them entinostat drives down the Myc activity and results in a change in the tumor microenvironment to one where immune checkpoint inhibition could be rendered effective.”


Patients from ENCORE-601 also were evaluated by baseline circulating classical monocyte levels as prior findings showed improved overall survival and progression-free survival (PFS) in melanoma patients with higher vs. lower counts, Dr. Ramalingam explained.

The overall response rate (ORR) in those with baseline levels above the median (MHi, 11 patients) was 21.1% vs. 6.5% in those with levels below the median (MLo, 32 patients); median PFS was 4.7 vs. 2.7 months in the MHi and MLo groups, respectively, said Dr. Ramalingam of Winship Cancer Institute, Emory University, Atlanta.

ENCORE-601 included 76 subjects who received entinostat at a dose of 5 mg per week plus intravenous pembrolizumab at 200 mg every 3 weeks. The confirmed ORR with treatment in 72 efficacy-evaluable patients was 10%, with an additional 50% of patients having stable disease. The median duration of response was 8 months, and median PFS was 2.8 months.

Top-line results from the study, which was undertaken based in part on preclinical data showing synergy between the oral class 1-selective histone deacetylase inhibitor entinostat and anti-PD-1 inhibition, were presented at the 2018 World Conference on Lung Cancer, and the current findings represent secondary outcome measures involving analyses in pretreatment tumor samples from patients with sufficient RNA yield for analysis.


The data may provide a mechanistic basis for the responses seen with entinostat and pembrolizumab in ENCORE-601, Dr. Ramalingam said.

“Now we acknowledge that this is a relatively small dataset, and therefore further studies are warranted using these biomarkers to further understand whether they can be used as predictive biomarkers for treatment,” he said, noting that one such clinical trial is currently in the discussion phase.

The ENCORE-601 findings are important given that “with the movement of checkpoint inhibitors to the front-line setting, there is now an unmet need in the second-line [setting] where patients have already received a checkpoint inhibitor and have developed disease progression,” he noted, adding that “while chemotherapy remains central to this group of patients, development of novel agents is an unmet need.”

Dr. Ramalingam disclosed ties to AbbVie, Advaxis, Amgen, Astra Zeneca, Bristol-Myers Squibb, Genentech/Roche, Loxo, Merck, Nektar, Takeda, and Syndax.

sworcester@mdedge.com

SOURCE: Ramalingam S et al. AACR 2019, Abstract CT041.

ATLANTA – Combination entinostat and pembrolizumab showed promising activity in a phase 2 study of non–small cell lung cancer patients who progressed on or after anti-programmed death-ligand 1 (PD-L1) therapy, and new analyses have identified gene signatures associated with treatment response.

Gene set analysis in tumors from 43 of the patients – 4 responders and 39 nonresponders – who participated in the open-label ENCORE-601 study revealed that Myc gene signaling was enriched in responders vs. nonresponders, Suresh S. Ramalingam, MD, said at the annual meeting of the American Association for Cancer Research.

High Myc gene activity is known from previous studies to be associated with response to immune checkpoint inhibition, and this has been attributed to high PD-L1 expression, decrease in interferon signatures, and exclusion of lymphocytes, he noted.

“And we know from other publications that entinostat is known to decrease Myc activity,” he said. “Therefore, our putative hypothesis at this time – albeit on a small set of patients – is that for patients with baseline high Myc activity, when they have developed resistance to PD-1 or PD-L1 inhibition ... giving them entinostat drives down the Myc activity and results in a change in the tumor microenvironment to one where immune checkpoint inhibition could be rendered effective.”


Patients from ENCORE-601 also were evaluated by baseline circulating classical monocyte levels as prior findings showed improved overall survival and progression-free survival (PFS) in melanoma patients with higher vs. lower counts, Dr. Ramalingam explained.

The overall response rate (ORR) in those with baseline levels above the median (MHi, 11 patients) was 21.1% vs. 6.5% in those with levels below the median (MLo, 32 patients); median PFS was 4.7 vs. 2.7 months in the MHi and MLo groups, respectively, said Dr. Ramalingam of Winship Cancer Institute, Emory University, Atlanta.

ENCORE-601 included 76 subjects who received entinostat at a dose of 5 mg per week plus intravenous pembrolizumab at 200 mg every 3 weeks. The confirmed ORR with treatment in 72 efficacy-evaluable patients was 10%, with an additional 50% of patients having stable disease. The median duration of response was 8 months, and median PFS was 2.8 months.

Top-line results from the study, which was undertaken based in part on preclinical data showing synergy between the oral class 1-selective histone deacetylase inhibitor entinostat and anti-PD-1 inhibition, were presented at the 2018 World Conference on Lung Cancer, and the current findings represent secondary outcome measures involving analyses in pretreatment tumor samples from patients with sufficient RNA yield for analysis.


The data may provide a mechanistic basis for the responses seen with entinostat and pembrolizumab in ENCORE-601, Dr. Ramalingam said.

“Now we acknowledge that this is a relatively small dataset, and therefore further studies are warranted using these biomarkers to further understand whether they can be used as predictive biomarkers for treatment,” he said, noting that one such clinical trial is currently in the discussion phase.

The ENCORE-601 findings are important given that “with the movement of checkpoint inhibitors to the front-line setting, there is now an unmet need in the second-line [setting] where patients have already received a checkpoint inhibitor and have developed disease progression,” he noted, adding that “while chemotherapy remains central to this group of patients, development of novel agents is an unmet need.”

Dr. Ramalingam disclosed ties to AbbVie, Advaxis, Amgen, Astra Zeneca, Bristol-Myers Squibb, Genentech/Roche, Loxo, Merck, Nektar, Takeda, and Syndax.

sworcester@mdedge.com

SOURCE: Ramalingam S et al. AACR 2019, Abstract CT041.

ATLANTA – Combined treatment with a programmed death-ligand 1 (PD-L1) inhibitor, the oral CHK1 inhibitor SRA737, and low-dose gemcitabine for small cell lung cancer (SCLC) resulted in dramatic antitumor activity and established a strong antitumor microenvironment in a preclinical model.

The findings provide a “strong rationale” for combining these agents in patients with SCLC, Triparna Sen, PhD, reported in a late-breaking abstract presentation at the annual meeting of the American Association for Cancer Research.

Dr. Sen and her colleagues assessed this triple regimen based on encouraging prior findings, including their own recent finding that DNA damage response (DDR) inhibition “actually increases antitumor immunity in this cancer type” by activating the STING/TBK1/RF3 innate immune pathway and increasing levels of chemokines-CXCL10 and CCL5 that induced activation of cytotoxic T lymphocytes.

“Based on this background and studies published in other cancer types, we hypothesized that ... SRA737... a very highly selective potent checkpoint inhibitor ... will upregulate the innate immune signaling, resulting in improved antitumor immune response in combination with anti–PD-L1,” she said, noting that bladder and colorectal cancer models were also studied.

The results varied by cancer type, but encouraging results in SCLC led to in vivo study, said Dr. Sen, who was a postdoctoral fellow, instructor, and member of the Byers Laboratory at MD Anderson Cancer Center, Houston, at the time the research was conducted.

She and her colleagues injected immunocompetent mice with Trp53, Rb1, and p130 triple-knockout SCLC cell lines that are “very highly representative of what we see in patients,” and resulting tumors were treated with SRA737 alone or in combination with an anti–PD-L1 agent.

PD-L1 alone did not work, and SRA737 with 5- out of 7-day dosing was associated with a significant delay in tumor growth.

“However, the combination does much better than either of the single agents alone. ... we never had tumor growth beyond baseline and there was regression as early as 12 days,” she said, noting that the combination activates the STING pathway.

Similar findings were seen for bladder and colorectal cancer models, she noted.

The next question is how chemotherapy plus immune checkpoint blockade – the currently approved first-line therapy in SCLC – can be improved, and how chemotherapy modulates the immune microenvironment in SCLC, she said.

To explore this, she and her colleagues treated the mice with subtherapeutic doses of SRA737 on 2 out of 7 days with low-dose gemcitabine, followed by anti–PD-L1 therapy, or with single-agent therapy and various double-agent combinations.

Again, none of the agents worked on their own.

“Even with the double combinations you see very, very modest benefit,” she said. “With the triple combination we wipe out the tumors; as early as 14 days we have 8 out of 10 complete responses, and we have followed the tumors up to 2 months and they stay gone.”

“In a nutshell, this works,” she added.

Additional analyses showed that the CD3+ T cells increase with the gemcitabine/SRA737 combination, and even more so with the triple-combination therapy.

“So we not only increase the CD3+ total T cells, we do increase CD8+ cytotoxic T cells,” she said. “Interestingly, we also decrease exhausted T-cell populations, and also [regulatory T] cells.”

Additionally, the M1 macrophage population was significantly higher with the triple regimen, there was a trend toward a decrease in the antimacrophage population, and there was a higher population of dendritic cells and myeloid-derived suppressor cells.

“What I believe is we are still scratching the surface, and we need to go deeper into the tumor microenvironment and see how these combinations really work,” she said, concluding that SRA737 is cytotoxic and induces micro-nuclei formation in a subset of SCLC and other cancer models in vitro, that in combination with anti–PD-L1 it activates innate immune signaling and causes tumor regression in SCLC, and that with low-dose gemcitabine it results in durable tumor regression in combination with SRA737 and anti–PD-L1.

“What is the most interesting is that this triple combination enhances antitumor immunity by increasing cytotoxic T-cell infiltration, decreasing T-cell exhaustion, and a favorable modulation of antigen presenting cells,” she said. “Why do we care? The anti–PD-L1 drug ... atezolizumab ... is right now FDA approved as a first-line treatment in combination with chemotherapy, and we already have DDR inhibitors in the clinic, we have PARP inhibitors in the clinic, we have checkpoint inhibitors in the clinic, SRA737 is in the clinic.

“So our preclinical data provides a strong rationale for combining low-dose gemcitabine with checkpoint inhibition and with anti–PD-L1 to enhance the clinical efficacy of these drugs,” she concluded.

Dr. Sen reported having no disclosures.

sworcester@mdedge.com

SOURCE: Sen T et al. AACR 2019, Abstract LB-148.

ATLANTA – Combined treatment with a programmed death-ligand 1 (PD-L1) inhibitor, the oral CHK1 inhibitor SRA737, and low-dose gemcitabine for small cell lung cancer (SCLC) resulted in dramatic antitumor activity and established a strong antitumor microenvironment in a preclinical model.

The findings provide a “strong rationale” for combining these agents in patients with SCLC, Triparna Sen, PhD, reported in a late-breaking abstract presentation at the annual meeting of the American Association for Cancer Research.

Dr. Sen and her colleagues assessed this triple regimen based on encouraging prior findings, including their own recent finding that DNA damage response (DDR) inhibition “actually increases antitumor immunity in this cancer type” by activating the STING/TBK1/RF3 innate immune pathway and increasing levels of chemokines-CXCL10 and CCL5 that induced activation of cytotoxic T lymphocytes.

“Based on this background and studies published in other cancer types, we hypothesized that ... SRA737... a very highly selective potent checkpoint inhibitor ... will upregulate the innate immune signaling, resulting in improved antitumor immune response in combination with anti–PD-L1,” she said, noting that bladder and colorectal cancer models were also studied.

The results varied by cancer type, but encouraging results in SCLC led to in vivo study, said Dr. Sen, who was a postdoctoral fellow, instructor, and member of the Byers Laboratory at MD Anderson Cancer Center, Houston, at the time the research was conducted.

She and her colleagues injected immunocompetent mice with Trp53, Rb1, and p130 triple-knockout SCLC cell lines that are “very highly representative of what we see in patients,” and resulting tumors were treated with SRA737 alone or in combination with an anti–PD-L1 agent.

PD-L1 alone did not work, and SRA737 with 5- out of 7-day dosing was associated with a significant delay in tumor growth.

“However, the combination does much better than either of the single agents alone. ... we never had tumor growth beyond baseline and there was regression as early as 12 days,” she said, noting that the combination activates the STING pathway.

Similar findings were seen for bladder and colorectal cancer models, she noted.

