TBD Meeting (5324-18)

WASHINGTON – Combination enoblituzumab and pembrolizumab showed acceptable safety and encouraging antitumor activity in select patients with B7-H3-expressing non–small-cell lung cancer (NSCLC), squamous cell carcinoma of the head and neck (SCCHN), and other solid tumors in a phase 1 dose-escalation and expansion study.

Of note, the combination showed activity in patients anticipated to be poorly responsive to checkpoint inhibitor therapy alone, Charu Aggarwal, MD, of the University of Pennsylvania, Philadelphia, reported at the annual meeting of the Society for Immunotherapy of Cancer.

In all, 133 patients were treated weekly with 3, 10 or 15 mg/kg intravenous doses of the investigational anti-B7-H3 monoclonal antibody enoblituzumab plus 2 mg/kg intravenous doses of the programmed death-1 (PD-1) inhibitor pembrolizumab every 3 weeks (the standard dose at the time) for up to 1 year in the open-label dose-escalation study. Of those, 85% experienced treatment-related adverse events (AEs), and 27.1% experienced grade 3 or higher AEs, Dr. Aggarwal said.

These AEs were mostly infusion-related reactions typically seen with the first dose, and they were not usually cumulative, she said, noting that the rates of immune-related adverse events were less than 5%, about 7% of patients discontinued treatment because of a drug-related AE, and 1 treatment-related death due to pneumonitis occurred.

“No maximum tolerated dose was reached,” she added. “What I want to emphasize is that this is a combination immunotherapy approach, and what we found was that despite a combination approach, the nature, rate, and incidence of immune-related adverse events was not different than what is expected compared to single-agent [therapy] alone.”

Patients were then divided into disease-specific dose-expansion cohorts and the SCCHN and NSCLC cohorts were further stratified based on whether or not they had prior exposure to PD-1 inhibitor therapy.

Antitumor activity was noted in anti-PD-1-naive SCCHN patients, and objective responses were also seen in NSCLC patient with tumor programmed death-ligand 1 (PD-L1) expression of less than 1% and patients with checkpoint inhibitor–refractory urothelial carcinoma.

“We saw a 33.3% response rate in IO [immunotherapy]-naive head and neck cancer patients, and a 35.7% response rate in patients with PD-L1-negative immunotherapy-naive non–small-cell lung cancer patients,” she said.

No objective radiographic responses were seen in the IO-exposed SCCHN patients, but a few were seen in the other tumor cohorts, she noted.

“What was more interesting is this prolonged and high level of stable disease that we found in patients who had been previously treated with IO and had actually experienced significant clinical and radiographic progression then experienced stability with this combination,” she said, noting that “a fair amount of stable disease” was also seen in the IO-naive SCCHN and NSCLC patients.

In the immunotherapy-naive SCCHN patients, responses were seen regardless of human papillomavirus status, and four are still on treatment. One had a confirmed complete response.

“The majority of our patients on our trial and in this cohort were B7-H3-positive, she said, adding that the responses that were seen, including in those with stable disease, were “sustained and durable.”

Responses were similar in the immunotherapy-naive NSCLC patients who were PD-L1 negative, she said.

“Responses were seen irrespective of histology ... and many of these patients are still on treatment,” she added, noting that most were B7-H3-positive, which “seems to select our patients who have an even higher response rate of about 45%.”

The responses in that cohort also occurred early, were durable, and are sustained, and some patients remain on treatment and “are enjoying the clinical benefit afforded by this combination,” she said.

The findings are notable, because B7-H3 is highly expressed in many solid tumors, and monotherapy with enoblituzumab, which targets B7-H3 and is engineered to enhance antibody-dependent cell-mediated cytotoxicity, has demonstrated antitumor activity with an acceptable safety profile in patients with selected solid tumors.

In this study it was combined with pembrolizumab to test the hypothesis that coordinated engagement of both innate and adaptive immunity via the targeting of two distinct members of the B7 family could achieve greater antitumor activity than either agent alone, she explained.

The results “benchmark favorably” versus prior experience with PD-1 agents; pembrolizumab and nivolumab each lead to activity of about 13%-16%, she said.

“We acknowledge that our study has very small numbers. Nevertheless, these are encouraging data ... in this very tough-to-treat population,” Dr. Aggarwal said, adding that “further investigation of enoblituzumab with an anti-PD-1 molecule is warranted in both head and neck and lung cancer patients, perhaps including in combination with chemotherapy.”

Further, given the expression patterns of B7-H3 on a wide variety of solid tumors, further investigation of this combination ... is warranted in other tumor types, including in both checkpoint-naive and -treated populations, she concluded.

This study was sponsored by MacroGenics. Dr. Aggarwal reported receiving consulting fees from BMS.

SOURCE: Aggarwal C et al., SITC 2018 Abstract O24.

WASHINGTON – Combination enoblituzumab and pembrolizumab showed acceptable safety and encouraging antitumor activity in select patients with B7-H3-expressing non–small-cell lung cancer (NSCLC), squamous cell carcinoma of the head and neck (SCCHN), and other solid tumors in a phase 1 dose-escalation and expansion study.

Of note, the combination showed activity in patients anticipated to be poorly responsive to checkpoint inhibitor therapy alone, Charu Aggarwal, MD, of the University of Pennsylvania, Philadelphia, reported at the annual meeting of the Society for Immunotherapy of Cancer.

In all, 133 patients were treated weekly with 3, 10 or 15 mg/kg intravenous doses of the investigational anti-B7-H3 monoclonal antibody enoblituzumab plus 2 mg/kg intravenous doses of the programmed death-1 (PD-1) inhibitor pembrolizumab every 3 weeks (the standard dose at the time) for up to 1 year in the open-label dose-escalation study. Of those, 85% experienced treatment-related adverse events (AEs), and 27.1% experienced grade 3 or higher AEs, Dr. Aggarwal said.

These AEs were mostly infusion-related reactions typically seen with the first dose, and they were not usually cumulative, she said, noting that the rates of immune-related adverse events were less than 5%, about 7% of patients discontinued treatment because of a drug-related AE, and 1 treatment-related death due to pneumonitis occurred.

“No maximum tolerated dose was reached,” she added. “What I want to emphasize is that this is a combination immunotherapy approach, and what we found was that despite a combination approach, the nature, rate, and incidence of immune-related adverse events was not different than what is expected compared to single-agent [therapy] alone.”

Patients were then divided into disease-specific dose-expansion cohorts and the SCCHN and NSCLC cohorts were further stratified based on whether or not they had prior exposure to PD-1 inhibitor therapy.

Antitumor activity was noted in anti-PD-1-naive SCCHN patients, and objective responses were also seen in NSCLC patient with tumor programmed death-ligand 1 (PD-L1) expression of less than 1% and patients with checkpoint inhibitor–refractory urothelial carcinoma.

“We saw a 33.3% response rate in IO [immunotherapy]-naive head and neck cancer patients, and a 35.7% response rate in patients with PD-L1-negative immunotherapy-naive non–small-cell lung cancer patients,” she said.

No objective radiographic responses were seen in the IO-exposed SCCHN patients, but a few were seen in the other tumor cohorts, she noted.

“What was more interesting is this prolonged and high level of stable disease that we found in patients who had been previously treated with IO and had actually experienced significant clinical and radiographic progression then experienced stability with this combination,” she said, noting that “a fair amount of stable disease” was also seen in the IO-naive SCCHN and NSCLC patients.

In the immunotherapy-naive SCCHN patients, responses were seen regardless of human papillomavirus status, and four are still on treatment. One had a confirmed complete response.

“The majority of our patients on our trial and in this cohort were B7-H3-positive, she said, adding that the responses that were seen, including in those with stable disease, were “sustained and durable.”

Responses were similar in the immunotherapy-naive NSCLC patients who were PD-L1 negative, she said.

“Responses were seen irrespective of histology ... and many of these patients are still on treatment,” she added, noting that most were B7-H3-positive, which “seems to select our patients who have an even higher response rate of about 45%.”

The responses in that cohort also occurred early, were durable, and are sustained, and some patients remain on treatment and “are enjoying the clinical benefit afforded by this combination,” she said.

The findings are notable, because B7-H3 is highly expressed in many solid tumors, and monotherapy with enoblituzumab, which targets B7-H3 and is engineered to enhance antibody-dependent cell-mediated cytotoxicity, has demonstrated antitumor activity with an acceptable safety profile in patients with selected solid tumors.

In this study it was combined with pembrolizumab to test the hypothesis that coordinated engagement of both innate and adaptive immunity via the targeting of two distinct members of the B7 family could achieve greater antitumor activity than either agent alone, she explained.

The results “benchmark favorably” versus prior experience with PD-1 agents; pembrolizumab and nivolumab each lead to activity of about 13%-16%, she said.

“We acknowledge that our study has very small numbers. Nevertheless, these are encouraging data ... in this very tough-to-treat population,” Dr. Aggarwal said, adding that “further investigation of enoblituzumab with an anti-PD-1 molecule is warranted in both head and neck and lung cancer patients, perhaps including in combination with chemotherapy.”

Further, given the expression patterns of B7-H3 on a wide variety of solid tumors, further investigation of this combination ... is warranted in other tumor types, including in both checkpoint-naive and -treated populations, she concluded.

This study was sponsored by MacroGenics. Dr. Aggarwal reported receiving consulting fees from BMS.

SOURCE: Aggarwal C et al., SITC 2018 Abstract O24.

WASHINGTON – Combination enoblituzumab and pembrolizumab showed acceptable safety and encouraging antitumor activity in select patients with B7-H3-expressing non–small-cell lung cancer (NSCLC), squamous cell carcinoma of the head and neck (SCCHN), and other solid tumors in a phase 1 dose-escalation and expansion study.

Of note, the combination showed activity in patients anticipated to be poorly responsive to checkpoint inhibitor therapy alone, Charu Aggarwal, MD, of the University of Pennsylvania, Philadelphia, reported at the annual meeting of the Society for Immunotherapy of Cancer.

In all, 133 patients were treated weekly with 3, 10 or 15 mg/kg intravenous doses of the investigational anti-B7-H3 monoclonal antibody enoblituzumab plus 2 mg/kg intravenous doses of the programmed death-1 (PD-1) inhibitor pembrolizumab every 3 weeks (the standard dose at the time) for up to 1 year in the open-label dose-escalation study. Of those, 85% experienced treatment-related adverse events (AEs), and 27.1% experienced grade 3 or higher AEs, Dr. Aggarwal said.

These AEs were mostly infusion-related reactions typically seen with the first dose, and they were not usually cumulative, she said, noting that the rates of immune-related adverse events were less than 5%, about 7% of patients discontinued treatment because of a drug-related AE, and 1 treatment-related death due to pneumonitis occurred.

“No maximum tolerated dose was reached,” she added. “What I want to emphasize is that this is a combination immunotherapy approach, and what we found was that despite a combination approach, the nature, rate, and incidence of immune-related adverse events was not different than what is expected compared to single-agent [therapy] alone.”

Patients were then divided into disease-specific dose-expansion cohorts and the SCCHN and NSCLC cohorts were further stratified based on whether or not they had prior exposure to PD-1 inhibitor therapy.

Antitumor activity was noted in anti-PD-1-naive SCCHN patients, and objective responses were also seen in NSCLC patient with tumor programmed death-ligand 1 (PD-L1) expression of less than 1% and patients with checkpoint inhibitor–refractory urothelial carcinoma.

“We saw a 33.3% response rate in IO [immunotherapy]-naive head and neck cancer patients, and a 35.7% response rate in patients with PD-L1-negative immunotherapy-naive non–small-cell lung cancer patients,” she said.

No objective radiographic responses were seen in the IO-exposed SCCHN patients, but a few were seen in the other tumor cohorts, she noted.

“What was more interesting is this prolonged and high level of stable disease that we found in patients who had been previously treated with IO and had actually experienced significant clinical and radiographic progression then experienced stability with this combination,” she said, noting that “a fair amount of stable disease” was also seen in the IO-naive SCCHN and NSCLC patients.

In the immunotherapy-naive SCCHN patients, responses were seen regardless of human papillomavirus status, and four are still on treatment. One had a confirmed complete response.

“The majority of our patients on our trial and in this cohort were B7-H3-positive, she said, adding that the responses that were seen, including in those with stable disease, were “sustained and durable.”

Responses were similar in the immunotherapy-naive NSCLC patients who were PD-L1 negative, she said.

“Responses were seen irrespective of histology ... and many of these patients are still on treatment,” she added, noting that most were B7-H3-positive, which “seems to select our patients who have an even higher response rate of about 45%.”

The responses in that cohort also occurred early, were durable, and are sustained, and some patients remain on treatment and “are enjoying the clinical benefit afforded by this combination,” she said.

The findings are notable, because B7-H3 is highly expressed in many solid tumors, and monotherapy with enoblituzumab, which targets B7-H3 and is engineered to enhance antibody-dependent cell-mediated cytotoxicity, has demonstrated antitumor activity with an acceptable safety profile in patients with selected solid tumors.

In this study it was combined with pembrolizumab to test the hypothesis that coordinated engagement of both innate and adaptive immunity via the targeting of two distinct members of the B7 family could achieve greater antitumor activity than either agent alone, she explained.

The results “benchmark favorably” versus prior experience with PD-1 agents; pembrolizumab and nivolumab each lead to activity of about 13%-16%, she said.

“We acknowledge that our study has very small numbers. Nevertheless, these are encouraging data ... in this very tough-to-treat population,” Dr. Aggarwal said, adding that “further investigation of enoblituzumab with an anti-PD-1 molecule is warranted in both head and neck and lung cancer patients, perhaps including in combination with chemotherapy.”

Further, given the expression patterns of B7-H3 on a wide variety of solid tumors, further investigation of this combination ... is warranted in other tumor types, including in both checkpoint-naive and -treated populations, she concluded.

This study was sponsored by MacroGenics. Dr. Aggarwal reported receiving consulting fees from BMS.

SOURCE: Aggarwal C et al., SITC 2018 Abstract O24.

WASHINGTON – The personalized NEO-PV-1 neoantigen vaccine plus poly-ICLC adjuvant in combination with the checkpoint inhibitor nivolumab is well tolerated and shows clinical activity, according to findings from the ongoing phase 1b NT-001study of patients with metastatic melanoma, smoking-associated non–small cell lung cancer (NSCLC), and bladder cancer.

No vaccine-related serious adverse events occurred in 34 patients in a per-protocol set who were treated with the regimen, Siwen Hu-Lieskovan, MD, PhD, reported at the annual meeting of the Society for Immunotherapy of Cancer.

“We found that NEO-PV-01 in combination with nivolumab was very safe; we did not see any grade 3 to grade 4 toxicity associated with the combination,” said Dr. Hu-Lieskovan, a medical oncologist at the University of California, Los Angeles.

Most adverse events that occurred were mild and related to the local injection, she noted.

Although safety was the primary endpoint of the study, Dr. Hu-Lieskovan and her colleagues also looked at immune responses and treatment efficacy, however, with respect to translational data her presentation addressed only the findings in the melanoma and lung cancer patients.

All patients exhibited an immune response to the vaccine, with 56% of the epitopes generating CD4- and/or CD8-positive T cell responses.

“These immune responses were very durable and still could be detected 52 weeks into the treatment,” she said. Additionally, epitope spreading – increased immune response targeting nonvaccine epitopes (which is indirect evidence of vaccine-induced tumor toxicity) – was observed in 8 of 10 patients tested.

The study subjects, including 16 adults with melanoma, 11 with NSCLC, and 7 with bladder cancer, were treated with nivolumab every 2 weeks for 12 weeks prior to vaccination (while their personalized vaccine was being developed). NEO-PV-01 – which included up to 20 unique peptides plus the immunostimulant poly-ICLC – was then administered subcutaneously in five priming doses followed by two booster doses over the next 12 weeks. Of note, very few patients had programmed cell death protein 1 expression of 50% or greater, including only 13.3%, 28.6%, and 0% of the melanoma, NSCLC, and bladder cancer patients, respectively, and tumor mutation burden was consistent with published reports, she said.

As for efficacy, 11 of 16 melanoma patients (68.6%) had either a partial response (8 pre vaccination and an additional 3 post vaccination) or stable disease. One (6.3%) had a postvaccination complete response, Dr. Hu-Lieskovan said.

“[This is] much better than the historical data,” she noted, adding that 12 patients (75%) are still on the study and continuing treatment with response duration of at least 39.7 weeks.

Of the 11 NSCLC patients, 5 (45.5%) had a partial response (3 pre vaccination and 2 post vaccination), and none had a complete response. Seven (63.6%) remained on the study and were continuing treatment, and response duration was at least 30.6 weeks.

An exploratory analysis of tumor responses after vaccination showed that the majority of melanoma patients and half of the lung cancer patients had further tumor shrinkage after vaccination, and some patients were converted to responders. Most – including some with stable or progressive disease – stayed on treatment, she said.

The findings demonstrate that NEO-PV-01 is very well tolerated and associated with post vaccine responses observed after week 24.

“We saw evidence of vaccination-induced immune response specific to the injected vaccine, as well as epitope spreading, and the T cells induced by these neoantigens can traffic into the tumor and they seem to be functional,” she concluded.

Dr. Hu-Lieskovan reported receiving consulting fees and/or research support from Amgen, BMS, Genmab, Merck, and Vaccinex. She is the UCLA site principal investigator for the NT-001 study and has conducted contracted research for Astellas, F Star, Genentech, Nektar Therapeutics, Neon Therapeutics, Pfizer, Plexxikon, and Xencor.

SOURCE: Hu-Lieskovan S et al. SITC 2018, Abstract 07.