The next question is how chemotherapy plus immune checkpoint blockade – the currently approved first-line therapy in SCLC – can be improved, and how chemotherapy modulates the immune microenvironment in SCLC, she said.

To explore this, she and her colleagues treated the mice with subtherapeutic doses of SRA737 on 2 out of 7 days with low-dose gemcitabine, followed by anti–PD-L1 therapy, or with single-agent therapy and various double-agent combinations.

Again, none of the agents worked on their own.

“Even with the double combinations you see very, very modest benefit,” she said. “With the triple combination we wipe out the tumors; as early as 14 days we have 8 out of 10 complete responses, and we have followed the tumors up to 2 months and they stay gone.”

“In a nutshell, this works,” she added.

Additional analyses showed that the CD3+ T cells increase with the gemcitabine/SRA737 combination, and even more so with the triple-combination therapy.

“So we not only increase the CD3+ total T cells, we do increase CD8+ cytotoxic T cells,” she said. “Interestingly, we also decrease exhausted T-cell populations, and also [regulatory T] cells.”

Additionally, the M1 macrophage population was significantly higher with the triple regimen, there was a trend toward a decrease in the antimacrophage population, and there was a higher population of dendritic cells and myeloid-derived suppressor cells.

“What I believe is we are still scratching the surface, and we need to go deeper into the tumor microenvironment and see how these combinations really work,” she said, concluding that SRA737 is cytotoxic and induces micro-nuclei formation in a subset of SCLC and other cancer models in vitro, that in combination with anti–PD-L1 it activates innate immune signaling and causes tumor regression in SCLC, and that with low-dose gemcitabine it results in durable tumor regression in combination with SRA737 and anti–PD-L1.

“What is the most interesting is that this triple combination enhances antitumor immunity by increasing cytotoxic T-cell infiltration, decreasing T-cell exhaustion, and a favorable modulation of antigen presenting cells,” she said. “Why do we care? The anti–PD-L1 drug ... atezolizumab ... is right now FDA approved as a first-line treatment in combination with chemotherapy, and we already have DDR inhibitors in the clinic, we have PARP inhibitors in the clinic, we have checkpoint inhibitors in the clinic, SRA737 is in the clinic.

“So our preclinical data provides a strong rationale for combining low-dose gemcitabine with checkpoint inhibition and with anti–PD-L1 to enhance the clinical efficacy of these drugs,” she concluded.

Dr. Sen reported having no disclosures.

sworcester@mdedge.com

SOURCE: Sen T et al. AACR 2019, Abstract LB-148.

ATLANTA – Combined treatment with a programmed death-ligand 1 (PD-L1) inhibitor, the oral CHK1 inhibitor SRA737, and low-dose gemcitabine for small cell lung cancer (SCLC) resulted in dramatic antitumor activity and established a strong antitumor microenvironment in a preclinical model.

The findings provide a “strong rationale” for combining these agents in patients with SCLC, Triparna Sen, PhD, reported in a late-breaking abstract presentation at the annual meeting of the American Association for Cancer Research.

Dr. Sen and her colleagues assessed this triple regimen based on encouraging prior findings, including their own recent finding that DNA damage response (DDR) inhibition “actually increases antitumor immunity in this cancer type” by activating the STING/TBK1/RF3 innate immune pathway and increasing levels of chemokines-CXCL10 and CCL5 that induced activation of cytotoxic T lymphocytes.

“Based on this background and studies published in other cancer types, we hypothesized that ... SRA737... a very highly selective potent checkpoint inhibitor ... will upregulate the innate immune signaling, resulting in improved antitumor immune response in combination with anti–PD-L1,” she said, noting that bladder and colorectal cancer models were also studied.

The results varied by cancer type, but encouraging results in SCLC led to in vivo study, said Dr. Sen, who was a postdoctoral fellow, instructor, and member of the Byers Laboratory at MD Anderson Cancer Center, Houston, at the time the research was conducted.

She and her colleagues injected immunocompetent mice with Trp53, Rb1, and p130 triple-knockout SCLC cell lines that are “very highly representative of what we see in patients,” and resulting tumors were treated with SRA737 alone or in combination with an anti–PD-L1 agent.

PD-L1 alone did not work, and SRA737 with 5- out of 7-day dosing was associated with a significant delay in tumor growth.

“However, the combination does much better than either of the single agents alone. ... we never had tumor growth beyond baseline and there was regression as early as 12 days,” she said, noting that the combination activates the STING pathway.

Similar findings were seen for bladder and colorectal cancer models, she noted.

The next question is how chemotherapy plus immune checkpoint blockade – the currently approved first-line therapy in SCLC – can be improved, and how chemotherapy modulates the immune microenvironment in SCLC, she said.

To explore this, she and her colleagues treated the mice with subtherapeutic doses of SRA737 on 2 out of 7 days with low-dose gemcitabine, followed by anti–PD-L1 therapy, or with single-agent therapy and various double-agent combinations.

Again, none of the agents worked on their own.

“Even with the double combinations you see very, very modest benefit,” she said. “With the triple combination we wipe out the tumors; as early as 14 days we have 8 out of 10 complete responses, and we have followed the tumors up to 2 months and they stay gone.”

“In a nutshell, this works,” she added.

Additional analyses showed that the CD3+ T cells increase with the gemcitabine/SRA737 combination, and even more so with the triple-combination therapy.

“So we not only increase the CD3+ total T cells, we do increase CD8+ cytotoxic T cells,” she said. “Interestingly, we also decrease exhausted T-cell populations, and also [regulatory T] cells.”

Additionally, the M1 macrophage population was significantly higher with the triple regimen, there was a trend toward a decrease in the antimacrophage population, and there was a higher population of dendritic cells and myeloid-derived suppressor cells.

“What I believe is we are still scratching the surface, and we need to go deeper into the tumor microenvironment and see how these combinations really work,” she said, concluding that SRA737 is cytotoxic and induces micro-nuclei formation in a subset of SCLC and other cancer models in vitro, that in combination with anti–PD-L1 it activates innate immune signaling and causes tumor regression in SCLC, and that with low-dose gemcitabine it results in durable tumor regression in combination with SRA737 and anti–PD-L1.

“What is the most interesting is that this triple combination enhances antitumor immunity by increasing cytotoxic T-cell infiltration, decreasing T-cell exhaustion, and a favorable modulation of antigen presenting cells,” she said. “Why do we care? The anti–PD-L1 drug ... atezolizumab ... is right now FDA approved as a first-line treatment in combination with chemotherapy, and we already have DDR inhibitors in the clinic, we have PARP inhibitors in the clinic, we have checkpoint inhibitors in the clinic, SRA737 is in the clinic.

“So our preclinical data provides a strong rationale for combining low-dose gemcitabine with checkpoint inhibition and with anti–PD-L1 to enhance the clinical efficacy of these drugs,” she concluded.

Dr. Sen reported having no disclosures.

sworcester@mdedge.com

SOURCE: Sen T et al. AACR 2019, Abstract LB-148.

ATLANTA – For patients with locally advanced head and neck squamous cell carcinomas positive for human papillomavirus type 16, neoadjuvant therapy with the immune checkpoint inhibitor nivolumab combined with stereotactic body radiation therapy (SBRT) was associated with high response rates and a lower toxicity profile compared with the current standard of care, results of a phase 1/1b study suggest.

Neil Osterweil/MDedge News

All of five patients treated with SBRT doses of 8 Gy per day for 5 days (40 Gy total) had pathologic complete responses (pCR), as did four of five patients treated at a deescalated SBRT dose of 8 Gy on alternating days for 3 days (24 Gy total), reported Rom S. Leidner, MD, of Providence Cancer Center in Portland, Ore.

“We’ve met the primary endpoint. This approach certainly was safe as far as not preventing definitive surgery. The potency was much greater than expected, with a pCR rate of 90% and a major response in 100% of patients,” he said at the annual meeting of the American Association for Cancer Research.

Dr. Leidner and colleagues are investigating therapies for locally advanced HPV-associated head and neck squamous cell carcinoma (HNSCC) that are as effective as but less toxic than the current standard of care: definitive chemoradiotherapy or surgery followed by risk-adapted adjuvant radiotherapy with or without chemotherapy.

They enrolled 10 patients, all men, with a mean age of 64.5 years. Seven patients had HPV16-positive oropharyngeal HNSCC, and three had unknown primary HNSCC (HPV-positive lymph nodes in the neck without an identifiable mucosal primary site). All patients had clinical indications for adjuvant radiotherapy or upfront transoral robotic surgery (TORS) but were ineligible because of tumor size.

The patients were assigned to one of two dose-finding cohorts in groups of five each to receive nivolumab (Opdivo) 240 mg intravenously every other week for three cycles prior to surgery, with SBRT to gross tumor volume plus 3 mm delivered between the first and second doses of nivolumab.

One cohort of patients received SBRT 8 Gy daily for 5 consecutive days (Monday-Friday), and the other received deescalated SBRT 8 Gy delivered on alternating days (Monday, Wednesday, Friday).

Patients underwent surgery 5 weeks after SBRT, and 4 weeks after surgery were started on adjuvant nivolumab 480 mg IV every 4 weeks for three cycles.

The trial met its primary endpoint of fewer than one-third of patients having an unplanned surgical delay. None of the 10 patients required a surgical delay, in fact.

Although all patients had radiologic evidence of tumor shrinkage prior to surgery, there were no complete responses according to Response Criteria in Solid Tumors (RECIST, version 1.1). Seven patients had a partial response (PR), and three had stable disease.

Dr. Leidner noted that when a patient with stable disease according to RECIST went to surgery “we found a [pCR] in the primary site, and residual cancer in the neck nodes with less than 10% viable tumor cells and evidence of immune eradication.”

As noted, all five patients in the 40-Gy dose group had complete pathologic responses, as did four of the five patients in the deescalated dose group. The remaining patient in this group had a major pathologic response, with less than 10% residual tumor.

“The secondary tissue endpoint far exceeded our expectations on this trial,” Dr. Leidner said.

There were no reports of acute toxicity in the neoadjuvant phase, but delayed mucositis (grade 1 or 2) and immune-related grade 1 dermatologic and rhinitis events were seen. Mucositis resolved by week 4 in all patients, at least 2 weeks before surgery.

Postoperative delayed toxicities up to grade 3 were seen, with delays in mucosal healing in patients who underwent mucosal resections; there were no cases of delayed healing among patients who underwent neck dissection only.

Grade 3 oropharyngeal pain requiring opiates for more than 4 weeks after surgery was seen in both cohorts, but lasted longer among patients in the 8-Gy-times-5 cohort.

Half of all patients were found to have adrenal insufficiency, a rate higher than that previously reported with the use of anti-PD-1 immune checkpoint inhibitors in HNSCC, Dr. Leidner said.

“Clinically we’re seeing, as one might expect, substantially reduced xerostomia and ageusia, but that was not formally measured,” he said.

Based on the study findings, investigations are proceeding at the deescalated dose.

Neil Osterweil/MDedge News

Invited discussant Christine H. Chung, MD, of H. Lee Moffitt Cancer Center and Research Institute in Tampa, did not appear to share Dr. Leidner’s enthusiasm for the approach, saying that “overall, path CR in already resectable patients with an extremely high cure rate may not be clinically meaningful.”

She said that the role of adjuvant nivolumab following neoadjuvant nivolumab, radiotherapy, and surgery in HPV-positive patients is unclear, and that “the approach may be more suitable for HPV-negative patients with poor prognosis and in need of treatment intensification.”

Providence Cancer Center sponsored the study. Dr. Leidner reported having no relevant disclosures. Dr. Chung reported research funding from Lilly Oncology, and advisory board honoraria from BMS, CUE, and Ignyta.

SOURCE: Leidner RS et al. AACR 2019, Abstract CT182.

ATLANTA – For patients with locally advanced head and neck squamous cell carcinomas positive for human papillomavirus type 16, neoadjuvant therapy with the immune checkpoint inhibitor nivolumab combined with stereotactic body radiation therapy (SBRT) was associated with high response rates and a lower toxicity profile compared with the current standard of care, results of a phase 1/1b study suggest.