WASHINGTON – The personalized NEO-PV-1 neoantigen vaccine plus poly-ICLC adjuvant in combination with the checkpoint inhibitor nivolumab is well tolerated and shows clinical activity, according to findings from the ongoing phase 1b NT-001study of patients with metastatic melanoma, smoking-associated non–small cell lung cancer (NSCLC), and bladder cancer.

No vaccine-related serious adverse events occurred in 34 patients in a per-protocol set who were treated with the regimen, Siwen Hu-Lieskovan, MD, PhD, reported at the annual meeting of the Society for Immunotherapy of Cancer.

“We found that NEO-PV-01 in combination with nivolumab was very safe; we did not see any grade 3 to grade 4 toxicity associated with the combination,” said Dr. Hu-Lieskovan, a medical oncologist at the University of California, Los Angeles.

Most adverse events that occurred were mild and related to the local injection, she noted.

Although safety was the primary endpoint of the study, Dr. Hu-Lieskovan and her colleagues also looked at immune responses and treatment efficacy, however, with respect to translational data her presentation addressed only the findings in the melanoma and lung cancer patients.

All patients exhibited an immune response to the vaccine, with 56% of the epitopes generating CD4- and/or CD8-positive T cell responses.

“These immune responses were very durable and still could be detected 52 weeks into the treatment,” she said. Additionally, epitope spreading – increased immune response targeting nonvaccine epitopes (which is indirect evidence of vaccine-induced tumor toxicity) – was observed in 8 of 10 patients tested.

The study subjects, including 16 adults with melanoma, 11 with NSCLC, and 7 with bladder cancer, were treated with nivolumab every 2 weeks for 12 weeks prior to vaccination (while their personalized vaccine was being developed). NEO-PV-01 – which included up to 20 unique peptides plus the immunostimulant poly-ICLC – was then administered subcutaneously in five priming doses followed by two booster doses over the next 12 weeks. Of note, very few patients had programmed cell death protein 1 expression of 50% or greater, including only 13.3%, 28.6%, and 0% of the melanoma, NSCLC, and bladder cancer patients, respectively, and tumor mutation burden was consistent with published reports, she said.

As for efficacy, 11 of 16 melanoma patients (68.6%) had either a partial response (8 pre vaccination and an additional 3 post vaccination) or stable disease. One (6.3%) had a postvaccination complete response, Dr. Hu-Lieskovan said.

“[This is] much better than the historical data,” she noted, adding that 12 patients (75%) are still on the study and continuing treatment with response duration of at least 39.7 weeks.

Of the 11 NSCLC patients, 5 (45.5%) had a partial response (3 pre vaccination and 2 post vaccination), and none had a complete response. Seven (63.6%) remained on the study and were continuing treatment, and response duration was at least 30.6 weeks.

An exploratory analysis of tumor responses after vaccination showed that the majority of melanoma patients and half of the lung cancer patients had further tumor shrinkage after vaccination, and some patients were converted to responders. Most – including some with stable or progressive disease – stayed on treatment, she said.

The findings demonstrate that NEO-PV-01 is very well tolerated and associated with post vaccine responses observed after week 24.

“We saw evidence of vaccination-induced immune response specific to the injected vaccine, as well as epitope spreading, and the T cells induced by these neoantigens can traffic into the tumor and they seem to be functional,” she concluded.

Dr. Hu-Lieskovan reported receiving consulting fees and/or research support from Amgen, BMS, Genmab, Merck, and Vaccinex. She is the UCLA site principal investigator for the NT-001 study and has conducted contracted research for Astellas, F Star, Genentech, Nektar Therapeutics, Neon Therapeutics, Pfizer, Plexxikon, and Xencor.

SOURCE: Hu-Lieskovan S et al. SITC 2018, Abstract 07.

WASHINGTON – The personalized NEO-PV-1 neoantigen vaccine plus poly-ICLC adjuvant in combination with the checkpoint inhibitor nivolumab is well tolerated and shows clinical activity, according to findings from the ongoing phase 1b NT-001study of patients with metastatic melanoma, smoking-associated non–small cell lung cancer (NSCLC), and bladder cancer.

No vaccine-related serious adverse events occurred in 34 patients in a per-protocol set who were treated with the regimen, Siwen Hu-Lieskovan, MD, PhD, reported at the annual meeting of the Society for Immunotherapy of Cancer.

“We found that NEO-PV-01 in combination with nivolumab was very safe; we did not see any grade 3 to grade 4 toxicity associated with the combination,” said Dr. Hu-Lieskovan, a medical oncologist at the University of California, Los Angeles.

Most adverse events that occurred were mild and related to the local injection, she noted.

Although safety was the primary endpoint of the study, Dr. Hu-Lieskovan and her colleagues also looked at immune responses and treatment efficacy, however, with respect to translational data her presentation addressed only the findings in the melanoma and lung cancer patients.

All patients exhibited an immune response to the vaccine, with 56% of the epitopes generating CD4- and/or CD8-positive T cell responses.

“These immune responses were very durable and still could be detected 52 weeks into the treatment,” she said. Additionally, epitope spreading – increased immune response targeting nonvaccine epitopes (which is indirect evidence of vaccine-induced tumor toxicity) – was observed in 8 of 10 patients tested.

The study subjects, including 16 adults with melanoma, 11 with NSCLC, and 7 with bladder cancer, were treated with nivolumab every 2 weeks for 12 weeks prior to vaccination (while their personalized vaccine was being developed). NEO-PV-01 – which included up to 20 unique peptides plus the immunostimulant poly-ICLC – was then administered subcutaneously in five priming doses followed by two booster doses over the next 12 weeks. Of note, very few patients had programmed cell death protein 1 expression of 50% or greater, including only 13.3%, 28.6%, and 0% of the melanoma, NSCLC, and bladder cancer patients, respectively, and tumor mutation burden was consistent with published reports, she said.

As for efficacy, 11 of 16 melanoma patients (68.6%) had either a partial response (8 pre vaccination and an additional 3 post vaccination) or stable disease. One (6.3%) had a postvaccination complete response, Dr. Hu-Lieskovan said.

“[This is] much better than the historical data,” she noted, adding that 12 patients (75%) are still on the study and continuing treatment with response duration of at least 39.7 weeks.

Of the 11 NSCLC patients, 5 (45.5%) had a partial response (3 pre vaccination and 2 post vaccination), and none had a complete response. Seven (63.6%) remained on the study and were continuing treatment, and response duration was at least 30.6 weeks.

An exploratory analysis of tumor responses after vaccination showed that the majority of melanoma patients and half of the lung cancer patients had further tumor shrinkage after vaccination, and some patients were converted to responders. Most – including some with stable or progressive disease – stayed on treatment, she said.

The findings demonstrate that NEO-PV-01 is very well tolerated and associated with post vaccine responses observed after week 24.

“We saw evidence of vaccination-induced immune response specific to the injected vaccine, as well as epitope spreading, and the T cells induced by these neoantigens can traffic into the tumor and they seem to be functional,” she concluded.

Dr. Hu-Lieskovan reported receiving consulting fees and/or research support from Amgen, BMS, Genmab, Merck, and Vaccinex. She is the UCLA site principal investigator for the NT-001 study and has conducted contracted research for Astellas, F Star, Genentech, Nektar Therapeutics, Neon Therapeutics, Pfizer, Plexxikon, and Xencor.

SOURCE: Hu-Lieskovan S et al. SITC 2018, Abstract 07.

WASHINGTON – Positron emission tomography (PET) using the CD8-tracer ⁸⁹Zr-IAB22M2C was safe and provided detailed whole-body information on the biodistribution of CD8 T-cells in advanced solid tumors and reference tissue in an open-label, phase 1, first-in-human study.

The findings demonstrate the ability of the tracer–an anti-CD8 zirconium-labeled minibody–to noninvasively detect CD8 distribution in patients with metastatic solid tumors, potentially providing more information – and more quickly – than is possible with a single biopsy, Michael S. Gordon, MD, reported during a late-breaking abstract session at the annual meeting of the Society for Immunotherapy of Cancer.

During a dose escalation period (stage 1) of the study, six patients received 3 mCi of ⁸⁹Zr-IAB22M2C once intravenously followed by serial PET scans over a period of 5-7 days. The patients received increasing protein doses of 0.2 through 10 mg to establish safety and determine a “recommended protein dose and scanning parameters for subsequent trials,” explained Dr. Gordon of HonorHealth Research Institute, Scottsdale, Ariz.

Stage 1 was followed by a dose expansion period (stage 2) in which an additional nine subjects were scanned to better delineate the recommended phase 2 study dose, he said.

All patients were monitored for drug-related adverse events and evaluated with blood chemistry, hematology, cytokine assay, and anti-drug antibodies. Biodistribution, radiodosimetry and semi-quantitative evaluation of CD8-tracer uptake were performed in all patients.

“We saw rapid clearance with excretion through the hepatobiliary mechanism, uptake in T-cell rich tissues, and no uptake in background normal tissues – so no uptake in muscle, heart, brain, or lungs,” he said, adding that “tumor uptake was variable and was clearly seen in 10 out of 15 patients.