Neil Osterweil/MDedge News

All of five patients treated with SBRT doses of 8 Gy per day for 5 days (40 Gy total) had pathologic complete responses (pCR), as did four of five patients treated at a deescalated SBRT dose of 8 Gy on alternating days for 3 days (24 Gy total), reported Rom S. Leidner, MD, of Providence Cancer Center in Portland, Ore.

“We’ve met the primary endpoint. This approach certainly was safe as far as not preventing definitive surgery. The potency was much greater than expected, with a pCR rate of 90% and a major response in 100% of patients,” he said at the annual meeting of the American Association for Cancer Research.

Dr. Leidner and colleagues are investigating therapies for locally advanced HPV-associated head and neck squamous cell carcinoma (HNSCC) that are as effective as but less toxic than the current standard of care: definitive chemoradiotherapy or surgery followed by risk-adapted adjuvant radiotherapy with or without chemotherapy.

They enrolled 10 patients, all men, with a mean age of 64.5 years. Seven patients had HPV16-positive oropharyngeal HNSCC, and three had unknown primary HNSCC (HPV-positive lymph nodes in the neck without an identifiable mucosal primary site). All patients had clinical indications for adjuvant radiotherapy or upfront transoral robotic surgery (TORS) but were ineligible because of tumor size.

The patients were assigned to one of two dose-finding cohorts in groups of five each to receive nivolumab (Opdivo) 240 mg intravenously every other week for three cycles prior to surgery, with SBRT to gross tumor volume plus 3 mm delivered between the first and second doses of nivolumab.

One cohort of patients received SBRT 8 Gy daily for 5 consecutive days (Monday-Friday), and the other received deescalated SBRT 8 Gy delivered on alternating days (Monday, Wednesday, Friday).

Patients underwent surgery 5 weeks after SBRT, and 4 weeks after surgery were started on adjuvant nivolumab 480 mg IV every 4 weeks for three cycles.

The trial met its primary endpoint of fewer than one-third of patients having an unplanned surgical delay. None of the 10 patients required a surgical delay, in fact.

Although all patients had radiologic evidence of tumor shrinkage prior to surgery, there were no complete responses according to Response Criteria in Solid Tumors (RECIST, version 1.1). Seven patients had a partial response (PR), and three had stable disease.

Dr. Leidner noted that when a patient with stable disease according to RECIST went to surgery “we found a [pCR] in the primary site, and residual cancer in the neck nodes with less than 10% viable tumor cells and evidence of immune eradication.”

As noted, all five patients in the 40-Gy dose group had complete pathologic responses, as did four of the five patients in the deescalated dose group. The remaining patient in this group had a major pathologic response, with less than 10% residual tumor.

“The secondary tissue endpoint far exceeded our expectations on this trial,” Dr. Leidner said.

There were no reports of acute toxicity in the neoadjuvant phase, but delayed mucositis (grade 1 or 2) and immune-related grade 1 dermatologic and rhinitis events were seen. Mucositis resolved by week 4 in all patients, at least 2 weeks before surgery.

Postoperative delayed toxicities up to grade 3 were seen, with delays in mucosal healing in patients who underwent mucosal resections; there were no cases of delayed healing among patients who underwent neck dissection only.

Grade 3 oropharyngeal pain requiring opiates for more than 4 weeks after surgery was seen in both cohorts, but lasted longer among patients in the 8-Gy-times-5 cohort.

Half of all patients were found to have adrenal insufficiency, a rate higher than that previously reported with the use of anti-PD-1 immune checkpoint inhibitors in HNSCC, Dr. Leidner said.

“Clinically we’re seeing, as one might expect, substantially reduced xerostomia and ageusia, but that was not formally measured,” he said.

Based on the study findings, investigations are proceeding at the deescalated dose.

Neil Osterweil/MDedge News

Invited discussant Christine H. Chung, MD, of H. Lee Moffitt Cancer Center and Research Institute in Tampa, did not appear to share Dr. Leidner’s enthusiasm for the approach, saying that “overall, path CR in already resectable patients with an extremely high cure rate may not be clinically meaningful.”

She said that the role of adjuvant nivolumab following neoadjuvant nivolumab, radiotherapy, and surgery in HPV-positive patients is unclear, and that “the approach may be more suitable for HPV-negative patients with poor prognosis and in need of treatment intensification.”

Providence Cancer Center sponsored the study. Dr. Leidner reported having no relevant disclosures. Dr. Chung reported research funding from Lilly Oncology, and advisory board honoraria from BMS, CUE, and Ignyta.

SOURCE: Leidner RS et al. AACR 2019, Abstract CT182.

ATLANTA – For patients with locally advanced head and neck squamous cell carcinomas positive for human papillomavirus type 16, neoadjuvant therapy with the immune checkpoint inhibitor nivolumab combined with stereotactic body radiation therapy (SBRT) was associated with high response rates and a lower toxicity profile compared with the current standard of care, results of a phase 1/1b study suggest.

Neil Osterweil/MDedge News

All of five patients treated with SBRT doses of 8 Gy per day for 5 days (40 Gy total) had pathologic complete responses (pCR), as did four of five patients treated at a deescalated SBRT dose of 8 Gy on alternating days for 3 days (24 Gy total), reported Rom S. Leidner, MD, of Providence Cancer Center in Portland, Ore.

“We’ve met the primary endpoint. This approach certainly was safe as far as not preventing definitive surgery. The potency was much greater than expected, with a pCR rate of 90% and a major response in 100% of patients,” he said at the annual meeting of the American Association for Cancer Research.

Dr. Leidner and colleagues are investigating therapies for locally advanced HPV-associated head and neck squamous cell carcinoma (HNSCC) that are as effective as but less toxic than the current standard of care: definitive chemoradiotherapy or surgery followed by risk-adapted adjuvant radiotherapy with or without chemotherapy.

They enrolled 10 patients, all men, with a mean age of 64.5 years. Seven patients had HPV16-positive oropharyngeal HNSCC, and three had unknown primary HNSCC (HPV-positive lymph nodes in the neck without an identifiable mucosal primary site). All patients had clinical indications for adjuvant radiotherapy or upfront transoral robotic surgery (TORS) but were ineligible because of tumor size.

The patients were assigned to one of two dose-finding cohorts in groups of five each to receive nivolumab (Opdivo) 240 mg intravenously every other week for three cycles prior to surgery, with SBRT to gross tumor volume plus 3 mm delivered between the first and second doses of nivolumab.

One cohort of patients received SBRT 8 Gy daily for 5 consecutive days (Monday-Friday), and the other received deescalated SBRT 8 Gy delivered on alternating days (Monday, Wednesday, Friday).

Patients underwent surgery 5 weeks after SBRT, and 4 weeks after surgery were started on adjuvant nivolumab 480 mg IV every 4 weeks for three cycles.

The trial met its primary endpoint of fewer than one-third of patients having an unplanned surgical delay. None of the 10 patients required a surgical delay, in fact.

Although all patients had radiologic evidence of tumor shrinkage prior to surgery, there were no complete responses according to Response Criteria in Solid Tumors (RECIST, version 1.1). Seven patients had a partial response (PR), and three had stable disease.

Dr. Leidner noted that when a patient with stable disease according to RECIST went to surgery “we found a [pCR] in the primary site, and residual cancer in the neck nodes with less than 10% viable tumor cells and evidence of immune eradication.”

As noted, all five patients in the 40-Gy dose group had complete pathologic responses, as did four of the five patients in the deescalated dose group. The remaining patient in this group had a major pathologic response, with less than 10% residual tumor.

“The secondary tissue endpoint far exceeded our expectations on this trial,” Dr. Leidner said.

There were no reports of acute toxicity in the neoadjuvant phase, but delayed mucositis (grade 1 or 2) and immune-related grade 1 dermatologic and rhinitis events were seen. Mucositis resolved by week 4 in all patients, at least 2 weeks before surgery.

Postoperative delayed toxicities up to grade 3 were seen, with delays in mucosal healing in patients who underwent mucosal resections; there were no cases of delayed healing among patients who underwent neck dissection only.

Grade 3 oropharyngeal pain requiring opiates for more than 4 weeks after surgery was seen in both cohorts, but lasted longer among patients in the 8-Gy-times-5 cohort.

Half of all patients were found to have adrenal insufficiency, a rate higher than that previously reported with the use of anti-PD-1 immune checkpoint inhibitors in HNSCC, Dr. Leidner said.

“Clinically we’re seeing, as one might expect, substantially reduced xerostomia and ageusia, but that was not formally measured,” he said.

Based on the study findings, investigations are proceeding at the deescalated dose.

Neil Osterweil/MDedge News

Invited discussant Christine H. Chung, MD, of H. Lee Moffitt Cancer Center and Research Institute in Tampa, did not appear to share Dr. Leidner’s enthusiasm for the approach, saying that “overall, path CR in already resectable patients with an extremely high cure rate may not be clinically meaningful.”

She said that the role of adjuvant nivolumab following neoadjuvant nivolumab, radiotherapy, and surgery in HPV-positive patients is unclear, and that “the approach may be more suitable for HPV-negative patients with poor prognosis and in need of treatment intensification.”

Providence Cancer Center sponsored the study. Dr. Leidner reported having no relevant disclosures. Dr. Chung reported research funding from Lilly Oncology, and advisory board honoraria from BMS, CUE, and Ignyta.

SOURCE: Leidner RS et al. AACR 2019, Abstract CT182.

ATLANTA – Blood tumor mutational burden (bTMB) predicts survival benefit in metastatic non–small cell lung cancer (mNSCLC) patients treated with first-line durvalumab plus tremelimumab versus platinum-based chemotherapy, according to findings from the open-label, phase 3 MYSTIC trial.

Frontline Medical News

Specifically, in patients with bTMB based on circulating tumor DNA at levels of 20 mutations (mut)/megabase (Mb) or greater, overall survival (OS) was significantly improved with durvalumab alone and with durvalumab plus tremelimumab versus chemotherapy (hazard ratios, 0.74 and 0.49, respectively). Progression-free survival (PFS) was also improved (HRs, 0.76 and 0.53, respectively), Solange Peters, MD, PhD, reported at the annual meeting of the American Association for Cancer Research.

Among patients with bTMB less than 20 mut/Mb, the corresponding OS hazard ratios were 1.55 and 1.26, and the corresponding PFS hazard ratios were 1.22 and 1.16, said Dr. Peters, director of teaching and patient care in the area of medical oncology and thoracic malignancies at Centre Hospitalier Universitaire Vaudois, Lausanne (Switzerland) University, and president-elect of the European Society for Medical Oncology.

Study subjects were 1,118 patients with immunotherapy- and chemotherapy-naive EGFR and ALK wild-type mNSCLC who were randomized 1:1 to receive either the programmed death–ligand 1 (PD-L1) agent durvalumab, durvalumab plus the anti-CTLA4 agent tremelimumab, or chemotherapy. At a tissue TMB (tTMB) level of 10 mut/Mb or greater, those who received either durvalumab or durvalumab plus tremelimumab had better OS than did those who received chemotherapy (HRs, 0.70 and 0.72, respectively).

Further, bTMB levels of at least 16 mut/Mb correlated positively with tTMB (Spearman correlation coefficient, 0.6; Pearson correlation coefficient, 0.7), she said, adding that survival probability at 24 months was 41.7% with durvalumab plus tremelimumab versus 35.0% with durvalumab alone and 22.7% with chemotherapy in this patient subgroup.

“When you look at the subgroup of patients with lower number of mutations than 10, this phenomenon is not observed. If anything should be potentially stressed about these hazard ratios – all above 1 – is potentially that chemotherapy represents a better option in this patient population,” she said.

Treatment included intravenous durvalumab at a dose of 20 mg/kg every 4 weeks with or without IV tremelimumab at a dose of 1 mg/kg every 4 weeks for up to four doses (372 and 374 patients, respectively), or platinum-based chemotherapy (372 patients).

“Durvalumab ... is already approved for unresectable stage 3 NSCLC and has shown clinical activity in heavily pretreated patients with mNSCLC in the context of phase 2 and 3 previously presented trials,” Dr. Peters said, noting that the multicenter MYSTIC trial was designed to assess its potential role in the treatment of all-comers with stage IV disease.


Overall survival data from the study were presented at the 2018 ESMO Immuno-Oncology Congress, and showed that the primary endpoint of superiority of durvalumab or durvalumab plus tremelimumab versus chemotherapy for OS in patients with high PD-L1 expression (at least 25% of tumor cells expressing PD-L1) was not met. There did, however, appear to be a clinically meaningful 3-month survival benefit (HR, 0.76) with durvalumab, she said.

The idea of combining durvalumab with tremelimumab was based on the potential for “antitumor activity via nonredundant pathways,” she noted, further explaining that the interest in determining whether bTMB correlates with tTMB relates to the rapid availability and less invasive nature of the latter and the fact that bTMB measured from circulating tumor DNA, “biologically speaking, may be more representative of the heterogeneity of metastatic lesions in the context of an advanced disease.”

The current findings are from exploratory analyses looking at OS based on bTMB and tTMB at varying levels to “better understand optimal outcomes and potential contributions of tremelimumab,” she said, noting that survival benefit was observed in all subgroups defined by a high TMB (equal to or greater than vs. less than 4, 8, 12, 16, and 20 mut/Mb).

Outcomes using the bTMB cutoff of 16 or greater mut/Mb were also presented at the ESMO meeting, and showed an OS benefit with durvalumab and durvalumab plus tremelimumab versus chemotherapy in those patients; the finding was more pronounced with durvalumab plus tremelimumab (HR, 0.82 and 0.62, respectively), and the effect increased with increasing bTMB levels.

“Based on that, we decided to [use the 20 mut/Mb or greater] cutoff to conduct a subsequent analysis,” Dr. Peters said, noting again the “very significantly improved” OS and PFS for combined treatment versus chemotherapy with 20 or greater versus less than 20 mut/Mb, and the value of chemotherapy in those with lower bTMB.

Tumor response was also better with durvalumab plus tremelimumab versus chemotherapy at this cutoff; objective response rates were 29.9% and 48.4% with durvalumab and durvalumab plus tremelimumab, respectively, versus 21.4% with chemotherapy.

“Again, under this threshold [less than 20 mut/Mb], it looked like chemotherapy was offering a better response rate with 31.4% as compared to 20% and less for the immunotherapy strategy,” she said.

Also of note, the percentage of patients remaining in response at 6 and 12 months was much better in those who received immunotherapy with durvalumab plus tremelimumab versus chemotherapy; this was more pronounced in those with high TMB (85.6% vs. 14.4% at 6 months; 81.7% vs. 7.2% at 12 months).

No differences were seen in toxicity patterns in the subgroup of patients with bTMB greater than 20 mut/Mb when compared with the overall safety population from MYSTIC, she added.

“Based on this exploratory analysis, further investigation and prospective validation of bTMB as a predictive biomarker for immunotherapy is warranted and should potentially be evaluated in as many as possible future clinical trials looking at immunotherapy across various solid tumors,” Dr. Peters said.

MYSTIC is sponsored by AstraZeneca. Dr. Peters reported relationships – including receipt of honoraria or consulting fees, receipt of grant/research support, and/or speaking engagements – with numerous pharmaceutical companies.

sworcester@mdedge.com

ATLANTA – Blood tumor mutational burden (bTMB) predicts survival benefit in metastatic non–small cell lung cancer (mNSCLC) patients treated with first-line durvalumab plus tremelimumab versus platinum-based chemotherapy, according to findings from the open-label, phase 3 MYSTIC trial.

Frontline Medical News

Specifically, in patients with bTMB based on circulating tumor DNA at levels of 20 mutations (mut)/megabase (Mb) or greater, overall survival (OS) was significantly improved with durvalumab alone and with durvalumab plus tremelimumab versus chemotherapy (hazard ratios, 0.74 and 0.49, respectively). Progression-free survival (PFS) was also improved (HRs, 0.76 and 0.53, respectively), Solange Peters, MD, PhD, reported at the annual meeting of the American Association for Cancer Research.

Among patients with bTMB less than 20 mut/Mb, the corresponding OS hazard ratios were 1.55 and 1.26, and the corresponding PFS hazard ratios were 1.22 and 1.16, said Dr. Peters, director of teaching and patient care in the area of medical oncology and thoracic malignancies at Centre Hospitalier Universitaire Vaudois, Lausanne (Switzerland) University, and president-elect of the European Society for Medical Oncology.

Study subjects were 1,118 patients with immunotherapy- and chemotherapy-naive EGFR and ALK wild-type mNSCLC who were randomized 1:1 to receive either the programmed death–ligand 1 (PD-L1) agent durvalumab, durvalumab plus the anti-CTLA4 agent tremelimumab, or chemotherapy. At a tissue TMB (tTMB) level of 10 mut/Mb or greater, those who received either durvalumab or durvalumab plus tremelimumab had better OS than did those who received chemotherapy (HRs, 0.70 and 0.72, respectively).

Further, bTMB levels of at least 16 mut/Mb correlated positively with tTMB (Spearman correlation coefficient, 0.6; Pearson correlation coefficient, 0.7), she said, adding that survival probability at 24 months was 41.7% with durvalumab plus tremelimumab versus 35.0% with durvalumab alone and 22.7% with chemotherapy in this patient subgroup.

“When you look at the subgroup of patients with lower number of mutations than 10, this phenomenon is not observed. If anything should be potentially stressed about these hazard ratios – all above 1 – is potentially that chemotherapy represents a better option in this patient population,” she said.

Treatment included intravenous durvalumab at a dose of 20 mg/kg every 4 weeks with or without IV tremelimumab at a dose of 1 mg/kg every 4 weeks for up to four doses (372 and 374 patients, respectively), or platinum-based chemotherapy (372 patients).

“Durvalumab ... is already approved for unresectable stage 3 NSCLC and has shown clinical activity in heavily pretreated patients with mNSCLC in the context of phase 2 and 3 previously presented trials,” Dr. Peters said, noting that the multicenter MYSTIC trial was designed to assess its potential role in the treatment of all-comers with stage IV disease.


Overall survival data from the study were presented at the 2018 ESMO Immuno-Oncology Congress, and showed that the primary endpoint of superiority of durvalumab or durvalumab plus tremelimumab versus chemotherapy for OS in patients with high PD-L1 expression (at least 25% of tumor cells expressing PD-L1) was not met. There did, however, appear to be a clinically meaningful 3-month survival benefit (HR, 0.76) with durvalumab, she said.

The idea of combining durvalumab with tremelimumab was based on the potential for “antitumor activity via nonredundant pathways,” she noted, further explaining that the interest in determining whether bTMB correlates with tTMB relates to the rapid availability and less invasive nature of the latter and the fact that bTMB measured from circulating tumor DNA, “biologically speaking, may be more representative of the heterogeneity of metastatic lesions in the context of an advanced disease.”

The current findings are from exploratory analyses looking at OS based on bTMB and tTMB at varying levels to “better understand optimal outcomes and potential contributions of tremelimumab,” she said, noting that survival benefit was observed in all subgroups defined by a high TMB (equal to or greater than vs. less than 4, 8, 12, 16, and 20 mut/Mb).

Outcomes using the bTMB cutoff of 16 or greater mut/Mb were also presented at the ESMO meeting, and showed an OS benefit with durvalumab and durvalumab plus tremelimumab versus chemotherapy in those patients; the finding was more pronounced with durvalumab plus tremelimumab (HR, 0.82 and 0.62, respectively), and the effect increased with increasing bTMB levels.

“Based on that, we decided to [use the 20 mut/Mb or greater] cutoff to conduct a subsequent analysis,” Dr. Peters said, noting again the “very significantly improved” OS and PFS for combined treatment versus chemotherapy with 20 or greater versus less than 20 mut/Mb, and the value of chemotherapy in those with lower bTMB.

Tumor response was also better with durvalumab plus tremelimumab versus chemotherapy at this cutoff; objective response rates were 29.9% and 48.4% with durvalumab and durvalumab plus tremelimumab, respectively, versus 21.4% with chemotherapy.

“Again, under this threshold [less than 20 mut/Mb], it looked like chemotherapy was offering a better response rate with 31.4% as compared to 20% and less for the immunotherapy strategy,” she said.

Also of note, the percentage of patients remaining in response at 6 and 12 months was much better in those who received immunotherapy with durvalumab plus tremelimumab versus chemotherapy; this was more pronounced in those with high TMB (85.6% vs. 14.4% at 6 months; 81.7% vs. 7.2% at 12 months).

No differences were seen in toxicity patterns in the subgroup of patients with bTMB greater than 20 mut/Mb when compared with the overall safety population from MYSTIC, she added.

“Based on this exploratory analysis, further investigation and prospective validation of bTMB as a predictive biomarker for immunotherapy is warranted and should potentially be evaluated in as many as possible future clinical trials looking at immunotherapy across various solid tumors,” Dr. Peters said.

MYSTIC is sponsored by AstraZeneca. Dr. Peters reported relationships – including receipt of honoraria or consulting fees, receipt of grant/research support, and/or speaking engagements – with numerous pharmaceutical companies.

sworcester@mdedge.com

ATLANTA – Blood tumor mutational burden (bTMB) predicts survival benefit in metastatic non–small cell lung cancer (mNSCLC) patients treated with first-line durvalumab plus tremelimumab versus platinum-based chemotherapy, according to findings from the open-label, phase 3 MYSTIC trial.

Frontline Medical News

Specifically, in patients with bTMB based on circulating tumor DNA at levels of 20 mutations (mut)/megabase (Mb) or greater, overall survival (OS) was significantly improved with durvalumab alone and with durvalumab plus tremelimumab versus chemotherapy (hazard ratios, 0.74 and 0.49, respectively). Progression-free survival (PFS) was also improved (HRs, 0.76 and 0.53, respectively), Solange Peters, MD, PhD, reported at the annual meeting of the American Association for Cancer Research.

Among patients with bTMB less than 20 mut/Mb, the corresponding OS hazard ratios were 1.55 and 1.26, and the corresponding PFS hazard ratios were 1.22 and 1.16, said Dr. Peters, director of teaching and patient care in the area of medical oncology and thoracic malignancies at Centre Hospitalier Universitaire Vaudois, Lausanne (Switzerland) University, and president-elect of the European Society for Medical Oncology.

Study subjects were 1,118 patients with immunotherapy- and chemotherapy-naive EGFR and ALK wild-type mNSCLC who were randomized 1:1 to receive either the programmed death–ligand 1 (PD-L1) agent durvalumab, durvalumab plus the anti-CTLA4 agent tremelimumab, or chemotherapy. At a tissue TMB (tTMB) level of 10 mut/Mb or greater, those who received either durvalumab or durvalumab plus tremelimumab had better OS than did those who received chemotherapy (HRs, 0.70 and 0.72, respectively).

Further, bTMB levels of at least 16 mut/Mb correlated positively with tTMB (Spearman correlation coefficient, 0.6; Pearson correlation coefficient, 0.7), she said, adding that survival probability at 24 months was 41.7% with durvalumab plus tremelimumab versus 35.0% with durvalumab alone and 22.7% with chemotherapy in this patient subgroup.

“When you look at the subgroup of patients with lower number of mutations than 10, this phenomenon is not observed. If anything should be potentially stressed about these hazard ratios – all above 1 – is potentially that chemotherapy represents a better option in this patient population,” she said.

Treatment included intravenous durvalumab at a dose of 20 mg/kg every 4 weeks with or without IV tremelimumab at a dose of 1 mg/kg every 4 weeks for up to four doses (372 and 374 patients, respectively), or platinum-based chemotherapy (372 patients).

“Durvalumab ... is already approved for unresectable stage 3 NSCLC and has shown clinical activity in heavily pretreated patients with mNSCLC in the context of phase 2 and 3 previously presented trials,” Dr. Peters said, noting that the multicenter MYSTIC trial was designed to assess its potential role in the treatment of all-comers with stage IV disease.