“The protein dose that was considered to have favorable biodistribution was the range between 0.5 and 1.5, and based upon the analysis, the most favorable imaging time point ... was deemed to be 24 hours,” he said, noting that changes could be seen in as early as 6 hours.

SOURCE: Gordon M et al., SITC 2018: Abstract LB49.

WASHINGTON – Positron emission tomography (PET) using the CD8-tracer ⁸⁹Zr-IAB22M2C was safe and provided detailed whole-body information on the biodistribution of CD8 T-cells in advanced solid tumors and reference tissue in an open-label, phase 1, first-in-human study.

The findings demonstrate the ability of the tracer–an anti-CD8 zirconium-labeled minibody–to noninvasively detect CD8 distribution in patients with metastatic solid tumors, potentially providing more information – and more quickly – than is possible with a single biopsy, Michael S. Gordon, MD, reported during a late-breaking abstract session at the annual meeting of the Society for Immunotherapy of Cancer.

During a dose escalation period (stage 1) of the study, six patients received 3 mCi of ⁸⁹Zr-IAB22M2C once intravenously followed by serial PET scans over a period of 5-7 days. The patients received increasing protein doses of 0.2 through 10 mg to establish safety and determine a “recommended protein dose and scanning parameters for subsequent trials,” explained Dr. Gordon of HonorHealth Research Institute, Scottsdale, Ariz.

Stage 1 was followed by a dose expansion period (stage 2) in which an additional nine subjects were scanned to better delineate the recommended phase 2 study dose, he said.

All patients were monitored for drug-related adverse events and evaluated with blood chemistry, hematology, cytokine assay, and anti-drug antibodies. Biodistribution, radiodosimetry and semi-quantitative evaluation of CD8-tracer uptake were performed in all patients.

“We saw rapid clearance with excretion through the hepatobiliary mechanism, uptake in T-cell rich tissues, and no uptake in background normal tissues – so no uptake in muscle, heart, brain, or lungs,” he said, adding that “tumor uptake was variable and was clearly seen in 10 out of 15 patients.

“The protein dose that was considered to have favorable biodistribution was the range between 0.5 and 1.5, and based upon the analysis, the most favorable imaging time point ... was deemed to be 24 hours,” he said, noting that changes could be seen in as early as 6 hours.

SOURCE: Gordon M et al., SITC 2018: Abstract LB49.

WASHINGTON – Positron emission tomography (PET) using the CD8-tracer ⁸⁹Zr-IAB22M2C was safe and provided detailed whole-body information on the biodistribution of CD8 T-cells in advanced solid tumors and reference tissue in an open-label, phase 1, first-in-human study.

The findings demonstrate the ability of the tracer–an anti-CD8 zirconium-labeled minibody–to noninvasively detect CD8 distribution in patients with metastatic solid tumors, potentially providing more information – and more quickly – than is possible with a single biopsy, Michael S. Gordon, MD, reported during a late-breaking abstract session at the annual meeting of the Society for Immunotherapy of Cancer.

During a dose escalation period (stage 1) of the study, six patients received 3 mCi of ⁸⁹Zr-IAB22M2C once intravenously followed by serial PET scans over a period of 5-7 days. The patients received increasing protein doses of 0.2 through 10 mg to establish safety and determine a “recommended protein dose and scanning parameters for subsequent trials,” explained Dr. Gordon of HonorHealth Research Institute, Scottsdale, Ariz.

Stage 1 was followed by a dose expansion period (stage 2) in which an additional nine subjects were scanned to better delineate the recommended phase 2 study dose, he said.

All patients were monitored for drug-related adverse events and evaluated with blood chemistry, hematology, cytokine assay, and anti-drug antibodies. Biodistribution, radiodosimetry and semi-quantitative evaluation of CD8-tracer uptake were performed in all patients.

“We saw rapid clearance with excretion through the hepatobiliary mechanism, uptake in T-cell rich tissues, and no uptake in background normal tissues – so no uptake in muscle, heart, brain, or lungs,” he said, adding that “tumor uptake was variable and was clearly seen in 10 out of 15 patients.

“The protein dose that was considered to have favorable biodistribution was the range between 0.5 and 1.5, and based upon the analysis, the most favorable imaging time point ... was deemed to be 24 hours,” he said, noting that changes could be seen in as early as 6 hours.

SOURCE: Gordon M et al., SITC 2018: Abstract LB49.

WASHINGTON – Combination lenvatinib and pembrolizumab shows promising clinical activity and a manageable safety profile in previously treated patients with confirmed, measurable, metastatic non–small cell lung cancer (NSCLC), according to interim findings from a phase 1b/2 study.

Sharon Worcester/MDedge News

Of note, the 21 patients enrolled in the multicenter, open-label study as of March 2018 were not preselected for programmed death-ligand 1 (PD-L1) tumor expression status, Marcia S. Brose, MD, reported at the annual meeting of the Society for the Immunotherapy of Cancer.

They were treated with 20 mg of oral lenvatinib daily and 200 mg of intravenous pembrolizumab every 3 weeks, and the overall response rate at 24 weeks – the primary endpoint of the study – was 33.3%, said Dr. Brose of Abramson Cancer Center of the University of Pennsylvania, Philadelphia.

One patient had a complete response, six had a partial response, 10 had stable disease, two progressed on treatment, and the outcome in two was unknown or not evaluable, for an overall clinical benefit rate of 66%, she said, adding that the median duration of response was 10.9 months and median progression-free survival (PFS) was 5.9 months.

All patients had good performance status (ECOG score of 0-1), and nine (43%) were PD-L1–positive as defined by a tumor proportion score of at least 1%, five (24%) were PD-L1-negative, and seven (33%) were not tested for PD-L1 status. Three (14%) were treatment naive, while seven (33%), 10 (48%), and one (5%) had received one, two, or three or more prior lines of systemic therapy, respectively. No prior nivolumab or pembrolizumab treatment was allowed.

“At least one of the patients who was PD-L1–negative remained on study after 40 weeks and still continuing to respond, and ... the PD-L1–positive patients were also doing well,” Dr. Brose said.

Tumor assessments were performed by study investigators using immune-related Response Evaluation Criteria in Solid Tumors (irRECIST).

Grade 3 or greater treatment-related adverse events occurred in 10 patients (48%), and mainly included hypertension, fatigue, and diarrhea, but only four were considered serious treatment-related adverse events. Nineteen patients had treatment adjustments because of adverse events, four discontinued treatment due to adverse events, and one patient died from a pulmonary hemorrhage that was thought to possibly be treatment related, Dr. Brose said.

“The toxicity is really what you would have expected from either of these drugs on their own; it didn’t seem like there was anything that happened in synergy from the two that was unexpected,” she noted.

Lenvatinib is a multikinase inhibitor of vascular endothelial growth factor (VEGF) receptors 1-3, fibroblast growth factor receptors (FGFR) 1-4, platelet-derived growth factor receptor (PDGFR) alpha, and the RET and c-KIT proto-oncogenes. Pembrolizumab is an anti–PD-1 antibody approved as a monotherapy for previously treated patients with metastatic PD-L1–positive NSCLC, and it has been shown to be associated with an overall response rate of 18%, she explained.

The current results are from the NSCLC cohort of an ongoing trial of lenvatinib plus pembrolizumab in patients with solid tumors.

“Further investigation of this study drug combination in patients is warranted, but we will have to think carefully about what point in the treatment paradigm these patients should be treated in order to maximize the benefit from this combination therapy,” she concluded.

Dr. Brose has received consulting fees, research grants, and honorarium from Eisai.

SOURCE: Brose M et al. SITC 2018, Abstract P392.

WASHINGTON – Combination lenvatinib and pembrolizumab shows promising clinical activity and a manageable safety profile in previously treated patients with confirmed, measurable, metastatic non–small cell lung cancer (NSCLC), according to interim findings from a phase 1b/2 study.

Sharon Worcester/MDedge News

Of note, the 21 patients enrolled in the multicenter, open-label study as of March 2018 were not preselected for programmed death-ligand 1 (PD-L1) tumor expression status, Marcia S. Brose, MD, reported at the annual meeting of the Society for the Immunotherapy of Cancer.

They were treated with 20 mg of oral lenvatinib daily and 200 mg of intravenous pembrolizumab every 3 weeks, and the overall response rate at 24 weeks – the primary endpoint of the study – was 33.3%, said Dr. Brose of Abramson Cancer Center of the University of Pennsylvania, Philadelphia.

One patient had a complete response, six had a partial response, 10 had stable disease, two progressed on treatment, and the outcome in two was unknown or not evaluable, for an overall clinical benefit rate of 66%, she said, adding that the median duration of response was 10.9 months and median progression-free survival (PFS) was 5.9 months.

All patients had good performance status (ECOG score of 0-1), and nine (43%) were PD-L1–positive as defined by a tumor proportion score of at least 1%, five (24%) were PD-L1-negative, and seven (33%) were not tested for PD-L1 status. Three (14%) were treatment naive, while seven (33%), 10 (48%), and one (5%) had received one, two, or three or more prior lines of systemic therapy, respectively. No prior nivolumab or pembrolizumab treatment was allowed.

“At least one of the patients who was PD-L1–negative remained on study after 40 weeks and still continuing to respond, and ... the PD-L1–positive patients were also doing well,” Dr. Brose said.

Tumor assessments were performed by study investigators using immune-related Response Evaluation Criteria in Solid Tumors (irRECIST).

Grade 3 or greater treatment-related adverse events occurred in 10 patients (48%), and mainly included hypertension, fatigue, and diarrhea, but only four were considered serious treatment-related adverse events. Nineteen patients had treatment adjustments because of adverse events, four discontinued treatment due to adverse events, and one patient died from a pulmonary hemorrhage that was thought to possibly be treatment related, Dr. Brose said.

“The toxicity is really what you would have expected from either of these drugs on their own; it didn’t seem like there was anything that happened in synergy from the two that was unexpected,” she noted.

Lenvatinib is a multikinase inhibitor of vascular endothelial growth factor (VEGF) receptors 1-3, fibroblast growth factor receptors (FGFR) 1-4, platelet-derived growth factor receptor (PDGFR) alpha, and the RET and c-KIT proto-oncogenes. Pembrolizumab is an anti–PD-1 antibody approved as a monotherapy for previously treated patients with metastatic PD-L1–positive NSCLC, and it has been shown to be associated with an overall response rate of 18%, she explained.

The current results are from the NSCLC cohort of an ongoing trial of lenvatinib plus pembrolizumab in patients with solid tumors.

“Further investigation of this study drug combination in patients is warranted, but we will have to think carefully about what point in the treatment paradigm these patients should be treated in order to maximize the benefit from this combination therapy,” she concluded.

Dr. Brose has received consulting fees, research grants, and honorarium from Eisai.

SOURCE: Brose M et al. SITC 2018, Abstract P392.

WASHINGTON – Combination lenvatinib and pembrolizumab shows promising clinical activity and a manageable safety profile in previously treated patients with confirmed, measurable, metastatic non–small cell lung cancer (NSCLC), according to interim findings from a phase 1b/2 study.

Sharon Worcester/MDedge News

Of note, the 21 patients enrolled in the multicenter, open-label study as of March 2018 were not preselected for programmed death-ligand 1 (PD-L1) tumor expression status, Marcia S. Brose, MD, reported at the annual meeting of the Society for the Immunotherapy of Cancer.

They were treated with 20 mg of oral lenvatinib daily and 200 mg of intravenous pembrolizumab every 3 weeks, and the overall response rate at 24 weeks – the primary endpoint of the study – was 33.3%, said Dr. Brose of Abramson Cancer Center of the University of Pennsylvania, Philadelphia.

One patient had a complete response, six had a partial response, 10 had stable disease, two progressed on treatment, and the outcome in two was unknown or not evaluable, for an overall clinical benefit rate of 66%, she said, adding that the median duration of response was 10.9 months and median progression-free survival (PFS) was 5.9 months.

All patients had good performance status (ECOG score of 0-1), and nine (43%) were PD-L1–positive as defined by a tumor proportion score of at least 1%, five (24%) were PD-L1-negative, and seven (33%) were not tested for PD-L1 status. Three (14%) were treatment naive, while seven (33%), 10 (48%), and one (5%) had received one, two, or three or more prior lines of systemic therapy, respectively. No prior nivolumab or pembrolizumab treatment was allowed.

“At least one of the patients who was PD-L1–negative remained on study after 40 weeks and still continuing to respond, and ... the PD-L1–positive patients were also doing well,” Dr. Brose said.

Tumor assessments were performed by study investigators using immune-related Response Evaluation Criteria in Solid Tumors (irRECIST).

Grade 3 or greater treatment-related adverse events occurred in 10 patients (48%), and mainly included hypertension, fatigue, and diarrhea, but only four were considered serious treatment-related adverse events. Nineteen patients had treatment adjustments because of adverse events, four discontinued treatment due to adverse events, and one patient died from a pulmonary hemorrhage that was thought to possibly be treatment related, Dr. Brose said.

“The toxicity is really what you would have expected from either of these drugs on their own; it didn’t seem like there was anything that happened in synergy from the two that was unexpected,” she noted.

Lenvatinib is a multikinase inhibitor of vascular endothelial growth factor (VEGF) receptors 1-3, fibroblast growth factor receptors (FGFR) 1-4, platelet-derived growth factor receptor (PDGFR) alpha, and the RET and c-KIT proto-oncogenes. Pembrolizumab is an anti–PD-1 antibody approved as a monotherapy for previously treated patients with metastatic PD-L1–positive NSCLC, and it has been shown to be associated with an overall response rate of 18%, she explained.

The current results are from the NSCLC cohort of an ongoing trial of lenvatinib plus pembrolizumab in patients with solid tumors.

“Further investigation of this study drug combination in patients is warranted, but we will have to think carefully about what point in the treatment paradigm these patients should be treated in order to maximize the benefit from this combination therapy,” she concluded.

Dr. Brose has received consulting fees, research grants, and honorarium from Eisai.

SOURCE: Brose M et al. SITC 2018, Abstract P392.

WASHINGTON – High tumor mutational burden and development of immune-related adverse events are markers of response to immune checkpoint inhibitor therapy in patients with small cell lung cancer, and targeted next-generation sequencing may help identify those likely to benefit from immunotherapy, findings from a case series suggest.

Of 113 small cell lung cancer (SCLC) patients who had successful next-generation sequencing (NGS) with tumor mutational burden (TMB) assessment at the Dana-Farber Cancer Institute (DFCI) in Boston, 52 were treated with immune checkpoint inhibitors and 61 received chemotherapy but never received subsequent immunotherapy, Biagio Ricciuti, MD, of DFCI said at the annual meeting of the Society for the Immunotherapy of Cancer.

Median TMB for all patients was 9.68 mutations/megabase, with those with TMB above the median considered TMB high, and those with TMB below the median considered TMB low. Median progression-free survival (PFS) was significantly longer among TMB-high versus TMB-low patients (3.3 vs. 1.2 months; hazard ratio, 0.37), as was median overall survival (OS, 10.4 vs. 2.5 months; HR, 0.38), he said.

“To confirm that TMB was a predictive biomarker for immunotherapy only, we also looked at the outcome with chemotherapy according to tumor mutational burden, and as expected we found no difference in terms of median progression-free survival or median overall survival according to TMB-high versus TMB-low groups,” he said.

Additionally, patients with SCLC who were treated with immune checkpoint inhibitors and experienced at least one immune-related adverse event had significantly better median PFS and OS than did patients who experienced no immune-related adverse events (6.7 vs. 1.3 months; HR, 0.25; and 17.9 vs. 2.9 months; HR, 0.27, respectively), he said, noting that, in a 12-week landmark analysis, the differences in PFS and OS between the groups were “nearly double” but did not reach statistical significance.

TMB in the SCLC patients in this study was assessed using the DFCI NGS OncoPanel platform of more than 450 genes, and the TMB-high and TMB-low groups were similar with respect to baseline clinical and pathological features and known prognostic factors, Dr. Ricciuti said.

Prior studies have demonstrated that high TMB as assessed by whole exome sequencing correlates with benefits from immunotherapy. However, “whole exome sequencing is a very expensive technique, it’s challenging ... and it’s not really available to oncologists across countries,” he said.

Whether the more readily available targeted NGS could help identify the small fraction of SCLC patients who are likely to benefit from immunotherapy has been unclear, as has the relationship between the development of irAEs and immunotherapy response in SCLC; factors associated with clinical benefit from immunotherapy have not previously been well characterized, Dr. Ricciuti noted.

The current findings, though limited by the retrospective study design and small sample size, provide the first evidence for the use of targeted NGS panels to identify patients with advanced SCLC who are most likely to benefit from immunotherapy, he said, adding that, when compared with whole genome sequencing, TMB as assessed using targeted NGS “may offer a very useful tool for clinicians to optimize small cell lung cancer patient selection for immunotherapy.

“Our study also suggests that immune-related adverse events might be associated with improved efficacy of immunotherapy, although larger studies with longer follow-up are required to confirm this finding,” he concluded.

Dr. Ricciuti reported having no disclosures.

WASHINGTON – High tumor mutational burden and development of immune-related adverse events are markers of response to immune checkpoint inhibitor therapy in patients with small cell lung cancer, and targeted next-generation sequencing may help identify those likely to benefit from immunotherapy, findings from a case series suggest.

Of 113 small cell lung cancer (SCLC) patients who had successful next-generation sequencing (NGS) with tumor mutational burden (TMB) assessment at the Dana-Farber Cancer Institute (DFCI) in Boston, 52 were treated with immune checkpoint inhibitors and 61 received chemotherapy but never received subsequent immunotherapy, Biagio Ricciuti, MD, of DFCI said at the annual meeting of the Society for the Immunotherapy of Cancer.