Overall survival data from the study were presented at the 2018 ESMO Immuno-Oncology Congress, and showed that the primary endpoint of superiority of durvalumab or durvalumab plus tremelimumab versus chemotherapy for OS in patients with high PD-L1 expression (at least 25% of tumor cells expressing PD-L1) was not met. There did, however, appear to be a clinically meaningful 3-month survival benefit (HR, 0.76) with durvalumab, she said.

The idea of combining durvalumab with tremelimumab was based on the potential for “antitumor activity via nonredundant pathways,” she noted, further explaining that the interest in determining whether bTMB correlates with tTMB relates to the rapid availability and less invasive nature of the latter and the fact that bTMB measured from circulating tumor DNA, “biologically speaking, may be more representative of the heterogeneity of metastatic lesions in the context of an advanced disease.”

The current findings are from exploratory analyses looking at OS based on bTMB and tTMB at varying levels to “better understand optimal outcomes and potential contributions of tremelimumab,” she said, noting that survival benefit was observed in all subgroups defined by a high TMB (equal to or greater than vs. less than 4, 8, 12, 16, and 20 mut/Mb).

Outcomes using the bTMB cutoff of 16 or greater mut/Mb were also presented at the ESMO meeting, and showed an OS benefit with durvalumab and durvalumab plus tremelimumab versus chemotherapy in those patients; the finding was more pronounced with durvalumab plus tremelimumab (HR, 0.82 and 0.62, respectively), and the effect increased with increasing bTMB levels.

“Based on that, we decided to [use the 20 mut/Mb or greater] cutoff to conduct a subsequent analysis,” Dr. Peters said, noting again the “very significantly improved” OS and PFS for combined treatment versus chemotherapy with 20 or greater versus less than 20 mut/Mb, and the value of chemotherapy in those with lower bTMB.

Tumor response was also better with durvalumab plus tremelimumab versus chemotherapy at this cutoff; objective response rates were 29.9% and 48.4% with durvalumab and durvalumab plus tremelimumab, respectively, versus 21.4% with chemotherapy.

“Again, under this threshold [less than 20 mut/Mb], it looked like chemotherapy was offering a better response rate with 31.4% as compared to 20% and less for the immunotherapy strategy,” she said.

Also of note, the percentage of patients remaining in response at 6 and 12 months was much better in those who received immunotherapy with durvalumab plus tremelimumab versus chemotherapy; this was more pronounced in those with high TMB (85.6% vs. 14.4% at 6 months; 81.7% vs. 7.2% at 12 months).

No differences were seen in toxicity patterns in the subgroup of patients with bTMB greater than 20 mut/Mb when compared with the overall safety population from MYSTIC, she added.

“Based on this exploratory analysis, further investigation and prospective validation of bTMB as a predictive biomarker for immunotherapy is warranted and should potentially be evaluated in as many as possible future clinical trials looking at immunotherapy across various solid tumors,” Dr. Peters said.

MYSTIC is sponsored by AstraZeneca. Dr. Peters reported relationships – including receipt of honoraria or consulting fees, receipt of grant/research support, and/or speaking engagements – with numerous pharmaceutical companies.

sworcester@mdedge.com

ATLANTA – Combined therapy with the class I selective histone deacetylase (HDAC) inhibitor entinostat and the programmed cell death 1 (PD-1) inhibitor pembrolizumab has significant clinical activity and acceptable safety in melanoma patients who progressed on prior PD-1 blockade, according to findings from the open-label ENCORE-601 trial.

Of 53 patients with recurrent or metastatic melanoma who were treated with 5 mg of oral entinostat weekly plus 200 mg of intravenous pembrolizumab every 3 weeks, 1 had a complete response, and 9 had a partial response, for an objective response rate of 19%, Ryan J. Sullivan, MD, reported at the annual meeting of the American Association for Cancer Research.

The median duration of response at the January 2018 data cut-off was 13 months, and four responders had ongoing responses. An additional nine patients had stable disease for at least 6 months at that time, for a clinical benefit rate of 36%, said Dr. Sullivan of Massachusetts General Hospital, Boston.

“At 1 year, 10 patients remained on therapy or in response,” he said, noting that, although one patient had received only a very short course of therapy before developing “significant hepatitis” and coming off therapy, but this patient still had a response at 1 year. Five others also went off therapy and continue to have a response, and four patients remain on active therapy and are being followed, he said.

Study participants are adults with Eastern Cooperative Oncology Group Performance Status of less than 2 who were previously treated with a PD-1–blocking antibody and experienced progression on or after therapy. The 23% of patients with a BRAF V600 mutation were required to have received BRAF/MEK therapy, and 70% of patients had received both a prior PD-1 inhibitor and ipilimumab, either in combination or in sequence.

The response rate to prior anti–PD-1 therapy was 13%, which was “much lower than you would imagine in all-comers,” Dr Sullivan said.

Inhibitors of PD-1 and its ligand (PD-L1) have improved outcomes in patients with advanced melanoma, but despite the progress, most patients develop resistance and most will still die from metastatic melanoma, he said.

“I think its always important to define what the unmet need is, and here it’s quite clear: Most patients are not receiving ultimate benefit, and as a result we need a better therapeutic approach,” he said, adding that “the front-line treatment setting is a critical place to be in terms of clinical trials ... but the most relevant and most unmet need now is what do we do in patients who have received anti–PD-1 therapy and need something else.”


Addressing the unmet need requires an improved understanding of the mechanisms of resistance and the development of more effective therapies, he said.

Dr. Sullivan and his colleagues previously reported preliminary data from the current cohort showing promising activity with entinostat in combination with pembrolizumab, which was found to alter the immunosuppressive tumor microenvironment. The rationale for using entinostat in this setting relates to its down-regulation of immunosuppressive cell types in the tumor microenvironment and its “quite robust” synergy with PD-1 inhibition as demonstrated in preclinical models, he explained.

Following those initial dose and safety findings, four phase 2 expansion cohorts were opened, including two non–small cell lung cancer cohorts, one mismatched-repair proficient colorectal cancer cohort, and the melanoma cohort. The current report, which focused on the latter, showed that the treatment-related adverse events (AEs) occurring in at least 15% of patients included nausea, fatigue, diarrhea, and myelosuppression.

“Six patients discontinued due to related AEs, and importantly, there were only five grade 3 or 4 immune-related AEs,” Dr. Sullivan said, adding that these included one case each of immune-related hepatitis, pneumonitis, and colitis and two cases of significant dermatitis.

The findings show that in this group of patients with limited treatment options, entinostat with pembrolizumab is “clearly safe and tolerable,” he said.

Additionally, “very preliminary biomarker analyses” in a small number of patients demonstrated findings consistent with the mechanism of action of entinostat, including a reduction in circulating myeloid-derived suppressor cells, he said.

Dr. Sullivan reported consulting or serving on an advisory board for Novartis, Amgen, Merck, Array, Syndax, Replimmune, and Bristol-Myers Squibb and receiving research sponsorship from Amgen and Merck & Co.

sworcester@mdedge.com

SOURCE: Sullivan R et al. AACR 2019, Abstract CT-072.

ATLANTA – Combined therapy with the class I selective histone deacetylase (HDAC) inhibitor entinostat and the programmed cell death 1 (PD-1) inhibitor pembrolizumab has significant clinical activity and acceptable safety in melanoma patients who progressed on prior PD-1 blockade, according to findings from the open-label ENCORE-601 trial.

Of 53 patients with recurrent or metastatic melanoma who were treated with 5 mg of oral entinostat weekly plus 200 mg of intravenous pembrolizumab every 3 weeks, 1 had a complete response, and 9 had a partial response, for an objective response rate of 19%, Ryan J. Sullivan, MD, reported at the annual meeting of the American Association for Cancer Research.

The median duration of response at the January 2018 data cut-off was 13 months, and four responders had ongoing responses. An additional nine patients had stable disease for at least 6 months at that time, for a clinical benefit rate of 36%, said Dr. Sullivan of Massachusetts General Hospital, Boston.

“At 1 year, 10 patients remained on therapy or in response,” he said, noting that, although one patient had received only a very short course of therapy before developing “significant hepatitis” and coming off therapy, but this patient still had a response at 1 year. Five others also went off therapy and continue to have a response, and four patients remain on active therapy and are being followed, he said.

Study participants are adults with Eastern Cooperative Oncology Group Performance Status of less than 2 who were previously treated with a PD-1–blocking antibody and experienced progression on or after therapy. The 23% of patients with a BRAF V600 mutation were required to have received BRAF/MEK therapy, and 70% of patients had received both a prior PD-1 inhibitor and ipilimumab, either in combination or in sequence.

The response rate to prior anti–PD-1 therapy was 13%, which was “much lower than you would imagine in all-comers,” Dr Sullivan said.

Inhibitors of PD-1 and its ligand (PD-L1) have improved outcomes in patients with advanced melanoma, but despite the progress, most patients develop resistance and most will still die from metastatic melanoma, he said.

“I think its always important to define what the unmet need is, and here it’s quite clear: Most patients are not receiving ultimate benefit, and as a result we need a better therapeutic approach,” he said, adding that “the front-line treatment setting is a critical place to be in terms of clinical trials ... but the most relevant and most unmet need now is what do we do in patients who have received anti–PD-1 therapy and need something else.”


Addressing the unmet need requires an improved understanding of the mechanisms of resistance and the development of more effective therapies, he said.

Dr. Sullivan and his colleagues previously reported preliminary data from the current cohort showing promising activity with entinostat in combination with pembrolizumab, which was found to alter the immunosuppressive tumor microenvironment. The rationale for using entinostat in this setting relates to its down-regulation of immunosuppressive cell types in the tumor microenvironment and its “quite robust” synergy with PD-1 inhibition as demonstrated in preclinical models, he explained.

Following those initial dose and safety findings, four phase 2 expansion cohorts were opened, including two non–small cell lung cancer cohorts, one mismatched-repair proficient colorectal cancer cohort, and the melanoma cohort. The current report, which focused on the latter, showed that the treatment-related adverse events (AEs) occurring in at least 15% of patients included nausea, fatigue, diarrhea, and myelosuppression.

“Six patients discontinued due to related AEs, and importantly, there were only five grade 3 or 4 immune-related AEs,” Dr. Sullivan said, adding that these included one case each of immune-related hepatitis, pneumonitis, and colitis and two cases of significant dermatitis.

The findings show that in this group of patients with limited treatment options, entinostat with pembrolizumab is “clearly safe and tolerable,” he said.

Additionally, “very preliminary biomarker analyses” in a small number of patients demonstrated findings consistent with the mechanism of action of entinostat, including a reduction in circulating myeloid-derived suppressor cells, he said.

Dr. Sullivan reported consulting or serving on an advisory board for Novartis, Amgen, Merck, Array, Syndax, Replimmune, and Bristol-Myers Squibb and receiving research sponsorship from Amgen and Merck & Co.

sworcester@mdedge.com

SOURCE: Sullivan R et al. AACR 2019, Abstract CT-072.

ATLANTA – Combined therapy with the class I selective histone deacetylase (HDAC) inhibitor entinostat and the programmed cell death 1 (PD-1) inhibitor pembrolizumab has significant clinical activity and acceptable safety in melanoma patients who progressed on prior PD-1 blockade, according to findings from the open-label ENCORE-601 trial.

Of 53 patients with recurrent or metastatic melanoma who were treated with 5 mg of oral entinostat weekly plus 200 mg of intravenous pembrolizumab every 3 weeks, 1 had a complete response, and 9 had a partial response, for an objective response rate of 19%, Ryan J. Sullivan, MD, reported at the annual meeting of the American Association for Cancer Research.

The median duration of response at the January 2018 data cut-off was 13 months, and four responders had ongoing responses. An additional nine patients had stable disease for at least 6 months at that time, for a clinical benefit rate of 36%, said Dr. Sullivan of Massachusetts General Hospital, Boston.

“At 1 year, 10 patients remained on therapy or in response,” he said, noting that, although one patient had received only a very short course of therapy before developing “significant hepatitis” and coming off therapy, but this patient still had a response at 1 year. Five others also went off therapy and continue to have a response, and four patients remain on active therapy and are being followed, he said.