Median TMB for all patients was 9.68 mutations/megabase, with those with TMB above the median considered TMB high, and those with TMB below the median considered TMB low. Median progression-free survival (PFS) was significantly longer among TMB-high versus TMB-low patients (3.3 vs. 1.2 months; hazard ratio, 0.37), as was median overall survival (OS, 10.4 vs. 2.5 months; HR, 0.38), he said.

“To confirm that TMB was a predictive biomarker for immunotherapy only, we also looked at the outcome with chemotherapy according to tumor mutational burden, and as expected we found no difference in terms of median progression-free survival or median overall survival according to TMB-high versus TMB-low groups,” he said.

Additionally, patients with SCLC who were treated with immune checkpoint inhibitors and experienced at least one immune-related adverse event had significantly better median PFS and OS than did patients who experienced no immune-related adverse events (6.7 vs. 1.3 months; HR, 0.25; and 17.9 vs. 2.9 months; HR, 0.27, respectively), he said, noting that, in a 12-week landmark analysis, the differences in PFS and OS between the groups were “nearly double” but did not reach statistical significance.

TMB in the SCLC patients in this study was assessed using the DFCI NGS OncoPanel platform of more than 450 genes, and the TMB-high and TMB-low groups were similar with respect to baseline clinical and pathological features and known prognostic factors, Dr. Ricciuti said.

Prior studies have demonstrated that high TMB as assessed by whole exome sequencing correlates with benefits from immunotherapy. However, “whole exome sequencing is a very expensive technique, it’s challenging ... and it’s not really available to oncologists across countries,” he said.

Whether the more readily available targeted NGS could help identify the small fraction of SCLC patients who are likely to benefit from immunotherapy has been unclear, as has the relationship between the development of irAEs and immunotherapy response in SCLC; factors associated with clinical benefit from immunotherapy have not previously been well characterized, Dr. Ricciuti noted.

The current findings, though limited by the retrospective study design and small sample size, provide the first evidence for the use of targeted NGS panels to identify patients with advanced SCLC who are most likely to benefit from immunotherapy, he said, adding that, when compared with whole genome sequencing, TMB as assessed using targeted NGS “may offer a very useful tool for clinicians to optimize small cell lung cancer patient selection for immunotherapy.

“Our study also suggests that immune-related adverse events might be associated with improved efficacy of immunotherapy, although larger studies with longer follow-up are required to confirm this finding,” he concluded.

Dr. Ricciuti reported having no disclosures.

WASHINGTON – High tumor mutational burden and development of immune-related adverse events are markers of response to immune checkpoint inhibitor therapy in patients with small cell lung cancer, and targeted next-generation sequencing may help identify those likely to benefit from immunotherapy, findings from a case series suggest.

Of 113 small cell lung cancer (SCLC) patients who had successful next-generation sequencing (NGS) with tumor mutational burden (TMB) assessment at the Dana-Farber Cancer Institute (DFCI) in Boston, 52 were treated with immune checkpoint inhibitors and 61 received chemotherapy but never received subsequent immunotherapy, Biagio Ricciuti, MD, of DFCI said at the annual meeting of the Society for the Immunotherapy of Cancer.

Median TMB for all patients was 9.68 mutations/megabase, with those with TMB above the median considered TMB high, and those with TMB below the median considered TMB low. Median progression-free survival (PFS) was significantly longer among TMB-high versus TMB-low patients (3.3 vs. 1.2 months; hazard ratio, 0.37), as was median overall survival (OS, 10.4 vs. 2.5 months; HR, 0.38), he said.

“To confirm that TMB was a predictive biomarker for immunotherapy only, we also looked at the outcome with chemotherapy according to tumor mutational burden, and as expected we found no difference in terms of median progression-free survival or median overall survival according to TMB-high versus TMB-low groups,” he said.

Additionally, patients with SCLC who were treated with immune checkpoint inhibitors and experienced at least one immune-related adverse event had significantly better median PFS and OS than did patients who experienced no immune-related adverse events (6.7 vs. 1.3 months; HR, 0.25; and 17.9 vs. 2.9 months; HR, 0.27, respectively), he said, noting that, in a 12-week landmark analysis, the differences in PFS and OS between the groups were “nearly double” but did not reach statistical significance.

TMB in the SCLC patients in this study was assessed using the DFCI NGS OncoPanel platform of more than 450 genes, and the TMB-high and TMB-low groups were similar with respect to baseline clinical and pathological features and known prognostic factors, Dr. Ricciuti said.

Prior studies have demonstrated that high TMB as assessed by whole exome sequencing correlates with benefits from immunotherapy. However, “whole exome sequencing is a very expensive technique, it’s challenging ... and it’s not really available to oncologists across countries,” he said.

Whether the more readily available targeted NGS could help identify the small fraction of SCLC patients who are likely to benefit from immunotherapy has been unclear, as has the relationship between the development of irAEs and immunotherapy response in SCLC; factors associated with clinical benefit from immunotherapy have not previously been well characterized, Dr. Ricciuti noted.

The current findings, though limited by the retrospective study design and small sample size, provide the first evidence for the use of targeted NGS panels to identify patients with advanced SCLC who are most likely to benefit from immunotherapy, he said, adding that, when compared with whole genome sequencing, TMB as assessed using targeted NGS “may offer a very useful tool for clinicians to optimize small cell lung cancer patient selection for immunotherapy.

“Our study also suggests that immune-related adverse events might be associated with improved efficacy of immunotherapy, although larger studies with longer follow-up are required to confirm this finding,” he concluded.

Dr. Ricciuti reported having no disclosures.

WASHINGTON – Dual-antibody targeting with the novel immune checkpoint inhibitor monalizumab combined with the epidermal growth factor–receptor (EGFR) inhibitor cetuximab is safe and associated with deep and durable responses in patients with recurrent or metastatic squamous cell carcinoma (SCC) of the head and neck, according to data from an ongoing cohort expansion study.

As of Aug. 21, 2018, the primary study endpoint of overall response rate in 40 evaluable patients enrolled in the single-arm, nonrandomized phase 1/2 study was 27.5%, Roger Cohen, MD, reported at the annual meeting of the Society for Immunotherapy of Cancer.

There were 11 confirmed responses, including 1 complete response and 10 partial responses at a median follow-up of 8 months, said Dr. Cohen, a professor of medicine at the Hospital of the University of Pennsylvania and director of clinical research at the Abramson Cancer Center, Philadelphia.

Median progression-free survival and overall survival were 5.0 months and 10.3 months, respectively.

“We observed responses in patients who were naive to immunotherapy, as well as patients who had received and progressed after immunotherapy. We observed responses in patients who were platinum resistant, and we also saw responses in [human papillomavirus (HPV)]–positive and –negative patients,” he said, adding that responses occurred relatively early at a median of 1.6 months, and that there was little difference between those who had and had not received prior immunotherapy with programmed death-1 (PD-1) antibodies.

A number of the responses, as well as the stable diseases, were durable for “a considerable period of time.” The median duration of response was 5.6 months, he said.

Study participants were mainly middle-aged men with recurrent or metastatic HPV-positive or -negative advanced disease and “decent” performance status. They received monalizumab at a dose of 10 mg/kg every 2 weeks plus cetuximab at the labeled loading dose of 400 mg/m² once weekly then 250 mg/m² once weekly. All had progressed after prior platinum-based chemotherapy and had no more than two prior lines of therapy in the recurrent/metastatic setting; 17 (43%) had prior anti–programmed death-ligand 1 (PD-L1) therapy, 5 (13%) had prior cetuximab, but none of those patients were cetuximab resistant.

They were treated until disease progression or unacceptable toxicity and were assessed every 8 weeks for response per Response Evaluation Criteria in Solid Tumors (RECIST) criteria, he said.

This treatment combination was shown in the phase 1 portion of the study to have a favorable safety profile, and the safety profile was confirmed in this expansion cohort; adverse events related to the combination were dominated by EGFR antibody–related side effects in the skin, as well as hypomagnesemia. Most adverse events associated with monalizumab were grade 1-2.

“Serious adverse events are in the single digits,” Dr. Cohen said.

Monalizumab is a first-in-class humanized immunoglobulin-G4 monoclonal antibody against the human natural killer group 2A (NKG2A), which is the receptor for the NKG2A ligand, HLA-E.

“The HLA-E NKG2A diad shuts down NK cells and tumor-infiltrating CD8-positive T-cells,” he explained, adding that “the concept behind the antibody is that by blocking the interaction of the receptor for the ligand you can reduce this inhibitory signaling by NK cells and thereby unleash their ability to target tumor.”

Cetuximab is an established and approved EGFR inhibitor for the treatment of patients with head and neck SCC who progress after platinum-based chemotherapy. It has been associated with a 13% response rate.

“The therapeutic hypothesis is that dual targeting with these two antibodies will allow us to realize greater antitumor activity in head and neck cancer than is seen with cetuximab alone,” he said, later adding that “the combination of monalizumab and cetuximab results in early, deep, and durable responses in patients with squamous cell cancer of the head and neck ... and the activity indeed is higher than cetuximab alone, compared with historical data.”

Additionally, the safety is acceptable, and preliminary translational analyses do show some immunological proof-of-concept – mainly that infiltration of the tumor stroma with NK and CD8-positive T cells is correlated with response, he said.

“Importantly, this study is continuing to enroll patients, and taking account of the ever-changing landscape in the treatment of patients with advanced cancer, we are going to enroll another 40 patients, except this time we will require them to be platinum, as well as PD-1 antibody exposed. These patients still represent an enormous unmet medical need.

“We think these results do warrant further development of the combo of monalizumab and cetuximab in patients with advanced SCC of the head and neck,” he concluded.

Dr. Cohen reported receiving consulting fees and/or research funding from Cantargia, Celldex, Genocea, Innate, HEAT, Kyntherapeutics, Merck, Takeda Macrogenics, and Tmunity.

SOURCE: Cohen R et al. SITC 2018, Abstract 051.

WASHINGTON – Dual-antibody targeting with the novel immune checkpoint inhibitor monalizumab combined with the epidermal growth factor–receptor (EGFR) inhibitor cetuximab is safe and associated with deep and durable responses in patients with recurrent or metastatic squamous cell carcinoma (SCC) of the head and neck, according to data from an ongoing cohort expansion study.

As of Aug. 21, 2018, the primary study endpoint of overall response rate in 40 evaluable patients enrolled in the single-arm, nonrandomized phase 1/2 study was 27.5%, Roger Cohen, MD, reported at the annual meeting of the Society for Immunotherapy of Cancer.

There were 11 confirmed responses, including 1 complete response and 10 partial responses at a median follow-up of 8 months, said Dr. Cohen, a professor of medicine at the Hospital of the University of Pennsylvania and director of clinical research at the Abramson Cancer Center, Philadelphia.

Median progression-free survival and overall survival were 5.0 months and 10.3 months, respectively.

“We observed responses in patients who were naive to immunotherapy, as well as patients who had received and progressed after immunotherapy. We observed responses in patients who were platinum resistant, and we also saw responses in [human papillomavirus (HPV)]–positive and –negative patients,” he said, adding that responses occurred relatively early at a median of 1.6 months, and that there was little difference between those who had and had not received prior immunotherapy with programmed death-1 (PD-1) antibodies.

A number of the responses, as well as the stable diseases, were durable for “a considerable period of time.” The median duration of response was 5.6 months, he said.

Study participants were mainly middle-aged men with recurrent or metastatic HPV-positive or -negative advanced disease and “decent” performance status. They received monalizumab at a dose of 10 mg/kg every 2 weeks plus cetuximab at the labeled loading dose of 400 mg/m² once weekly then 250 mg/m² once weekly. All had progressed after prior platinum-based chemotherapy and had no more than two prior lines of therapy in the recurrent/metastatic setting; 17 (43%) had prior anti–programmed death-ligand 1 (PD-L1) therapy, 5 (13%) had prior cetuximab, but none of those patients were cetuximab resistant.

They were treated until disease progression or unacceptable toxicity and were assessed every 8 weeks for response per Response Evaluation Criteria in Solid Tumors (RECIST) criteria, he said.

This treatment combination was shown in the phase 1 portion of the study to have a favorable safety profile, and the safety profile was confirmed in this expansion cohort; adverse events related to the combination were dominated by EGFR antibody–related side effects in the skin, as well as hypomagnesemia. Most adverse events associated with monalizumab were grade 1-2.

“Serious adverse events are in the single digits,” Dr. Cohen said.

Monalizumab is a first-in-class humanized immunoglobulin-G4 monoclonal antibody against the human natural killer group 2A (NKG2A), which is the receptor for the NKG2A ligand, HLA-E.

“The HLA-E NKG2A diad shuts down NK cells and tumor-infiltrating CD8-positive T-cells,” he explained, adding that “the concept behind the antibody is that by blocking the interaction of the receptor for the ligand you can reduce this inhibitory signaling by NK cells and thereby unleash their ability to target tumor.”

Cetuximab is an established and approved EGFR inhibitor for the treatment of patients with head and neck SCC who progress after platinum-based chemotherapy. It has been associated with a 13% response rate.

“The therapeutic hypothesis is that dual targeting with these two antibodies will allow us to realize greater antitumor activity in head and neck cancer than is seen with cetuximab alone,” he said, later adding that “the combination of monalizumab and cetuximab results in early, deep, and durable responses in patients with squamous cell cancer of the head and neck ... and the activity indeed is higher than cetuximab alone, compared with historical data.”

Additionally, the safety is acceptable, and preliminary translational analyses do show some immunological proof-of-concept – mainly that infiltration of the tumor stroma with NK and CD8-positive T cells is correlated with response, he said.

“Importantly, this study is continuing to enroll patients, and taking account of the ever-changing landscape in the treatment of patients with advanced cancer, we are going to enroll another 40 patients, except this time we will require them to be platinum, as well as PD-1 antibody exposed. These patients still represent an enormous unmet medical need.

“We think these results do warrant further development of the combo of monalizumab and cetuximab in patients with advanced SCC of the head and neck,” he concluded.

Dr. Cohen reported receiving consulting fees and/or research funding from Cantargia, Celldex, Genocea, Innate, HEAT, Kyntherapeutics, Merck, Takeda Macrogenics, and Tmunity.

SOURCE: Cohen R et al. SITC 2018, Abstract 051.

WASHINGTON – Dual-antibody targeting with the novel immune checkpoint inhibitor monalizumab combined with the epidermal growth factor–receptor (EGFR) inhibitor cetuximab is safe and associated with deep and durable responses in patients with recurrent or metastatic squamous cell carcinoma (SCC) of the head and neck, according to data from an ongoing cohort expansion study.

As of Aug. 21, 2018, the primary study endpoint of overall response rate in 40 evaluable patients enrolled in the single-arm, nonrandomized phase 1/2 study was 27.5%, Roger Cohen, MD, reported at the annual meeting of the Society for Immunotherapy of Cancer.

There were 11 confirmed responses, including 1 complete response and 10 partial responses at a median follow-up of 8 months, said Dr. Cohen, a professor of medicine at the Hospital of the University of Pennsylvania and director of clinical research at the Abramson Cancer Center, Philadelphia.

Median progression-free survival and overall survival were 5.0 months and 10.3 months, respectively.

“We observed responses in patients who were naive to immunotherapy, as well as patients who had received and progressed after immunotherapy. We observed responses in patients who were platinum resistant, and we also saw responses in [human papillomavirus (HPV)]–positive and –negative patients,” he said, adding that responses occurred relatively early at a median of 1.6 months, and that there was little difference between those who had and had not received prior immunotherapy with programmed death-1 (PD-1) antibodies.

A number of the responses, as well as the stable diseases, were durable for “a considerable period of time.” The median duration of response was 5.6 months, he said.

Study participants were mainly middle-aged men with recurrent or metastatic HPV-positive or -negative advanced disease and “decent” performance status. They received monalizumab at a dose of 10 mg/kg every 2 weeks plus cetuximab at the labeled loading dose of 400 mg/m² once weekly then 250 mg/m² once weekly. All had progressed after prior platinum-based chemotherapy and had no more than two prior lines of therapy in the recurrent/metastatic setting; 17 (43%) had prior anti–programmed death-ligand 1 (PD-L1) therapy, 5 (13%) had prior cetuximab, but none of those patients were cetuximab resistant.

They were treated until disease progression or unacceptable toxicity and were assessed every 8 weeks for response per Response Evaluation Criteria in Solid Tumors (RECIST) criteria, he said.

This treatment combination was shown in the phase 1 portion of the study to have a favorable safety profile, and the safety profile was confirmed in this expansion cohort; adverse events related to the combination were dominated by EGFR antibody–related side effects in the skin, as well as hypomagnesemia. Most adverse events associated with monalizumab were grade 1-2.

“Serious adverse events are in the single digits,” Dr. Cohen said.

Monalizumab is a first-in-class humanized immunoglobulin-G4 monoclonal antibody against the human natural killer group 2A (NKG2A), which is the receptor for the NKG2A ligand, HLA-E.

“The HLA-E NKG2A diad shuts down NK cells and tumor-infiltrating CD8-positive T-cells,” he explained, adding that “the concept behind the antibody is that by blocking the interaction of the receptor for the ligand you can reduce this inhibitory signaling by NK cells and thereby unleash their ability to target tumor.”

Cetuximab is an established and approved EGFR inhibitor for the treatment of patients with head and neck SCC who progress after platinum-based chemotherapy. It has been associated with a 13% response rate.

“The therapeutic hypothesis is that dual targeting with these two antibodies will allow us to realize greater antitumor activity in head and neck cancer than is seen with cetuximab alone,” he said, later adding that “the combination of monalizumab and cetuximab results in early, deep, and durable responses in patients with squamous cell cancer of the head and neck ... and the activity indeed is higher than cetuximab alone, compared with historical data.”