Study participants are adults with Eastern Cooperative Oncology Group Performance Status of less than 2 who were previously treated with a PD-1–blocking antibody and experienced progression on or after therapy. The 23% of patients with a BRAF V600 mutation were required to have received BRAF/MEK therapy, and 70% of patients had received both a prior PD-1 inhibitor and ipilimumab, either in combination or in sequence.

The response rate to prior anti–PD-1 therapy was 13%, which was “much lower than you would imagine in all-comers,” Dr Sullivan said.

Inhibitors of PD-1 and its ligand (PD-L1) have improved outcomes in patients with advanced melanoma, but despite the progress, most patients develop resistance and most will still die from metastatic melanoma, he said.

“I think its always important to define what the unmet need is, and here it’s quite clear: Most patients are not receiving ultimate benefit, and as a result we need a better therapeutic approach,” he said, adding that “the front-line treatment setting is a critical place to be in terms of clinical trials ... but the most relevant and most unmet need now is what do we do in patients who have received anti–PD-1 therapy and need something else.”


Addressing the unmet need requires an improved understanding of the mechanisms of resistance and the development of more effective therapies, he said.

Dr. Sullivan and his colleagues previously reported preliminary data from the current cohort showing promising activity with entinostat in combination with pembrolizumab, which was found to alter the immunosuppressive tumor microenvironment. The rationale for using entinostat in this setting relates to its down-regulation of immunosuppressive cell types in the tumor microenvironment and its “quite robust” synergy with PD-1 inhibition as demonstrated in preclinical models, he explained.

Following those initial dose and safety findings, four phase 2 expansion cohorts were opened, including two non–small cell lung cancer cohorts, one mismatched-repair proficient colorectal cancer cohort, and the melanoma cohort. The current report, which focused on the latter, showed that the treatment-related adverse events (AEs) occurring in at least 15% of patients included nausea, fatigue, diarrhea, and myelosuppression.

“Six patients discontinued due to related AEs, and importantly, there were only five grade 3 or 4 immune-related AEs,” Dr. Sullivan said, adding that these included one case each of immune-related hepatitis, pneumonitis, and colitis and two cases of significant dermatitis.

The findings show that in this group of patients with limited treatment options, entinostat with pembrolizumab is “clearly safe and tolerable,” he said.

Additionally, “very preliminary biomarker analyses” in a small number of patients demonstrated findings consistent with the mechanism of action of entinostat, including a reduction in circulating myeloid-derived suppressor cells, he said.

Dr. Sullivan reported consulting or serving on an advisory board for Novartis, Amgen, Merck, Array, Syndax, Replimmune, and Bristol-Myers Squibb and receiving research sponsorship from Amgen and Merck & Co.

sworcester@mdedge.com

SOURCE: Sullivan R et al. AACR 2019, Abstract CT-072.

ATLANTA – Intrapleurally administered, mesothelin-targeted chimeric antigen receptor (CAR) T cells combined with programmed death 1 (PD-1) inhibition showed CAR T-cell antitumor activity without toxicity in a phase 1 clinical trial of patients with malignant pleural disease.

The findings are encouraging, particularly given the aggressive nature of such tumors and the poor prognosis associated with mesothelin – a cell-surface antigen expressed on them, Prasad S. Adusumilli, MD, reported during a press briefing at the annual meeting of the American Association for Cancer Research.

In 21 patients, including 19 with malignant pleural mesothelioma and 1 each with metastatic lung cancer and metastatic breast cancer, a single dose of a second-generation, CD28-costimulated mesothelin CAR T-cell therapy (iCasM28z) was administered intrapleurally either with or without cyclophosphamide preconditioning.

Antitumor activity, as evidenced by the presence of CAR T cells in the blood for several months, was noted in 13 patients, and the presence of the cells was associated with a reduction in a mesothelin-related peptide in the blood, as well as with evidence of tumor regression on imaging studies, said Dr. Adusumilli, deputy chief of the thoracic service at Memorial Sloan Kettering Cancer Center, New York, and lead study author.


Intense clinical, laboratory, and radiological monitoring along with electrocardiography showed no evidence of toxicity.

“Most importantly, the neurotoxicity, serious cytokine release syndrome, and on-target off-target tumor toxicity that has been seen in other CAR T-cell trials, we did not notice in our trial,” he said.

Additionally, one patient successfully underwent curative-intent surgical resection 6 weeks after CAR T-cell infusion, followed by radiation therapy to the chest, said Dr. Adusumilli, who also is director of the mesothelioma program and head of solid tumor cell therapy at the at Memorial Sloan Kettering Cellular Therapeutic Center.

That patient is doing well at 20 months without further treatment, he noted.

Of a subset of 14 patients who received off-protocol anti-PD-1 checkpoint blockade once lack of toxicity was established for the CAR T-cell therapy, 2 achieved a complete metabolic response at 38 and 60 weeks following checkpoint blockade, 5 had a partial response, and 4 had stable disease.

The anti-PD-1 therapy was initiated in those patients based on prior preclinical data, showing that CAR T cells can become functionally exhausted in large tumors and that anti-PD-1 therapy can reactivate the exhausted cells and eradicate the tumors, he explained.

The findings are notable because malignant pleural disease from primary malignant pleural mesothelioma or secondary metastatic disease affects more than 150,000 patients a year in the United States alone, and effective therapies are lacking.

“[Our finding] strongly supports pursuing a CAR T-cell therapy combined with anti-PD-1 strategies is in solid tumors,” Dr. Adusumilli said, adding that such a trial is being planned for 2019, and another, with CAR T-cell intrinsic PD-1 dominant negative receptor (a decoy receptor) is planned for 2020.

Press briefing moderator Nilofer S. Azad, MD, of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, said the findings represent “potentially the most compelling CAR T data that we’ve ever seen in solid tumors at this point,” and noted that a “vast number of patients” could potentially benefit from the approach.

Dr. Adusumilli agreed, suggesting that, with a system of regional factories and distribution centers and development of “some clever strategies,” it is possible the technology and treatment approach could be scaled up to the level necessary to help increasing numbers of patients.

Dr. Adusumilli reported receiving federal grant support from the National Cancer Institute and Department of Defense; peer-reviewed grant support from the Mesothelioma Applied Research Foundation, Experimental Therapeutics Center, Baker Street Foundation, Batishwa Fellowship, Dallepezze Foundation, Derfner Foundation, Emerson Collective Foundation, and MSK Technology Development Fund; and research grant support from OSE Immunotherapeutics, ACEA Biosciences, and Atara Biotherapeutics. He also has a licensing/royalty agreement for Mesothelin CAR and PD-1 DNR (licensed to Atara Biotherapeutics).

sworcester@mdedge.com

SOURCE: Adusumilli PS et al. AACR 2019, Abstract CT036.

ATLANTA – Intrapleurally administered, mesothelin-targeted chimeric antigen receptor (CAR) T cells combined with programmed death 1 (PD-1) inhibition showed CAR T-cell antitumor activity without toxicity in a phase 1 clinical trial of patients with malignant pleural disease.

The findings are encouraging, particularly given the aggressive nature of such tumors and the poor prognosis associated with mesothelin – a cell-surface antigen expressed on them, Prasad S. Adusumilli, MD, reported during a press briefing at the annual meeting of the American Association for Cancer Research.

In 21 patients, including 19 with malignant pleural mesothelioma and 1 each with metastatic lung cancer and metastatic breast cancer, a single dose of a second-generation, CD28-costimulated mesothelin CAR T-cell therapy (iCasM28z) was administered intrapleurally either with or without cyclophosphamide preconditioning.

Antitumor activity, as evidenced by the presence of CAR T cells in the blood for several months, was noted in 13 patients, and the presence of the cells was associated with a reduction in a mesothelin-related peptide in the blood, as well as with evidence of tumor regression on imaging studies, said Dr. Adusumilli, deputy chief of the thoracic service at Memorial Sloan Kettering Cancer Center, New York, and lead study author.


Intense clinical, laboratory, and radiological monitoring along with electrocardiography showed no evidence of toxicity.

“Most importantly, the neurotoxicity, serious cytokine release syndrome, and on-target off-target tumor toxicity that has been seen in other CAR T-cell trials, we did not notice in our trial,” he said.

Additionally, one patient successfully underwent curative-intent surgical resection 6 weeks after CAR T-cell infusion, followed by radiation therapy to the chest, said Dr. Adusumilli, who also is director of the mesothelioma program and head of solid tumor cell therapy at the at Memorial Sloan Kettering Cellular Therapeutic Center.

That patient is doing well at 20 months without further treatment, he noted.

Of a subset of 14 patients who received off-protocol anti-PD-1 checkpoint blockade once lack of toxicity was established for the CAR T-cell therapy, 2 achieved a complete metabolic response at 38 and 60 weeks following checkpoint blockade, 5 had a partial response, and 4 had stable disease.

The anti-PD-1 therapy was initiated in those patients based on prior preclinical data, showing that CAR T cells can become functionally exhausted in large tumors and that anti-PD-1 therapy can reactivate the exhausted cells and eradicate the tumors, he explained.

The findings are notable because malignant pleural disease from primary malignant pleural mesothelioma or secondary metastatic disease affects more than 150,000 patients a year in the United States alone, and effective therapies are lacking.

“[Our finding] strongly supports pursuing a CAR T-cell therapy combined with anti-PD-1 strategies is in solid tumors,” Dr. Adusumilli said, adding that such a trial is being planned for 2019, and another, with CAR T-cell intrinsic PD-1 dominant negative receptor (a decoy receptor) is planned for 2020.

Press briefing moderator Nilofer S. Azad, MD, of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, said the findings represent “potentially the most compelling CAR T data that we’ve ever seen in solid tumors at this point,” and noted that a “vast number of patients” could potentially benefit from the approach.

Dr. Adusumilli agreed, suggesting that, with a system of regional factories and distribution centers and development of “some clever strategies,” it is possible the technology and treatment approach could be scaled up to the level necessary to help increasing numbers of patients.

Dr. Adusumilli reported receiving federal grant support from the National Cancer Institute and Department of Defense; peer-reviewed grant support from the Mesothelioma Applied Research Foundation, Experimental Therapeutics Center, Baker Street Foundation, Batishwa Fellowship, Dallepezze Foundation, Derfner Foundation, Emerson Collective Foundation, and MSK Technology Development Fund; and research grant support from OSE Immunotherapeutics, ACEA Biosciences, and Atara Biotherapeutics. He also has a licensing/royalty agreement for Mesothelin CAR and PD-1 DNR (licensed to Atara Biotherapeutics).

sworcester@mdedge.com

SOURCE: Adusumilli PS et al. AACR 2019, Abstract CT036.

ATLANTA – Intrapleurally administered, mesothelin-targeted chimeric antigen receptor (CAR) T cells combined with programmed death 1 (PD-1) inhibition showed CAR T-cell antitumor activity without toxicity in a phase 1 clinical trial of patients with malignant pleural disease.

The findings are encouraging, particularly given the aggressive nature of such tumors and the poor prognosis associated with mesothelin – a cell-surface antigen expressed on them, Prasad S. Adusumilli, MD, reported during a press briefing at the annual meeting of the American Association for Cancer Research.

In 21 patients, including 19 with malignant pleural mesothelioma and 1 each with metastatic lung cancer and metastatic breast cancer, a single dose of a second-generation, CD28-costimulated mesothelin CAR T-cell therapy (iCasM28z) was administered intrapleurally either with or without cyclophosphamide preconditioning.

Antitumor activity, as evidenced by the presence of CAR T cells in the blood for several months, was noted in 13 patients, and the presence of the cells was associated with a reduction in a mesothelin-related peptide in the blood, as well as with evidence of tumor regression on imaging studies, said Dr. Adusumilli, deputy chief of the thoracic service at Memorial Sloan Kettering Cancer Center, New York, and lead study author.


Intense clinical, laboratory, and radiological monitoring along with electrocardiography showed no evidence of toxicity.

“Most importantly, the neurotoxicity, serious cytokine release syndrome, and on-target off-target tumor toxicity that has been seen in other CAR T-cell trials, we did not notice in our trial,” he said.

Additionally, one patient successfully underwent curative-intent surgical resection 6 weeks after CAR T-cell infusion, followed by radiation therapy to the chest, said Dr. Adusumilli, who also is director of the mesothelioma program and head of solid tumor cell therapy at the at Memorial Sloan Kettering Cellular Therapeutic Center.

That patient is doing well at 20 months without further treatment, he noted.

Of a subset of 14 patients who received off-protocol anti-PD-1 checkpoint blockade once lack of toxicity was established for the CAR T-cell therapy, 2 achieved a complete metabolic response at 38 and 60 weeks following checkpoint blockade, 5 had a partial response, and 4 had stable disease.

The anti-PD-1 therapy was initiated in those patients based on prior preclinical data, showing that CAR T cells can become functionally exhausted in large tumors and that anti-PD-1 therapy can reactivate the exhausted cells and eradicate the tumors, he explained.

The findings are notable because malignant pleural disease from primary malignant pleural mesothelioma or secondary metastatic disease affects more than 150,000 patients a year in the United States alone, and effective therapies are lacking.

“[Our finding] strongly supports pursuing a CAR T-cell therapy combined with anti-PD-1 strategies is in solid tumors,” Dr. Adusumilli said, adding that such a trial is being planned for 2019, and another, with CAR T-cell intrinsic PD-1 dominant negative receptor (a decoy receptor) is planned for 2020.

Press briefing moderator Nilofer S. Azad, MD, of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, said the findings represent “potentially the most compelling CAR T data that we’ve ever seen in solid tumors at this point,” and noted that a “vast number of patients” could potentially benefit from the approach.

Dr. Adusumilli agreed, suggesting that, with a system of regional factories and distribution centers and development of “some clever strategies,” it is possible the technology and treatment approach could be scaled up to the level necessary to help increasing numbers of patients.

Dr. Adusumilli reported receiving federal grant support from the National Cancer Institute and Department of Defense; peer-reviewed grant support from the Mesothelioma Applied Research Foundation, Experimental Therapeutics Center, Baker Street Foundation, Batishwa Fellowship, Dallepezze Foundation, Derfner Foundation, Emerson Collective Foundation, and MSK Technology Development Fund; and research grant support from OSE Immunotherapeutics, ACEA Biosciences, and Atara Biotherapeutics. He also has a licensing/royalty agreement for Mesothelin CAR and PD-1 DNR (licensed to Atara Biotherapeutics).

sworcester@mdedge.com

SOURCE: Adusumilli PS et al. AACR 2019, Abstract CT036.

ATLANTA – A combination of the epidermal growth factor receptor (EGFR)–targeted agent osimertinib (Tagrisso) with savolitinib, an investigational MET inhibitor, showed activity against MET-driven non–small cell lung cancer (NSCLC) in patients for whom prior lines of EGFR-targeted therapy had failed.

Neil Osterweil/MDedge News

Results of the phase 1b TATTON trial suggest that it may be possible to overcome MET-driven drug resistance to tyrosine kinase inhibitors (TKIs) by targeting MET amplification, said Lecia V. Sequist, MD, from the Massachusetts General Hospital Cancer Center in Boston.

“We’ve seen that up to 10% of patients at the time of acquired resistance progressing on first- or second-generation EGFR TKIs and up to 25% of patients progressing on third-generation TKIs will have resistance driven by MET amplification,” she said at a briefing at the annual meeting of the American Association for Cancer Research.

Preliminary analysis of next-generation sequencing of circulating tumor DNA showed that MET amplification was the most common resistance mechanism, occurring in 15% of patients treated for NSCLC with first-line osimertinib in the FLAURA trial. In the AURA3 trial, MET amplification was the mechanism of resistance to second-line osimertinib in 19% of patients, she said.

Savolitinib is a selective oral MET-targeted TKI that has shown preliminary antitumor activity in patients with resistance to EGFR TKIs caused by MET amplification.

Dr. Sequist presented updated interim data on two cohorts of patients enrolled in the phase 1b trial evaluating osimertinib and savolitinib in patients with advanced or metastatic NSCLC bearing EGFR mutations following failure of one or more prior EGFR-targeted TKIs. A separate cohort of patients was treated with osimertinib and selumetinib, an investigational inhibitor of MEK1/2.

In the dose-expansion phase of the trial, enrolled patients with EGFR mutation–positive and MET-positive NSCLC, and divided them into two groups: patients who received prior therapy with a first- and/or second-generation EGFR-targeted TKI who were negative for the T790M resistance mutation and patients who had received prior treatment with a third-generation EGFR TKI, regardless of mutational status.

Of 46 patients treated with first- and/or second-generation agents, 24 had partial responses for an overall response rate of 52%. Of the remaining 22 patients, 16 (35%) had stable disease for at least 6 weeks, 3 had disease progression, and 3 were not evaluable. The median time to response was 43 days.

The most common adverse events of grade 3 or greater in this cohort were nausea (4%), fatigue (7%), vomiting (4%), peripheral edema (2%), decreased white blood cell count (2%), pain (7%), AST increase (8%), rash (4%), and decreased neutrophil count (8%).

Among 48 patients treated with the combination after disease progression on a third-generation EGFR TKI, 12 had a partial response, for an overall response rate of 25%. In addition, 21 of the 36 patients without objective responses had stable disease for at least 6 weeks, 6 had disease progression, and 9 were not evaluable. The median time to response was 46 days.

In this cohort, the most common adverse events, independent of causality, included nausea (2%), vomiting (4%), diarrhea (2%), fatigue (4%), decreased appetite (6%), and myalgia (1%). “Our data suggest that the combination of osimertinib and savolitinib could overcome MET-driven resistance, but certainly further research is needed to determine the final effectiveness of these therapies,” Dr. Sequist said.

The combination is being explored in two studies: the ongoing single-arm, phase 2 SAVANNAH trial in patients with advanced EGFR-mutant, MET-positive NSCLC who had disease progression on a prior course of osimertinib; and ORCHARD, currently in the planning stages as a phase 2 trial in patients with advanced NSCLC who had disease progression on first-line osimertinib.

The ORCHARD trial will have multiple biomarker-matched and nonmatched treatment arms to examine both targeted and nontargeted combinations.

“I would say this is impressive early data,” said Roy S. Herbst, MD, PhD, chief of medical oncology at Yale Cancer Center and Smilow Cancer Hospital in New Haven, Conn., the invited discussant in the session where Dr. Sequist presented the data.

“We need randomized trials to confirm the results, need to better define MET-selection criteria, and this could in the future be a very useful refractory EGFR therapy,” he said.

The TATTON trial is sponsored by AstraZeneca. Dr. Sequist reported serving as an advisory board member and receiving research support and honoraria from the company. Dr. Herbst reported receiving research support from AstraZeneca, Eli Lilly, and Merck, and has served as a consultant for AstraZeneca, Eli Lilly, Genentech/Roche, Merck, NextCure, and Pfizer.

SOURCES: Yu H et al. AACR 2019, Abstract CT032; Sequist LV et al. AACR 2019, Abstract CT033.

ATLANTA – A combination of the epidermal growth factor receptor (EGFR)–targeted agent osimertinib (Tagrisso) with savolitinib, an investigational MET inhibitor, showed activity against MET-driven non–small cell lung cancer (NSCLC) in patients for whom prior lines of EGFR-targeted therapy had failed.

Neil Osterweil/MDedge News

Results of the phase 1b TATTON trial suggest that it may be possible to overcome MET-driven drug resistance to tyrosine kinase inhibitors (TKIs) by targeting MET amplification, said Lecia V. Sequist, MD, from the Massachusetts General Hospital Cancer Center in Boston.

“We’ve seen that up to 10% of patients at the time of acquired resistance progressing on first- or second-generation EGFR TKIs and up to 25% of patients progressing on third-generation TKIs will have resistance driven by MET amplification,” she said at a briefing at the annual meeting of the American Association for Cancer Research.

Preliminary analysis of next-generation sequencing of circulating tumor DNA showed that MET amplification was the most common resistance mechanism, occurring in 15% of patients treated for NSCLC with first-line osimertinib in the FLAURA trial. In the AURA3 trial, MET amplification was the mechanism of resistance to second-line osimertinib in 19% of patients, she said.

Savolitinib is a selective oral MET-targeted TKI that has shown preliminary antitumor activity in patients with resistance to EGFR TKIs caused by MET amplification.

Dr. Sequist presented updated interim data on two cohorts of patients enrolled in the phase 1b trial evaluating osimertinib and savolitinib in patients with advanced or metastatic NSCLC bearing EGFR mutations following failure of one or more prior EGFR-targeted TKIs. A separate cohort of patients was treated with osimertinib and selumetinib, an investigational inhibitor of MEK1/2.

In the dose-expansion phase of the trial, enrolled patients with EGFR mutation–positive and MET-positive NSCLC, and divided them into two groups: patients who received prior therapy with a first- and/or second-generation EGFR-targeted TKI who were negative for the T790M resistance mutation and patients who had received prior treatment with a third-generation EGFR TKI, regardless of mutational status.

Of 46 patients treated with first- and/or second-generation agents, 24 had partial responses for an overall response rate of 52%. Of the remaining 22 patients, 16 (35%) had stable disease for at least 6 weeks, 3 had disease progression, and 3 were not evaluable. The median time to response was 43 days.

The most common adverse events of grade 3 or greater in this cohort were nausea (4%), fatigue (7%), vomiting (4%), peripheral edema (2%), decreased white blood cell count (2%), pain (7%), AST increase (8%), rash (4%), and decreased neutrophil count (8%).

Among 48 patients treated with the combination after disease progression on a third-generation EGFR TKI, 12 had a partial response, for an overall response rate of 25%. In addition, 21 of the 36 patients without objective responses had stable disease for at least 6 weeks, 6 had disease progression, and 9 were not evaluable. The median time to response was 46 days.

In this cohort, the most common adverse events, independent of causality, included nausea (2%), vomiting (4%), diarrhea (2%), fatigue (4%), decreased appetite (6%), and myalgia (1%). “Our data suggest that the combination of osimertinib and savolitinib could overcome MET-driven resistance, but certainly further research is needed to determine the final effectiveness of these therapies,” Dr. Sequist said.

The combination is being explored in two studies: the ongoing single-arm, phase 2 SAVANNAH trial in patients with advanced EGFR-mutant, MET-positive NSCLC who had disease progression on a prior course of osimertinib; and ORCHARD, currently in the planning stages as a phase 2 trial in patients with advanced NSCLC who had disease progression on first-line osimertinib.

The ORCHARD trial will have multiple biomarker-matched and nonmatched treatment arms to examine both targeted and nontargeted combinations.

“I would say this is impressive early data,” said Roy S. Herbst, MD, PhD, chief of medical oncology at Yale Cancer Center and Smilow Cancer Hospital in New Haven, Conn., the invited discussant in the session where Dr. Sequist presented the data.

“We need randomized trials to confirm the results, need to better define MET-selection criteria, and this could in the future be a very useful refractory EGFR therapy,” he said.

The TATTON trial is sponsored by AstraZeneca. Dr. Sequist reported serving as an advisory board member and receiving research support and honoraria from the company. Dr. Herbst reported receiving research support from AstraZeneca, Eli Lilly, and Merck, and has served as a consultant for AstraZeneca, Eli Lilly, Genentech/Roche, Merck, NextCure, and Pfizer.

SOURCES: Yu H et al. AACR 2019, Abstract CT032; Sequist LV et al. AACR 2019, Abstract CT033.

ATLANTA – A combination of the epidermal growth factor receptor (EGFR)–targeted agent osimertinib (Tagrisso) with savolitinib, an investigational MET inhibitor, showed activity against MET-driven non–small cell lung cancer (NSCLC) in patients for whom prior lines of EGFR-targeted therapy had failed.

Neil Osterweil/MDedge News

Results of the phase 1b TATTON trial suggest that it may be possible to overcome MET-driven drug resistance to tyrosine kinase inhibitors (TKIs) by targeting MET amplification, said Lecia V. Sequist, MD, from the Massachusetts General Hospital Cancer Center in Boston.

“We’ve seen that up to 10% of patients at the time of acquired resistance progressing on first- or second-generation EGFR TKIs and up to 25% of patients progressing on third-generation TKIs will have resistance driven by MET amplification,” she said at a briefing at the annual meeting of the American Association for Cancer Research.

Preliminary analysis of next-generation sequencing of circulating tumor DNA showed that MET amplification was the most common resistance mechanism, occurring in 15% of patients treated for NSCLC with first-line osimertinib in the FLAURA trial. In the AURA3 trial, MET amplification was the mechanism of resistance to second-line osimertinib in 19% of patients, she said.

Savolitinib is a selective oral MET-targeted TKI that has shown preliminary antitumor activity in patients with resistance to EGFR TKIs caused by MET amplification.

Dr. Sequist presented updated interim data on two cohorts of patients enrolled in the phase 1b trial evaluating osimertinib and savolitinib in patients with advanced or metastatic NSCLC bearing EGFR mutations following failure of one or more prior EGFR-targeted TKIs. A separate cohort of patients was treated with osimertinib and selumetinib, an investigational inhibitor of MEK1/2.

In the dose-expansion phase of the trial, enrolled patients with EGFR mutation–positive and MET-positive NSCLC, and divided them into two groups: patients who received prior therapy with a first- and/or second-generation EGFR-targeted TKI who were negative for the T790M resistance mutation and patients who had received prior treatment with a third-generation EGFR TKI, regardless of mutational status.

Of 46 patients treated with first- and/or second-generation agents, 24 had partial responses for an overall response rate of 52%. Of the remaining 22 patients, 16 (35%) had stable disease for at least 6 weeks, 3 had disease progression, and 3 were not evaluable. The median time to response was 43 days.

The most common adverse events of grade 3 or greater in this cohort were nausea (4%), fatigue (7%), vomiting (4%), peripheral edema (2%), decreased white blood cell count (2%), pain (7%), AST increase (8%), rash (4%), and decreased neutrophil count (8%).

Among 48 patients treated with the combination after disease progression on a third-generation EGFR TKI, 12 had a partial response, for an overall response rate of 25%. In addition, 21 of the 36 patients without objective responses had stable disease for at least 6 weeks, 6 had disease progression, and 9 were not evaluable. The median time to response was 46 days.

In this cohort, the most common adverse events, independent of causality, included nausea (2%), vomiting (4%), diarrhea (2%), fatigue (4%), decreased appetite (6%), and myalgia (1%). “Our data suggest that the combination of osimertinib and savolitinib could overcome MET-driven resistance, but certainly further research is needed to determine the final effectiveness of these therapies,” Dr. Sequist said.

The combination is being explored in two studies: the ongoing single-arm, phase 2 SAVANNAH trial in patients with advanced EGFR-mutant, MET-positive NSCLC who had disease progression on a prior course of osimertinib; and ORCHARD, currently in the planning stages as a phase 2 trial in patients with advanced NSCLC who had disease progression on first-line osimertinib.

The ORCHARD trial will have multiple biomarker-matched and nonmatched treatment arms to examine both targeted and nontargeted combinations.

“I would say this is impressive early data,” said Roy S. Herbst, MD, PhD, chief of medical oncology at Yale Cancer Center and Smilow Cancer Hospital in New Haven, Conn., the invited discussant in the session where Dr. Sequist presented the data.

“We need randomized trials to confirm the results, need to better define MET-selection criteria, and this could in the future be a very useful refractory EGFR therapy,” he said.

The TATTON trial is sponsored by AstraZeneca. Dr. Sequist reported serving as an advisory board member and receiving research support and honoraria from the company. Dr. Herbst reported receiving research support from AstraZeneca, Eli Lilly, and Merck, and has served as a consultant for AstraZeneca, Eli Lilly, Genentech/Roche, Merck, NextCure, and Pfizer.

SOURCES: Yu H et al. AACR 2019, Abstract CT032; Sequist LV et al. AACR 2019, Abstract CT033.

ATLANTA – The FLT3 inhibitor gilteritinib (Xospata) significantly prolonged overall survival, compared with salvage chemotherapy, in patients with FLT3-mutated relapsed/refractory acute myeloid leukemia, Alexander E. Perl, MD, from the Abramson Cancer Center at the University of Pennsylvania in Philadelphia reported at the 2019 annual meeting of the American Association for Cancer Research (AACR).

In a video interview, Dr. Perl discussed the results of the ADMIRAL global phase 3 randomized trial and described the current state of therapy for patients with relapsed/refractory AML bearing FLT3 mutations. Up to 70% of patients with acute myeloid leukemia will experience a relapse, and up to 40% may have disease that is resistant to induction chemotherapy. Survival for these patients is generally poor.

In particular, patients with acute myeloid leukemia and FLT3-activating mutations are at increased risk for early relapse and poor overall survival.

The ADMIRAL trial is funded by Astellas Pharma. Dr. Perl disclosed advisory board participation, consulting fees, and institutional support from Astellas and others.

ATLANTA – The FLT3 inhibitor gilteritinib (Xospata) significantly prolonged overall survival, compared with salvage chemotherapy, in patients with FLT3-mutated relapsed/refractory acute myeloid leukemia, Alexander E. Perl, MD, from the Abramson Cancer Center at the University of Pennsylvania in Philadelphia reported at the 2019 annual meeting of the American Association for Cancer Research (AACR).

In a video interview, Dr. Perl discussed the results of the ADMIRAL global phase 3 randomized trial and described the current state of therapy for patients with relapsed/refractory AML bearing FLT3 mutations. Up to 70% of patients with acute myeloid leukemia will experience a relapse, and up to 40% may have disease that is resistant to induction chemotherapy. Survival for these patients is generally poor.

In particular, patients with acute myeloid leukemia and FLT3-activating mutations are at increased risk for early relapse and poor overall survival.

The ADMIRAL trial is funded by Astellas Pharma. Dr. Perl disclosed advisory board participation, consulting fees, and institutional support from Astellas and others.

ATLANTA – The FLT3 inhibitor gilteritinib (Xospata) significantly prolonged overall survival, compared with salvage chemotherapy, in patients with FLT3-mutated relapsed/refractory acute myeloid leukemia, Alexander E. Perl, MD, from the Abramson Cancer Center at the University of Pennsylvania in Philadelphia reported at the 2019 annual meeting of the American Association for Cancer Research (AACR).

In a video interview, Dr. Perl discussed the results of the ADMIRAL global phase 3 randomized trial and described the current state of therapy for patients with relapsed/refractory AML bearing FLT3 mutations. Up to 70% of patients with acute myeloid leukemia will experience a relapse, and up to 40% may have disease that is resistant to induction chemotherapy. Survival for these patients is generally poor.

In particular, patients with acute myeloid leukemia and FLT3-activating mutations are at increased risk for early relapse and poor overall survival.

The ADMIRAL trial is funded by Astellas Pharma. Dr. Perl disclosed advisory board participation, consulting fees, and institutional support from Astellas and others.

ATLANTA – Several studies featured during a press briefing at the annual meeting of the American Association for Cancer Research highlight the types of “transformative strategies” currently being developed and implemented, according to Louis Weiner, MD.

“Had this been the AACR [meeting] 20 years ago ... each one of them would have been a main plenary presentation and would have been the talk of the meeting,” Dr. Weiner, director of the Georgetown Lombardi Cancer Center at Georgetown University, Washington, and press briefing moderator, said of the findings.

While they are well accepted as being high quality presentations of great value, they don’t cause the same amount of stir, he said, adding: “I wouldn’t say we’re jaded, but we’ve come to the point where we almost expect great results at these meetings, and isn’t that wonderful?”

In this video interview he discussed the findings of two of the studies, including the phase 2 UNITY-NHL study and a preclinical Lynch syndrome mouse model used to develop a potential cancer preventive vaccine.

The Lynch syndrome data “suggest the strong possibility that we might be able to immunize people and combine that treatment with standard nonsteroidal anti-inflammatory agents such as naproxen to delay or reduce the impact of Lynch syndrome.”

“This set of findings ... opens the door to investigators in many different areas of cancer research to explore whether or not there are common frameshift mutations that might create novel neoantigens that we can go after with vaccines – be they for therapeutic benefit or for prevention,” he said.

The UNITY-NHL study, which showed that umbralisib is active and well tolerated as single-agent therapy in patients with relapsed or refractory marginal zone lymphoma, suggests “it’s quite possible that [the phosphoinositide 3-kinase delta inhibitor] is going to become a very important element in the treatment of patients with marginal zone lymphomas, and obviously it can be then used in earlier stages of diseases since it’s well tolerated, and it may well have useful activity in other B-cell malignancies,” he said.

Dr. Weiner reported having no relevant disclosures.

ATLANTA – Several studies featured during a press briefing at the annual meeting of the American Association for Cancer Research highlight the types of “transformative strategies” currently being developed and implemented, according to Louis Weiner, MD.

“Had this been the AACR [meeting] 20 years ago ... each one of them would have been a main plenary presentation and would have been the talk of the meeting,” Dr. Weiner, director of the Georgetown Lombardi Cancer Center at Georgetown University, Washington, and press briefing moderator, said of the findings.

While they are well accepted as being high quality presentations of great value, they don’t cause the same amount of stir, he said, adding: “I wouldn’t say we’re jaded, but we’ve come to the point where we almost expect great results at these meetings, and isn’t that wonderful?”

In this video interview he discussed the findings of two of the studies, including the phase 2 UNITY-NHL study and a preclinical Lynch syndrome mouse model used to develop a potential cancer preventive vaccine.

The Lynch syndrome data “suggest the strong possibility that we might be able to immunize people and combine that treatment with standard nonsteroidal anti-inflammatory agents such as naproxen to delay or reduce the impact of Lynch syndrome.”

“This set of findings ... opens the door to investigators in many different areas of cancer research to explore whether or not there are common frameshift mutations that might create novel neoantigens that we can go after with vaccines – be they for therapeutic benefit or for prevention,” he said.

The UNITY-NHL study, which showed that umbralisib is active and well tolerated as single-agent therapy in patients with relapsed or refractory marginal zone lymphoma, suggests “it’s quite possible that [the phosphoinositide 3-kinase delta inhibitor] is going to become a very important element in the treatment of patients with marginal zone lymphomas, and obviously it can be then used in earlier stages of diseases since it’s well tolerated, and it may well have useful activity in other B-cell malignancies,” he said.

Dr. Weiner reported having no relevant disclosures.

ATLANTA – Several studies featured during a press briefing at the annual meeting of the American Association for Cancer Research highlight the types of “transformative strategies” currently being developed and implemented, according to Louis Weiner, MD.

“Had this been the AACR [meeting] 20 years ago ... each one of them would have been a main plenary presentation and would have been the talk of the meeting,” Dr. Weiner, director of the Georgetown Lombardi Cancer Center at Georgetown University, Washington, and press briefing moderator, said of the findings.

While they are well accepted as being high quality presentations of great value, they don’t cause the same amount of stir, he said, adding: “I wouldn’t say we’re jaded, but we’ve come to the point where we almost expect great results at these meetings, and isn’t that wonderful?”

In this video interview he discussed the findings of two of the studies, including the phase 2 UNITY-NHL study and a preclinical Lynch syndrome mouse model used to develop a potential cancer preventive vaccine.

The Lynch syndrome data “suggest the strong possibility that we might be able to immunize people and combine that treatment with standard nonsteroidal anti-inflammatory agents such as naproxen to delay or reduce the impact of Lynch syndrome.”

“This set of findings ... opens the door to investigators in many different areas of cancer research to explore whether or not there are common frameshift mutations that might create novel neoantigens that we can go after with vaccines – be they for therapeutic benefit or for prevention,” he said.

The UNITY-NHL study, which showed that umbralisib is active and well tolerated as single-agent therapy in patients with relapsed or refractory marginal zone lymphoma, suggests “it’s quite possible that [the phosphoinositide 3-kinase delta inhibitor] is going to become a very important element in the treatment of patients with marginal zone lymphomas, and obviously it can be then used in earlier stages of diseases since it’s well tolerated, and it may well have useful activity in other B-cell malignancies,” he said.

Dr. Weiner reported having no relevant disclosures.