Additionally, the safety is acceptable, and preliminary translational analyses do show some immunological proof-of-concept – mainly that infiltration of the tumor stroma with NK and CD8-positive T cells is correlated with response, he said.

“Importantly, this study is continuing to enroll patients, and taking account of the ever-changing landscape in the treatment of patients with advanced cancer, we are going to enroll another 40 patients, except this time we will require them to be platinum, as well as PD-1 antibody exposed. These patients still represent an enormous unmet medical need.

“We think these results do warrant further development of the combo of monalizumab and cetuximab in patients with advanced SCC of the head and neck,” he concluded.

Dr. Cohen reported receiving consulting fees and/or research funding from Cantargia, Celldex, Genocea, Innate, HEAT, Kyntherapeutics, Merck, Takeda Macrogenics, and Tmunity.

SOURCE: Cohen R et al. SITC 2018, Abstract 051.

WASHINGTON, D.C. – Combined treatment with mocetinostat and durvalumab shows clinical activity with manageable side effects in patients with metastatic non–small cell lung cancer (mNSCLC) – including patients who progressed on prior checkpoint inhibitor therapy (CIT), according to preliminary findings from a phase 2 trial.

Of 29 evaluable patients who progressed on prior checkpoint blockade, 12 had “some degree of tumor regression” and 5 achieved a confirmed partial response, Manish Patel, DO, reported at the annual meeting of the Society for Immunotherapy of Cancer.

“Some of these responses were quite durable. The longest response ... was a little over 1 year,” said Dr. Patel, of the University of Minnesota Masonic Cancer Center, Minneapolis.

Several patients continue to show objective responses, and the initial estimate of response duration is a median of more than 5 months, he added.


Of note, no differences have been seen to date with respect to clinical benefit in patients who did and did not have prior clinical benefit on checkpoint blockade, Dr. Patel said.

Overall, the combination was very well tolerated. The most common adverse events were fatigue, nausea, and diarrhea, with more than 10% of patients experiencing grade 3 or higher fatigue.

“Otherwise the toxicities were relatively minor,” he said, noting, however, that 8% of patients had cardiac events during the study, including atrial fibrillation, pericardial effusion, and a few cases of pericardial tamponade.

Such effects have been described in prior mocetinostat monotherapy trials, and all patients in the current study underwent pretreatment echocardiograms and did not have evidence of pericardial effusion at the start.

“So I think this is likely to be related to mocetinostat,” Dr. Patel said.

Mocetinostat is a spectrum-selective class I and class IV histone deacetylase inhibitor with multiple potential immunomodulatory features.

For example, the agent induces major histocompatibility complex Class I and Class II expression on tumor cells, enhances the function of T effector cells, and decreases the function of immunosuppressive cell subsets, including regulatory T cells and myeloid derived suppressor cells, Dr. Patel noted.

“It was hypothesized that because of these pleiotropic immune-supportive effects, that the combination of mocetinostat and checkpoint blockade might be a successful strategy for patients with non–small cell lung cancer,” he said.

In phase 1, doses of 50 mg, 70 mg, or 90 mg given three times weekly in combination with 1,500 mg of durvalumab were studied in patients with advanced solid tumors. Based on the safety data from that phase of the study, the recommended phase 2 dose of mocetinostat was 70 mg three times weekly with 1,500 mg of durvalumab on day 1 of each 28-day cycle.

Study subjects were patients with mNSCLC who had received at least one platinum-based doublet and whose most recent treatment prior to enrollment was with a checkpoint inhibitor, or who were immunotherapy naive.

The findings show promising clinical efficacy and safety, and enrollment in the study, which began in June 2016, is currently ongoing in the United States, he said.

Dr. Patel is an advisory board member for Nektar Therapeutics and has received research funding from Merck.

SOURCE: Patel M et al. SITC 2018, Abstract 027.

WASHINGTON, D.C. – Combined treatment with mocetinostat and durvalumab shows clinical activity with manageable side effects in patients with metastatic non–small cell lung cancer (mNSCLC) – including patients who progressed on prior checkpoint inhibitor therapy (CIT), according to preliminary findings from a phase 2 trial.

Of 29 evaluable patients who progressed on prior checkpoint blockade, 12 had “some degree of tumor regression” and 5 achieved a confirmed partial response, Manish Patel, DO, reported at the annual meeting of the Society for Immunotherapy of Cancer.

“Some of these responses were quite durable. The longest response ... was a little over 1 year,” said Dr. Patel, of the University of Minnesota Masonic Cancer Center, Minneapolis.

Several patients continue to show objective responses, and the initial estimate of response duration is a median of more than 5 months, he added.


Of note, no differences have been seen to date with respect to clinical benefit in patients who did and did not have prior clinical benefit on checkpoint blockade, Dr. Patel said.

Overall, the combination was very well tolerated. The most common adverse events were fatigue, nausea, and diarrhea, with more than 10% of patients experiencing grade 3 or higher fatigue.

“Otherwise the toxicities were relatively minor,” he said, noting, however, that 8% of patients had cardiac events during the study, including atrial fibrillation, pericardial effusion, and a few cases of pericardial tamponade.

Such effects have been described in prior mocetinostat monotherapy trials, and all patients in the current study underwent pretreatment echocardiograms and did not have evidence of pericardial effusion at the start.

“So I think this is likely to be related to mocetinostat,” Dr. Patel said.

Mocetinostat is a spectrum-selective class I and class IV histone deacetylase inhibitor with multiple potential immunomodulatory features.

For example, the agent induces major histocompatibility complex Class I and Class II expression on tumor cells, enhances the function of T effector cells, and decreases the function of immunosuppressive cell subsets, including regulatory T cells and myeloid derived suppressor cells, Dr. Patel noted.

“It was hypothesized that because of these pleiotropic immune-supportive effects, that the combination of mocetinostat and checkpoint blockade might be a successful strategy for patients with non–small cell lung cancer,” he said.

In phase 1, doses of 50 mg, 70 mg, or 90 mg given three times weekly in combination with 1,500 mg of durvalumab were studied in patients with advanced solid tumors. Based on the safety data from that phase of the study, the recommended phase 2 dose of mocetinostat was 70 mg three times weekly with 1,500 mg of durvalumab on day 1 of each 28-day cycle.

Study subjects were patients with mNSCLC who had received at least one platinum-based doublet and whose most recent treatment prior to enrollment was with a checkpoint inhibitor, or who were immunotherapy naive.

The findings show promising clinical efficacy and safety, and enrollment in the study, which began in June 2016, is currently ongoing in the United States, he said.

Dr. Patel is an advisory board member for Nektar Therapeutics and has received research funding from Merck.

SOURCE: Patel M et al. SITC 2018, Abstract 027.

WASHINGTON, D.C. – Combined treatment with mocetinostat and durvalumab shows clinical activity with manageable side effects in patients with metastatic non–small cell lung cancer (mNSCLC) – including patients who progressed on prior checkpoint inhibitor therapy (CIT), according to preliminary findings from a phase 2 trial.

Of 29 evaluable patients who progressed on prior checkpoint blockade, 12 had “some degree of tumor regression” and 5 achieved a confirmed partial response, Manish Patel, DO, reported at the annual meeting of the Society for Immunotherapy of Cancer.

“Some of these responses were quite durable. The longest response ... was a little over 1 year,” said Dr. Patel, of the University of Minnesota Masonic Cancer Center, Minneapolis.

Several patients continue to show objective responses, and the initial estimate of response duration is a median of more than 5 months, he added.


Of note, no differences have been seen to date with respect to clinical benefit in patients who did and did not have prior clinical benefit on checkpoint blockade, Dr. Patel said.

Overall, the combination was very well tolerated. The most common adverse events were fatigue, nausea, and diarrhea, with more than 10% of patients experiencing grade 3 or higher fatigue.

“Otherwise the toxicities were relatively minor,” he said, noting, however, that 8% of patients had cardiac events during the study, including atrial fibrillation, pericardial effusion, and a few cases of pericardial tamponade.

Such effects have been described in prior mocetinostat monotherapy trials, and all patients in the current study underwent pretreatment echocardiograms and did not have evidence of pericardial effusion at the start.

“So I think this is likely to be related to mocetinostat,” Dr. Patel said.

Mocetinostat is a spectrum-selective class I and class IV histone deacetylase inhibitor with multiple potential immunomodulatory features.

For example, the agent induces major histocompatibility complex Class I and Class II expression on tumor cells, enhances the function of T effector cells, and decreases the function of immunosuppressive cell subsets, including regulatory T cells and myeloid derived suppressor cells, Dr. Patel noted.

“It was hypothesized that because of these pleiotropic immune-supportive effects, that the combination of mocetinostat and checkpoint blockade might be a successful strategy for patients with non–small cell lung cancer,” he said.

In phase 1, doses of 50 mg, 70 mg, or 90 mg given three times weekly in combination with 1,500 mg of durvalumab were studied in patients with advanced solid tumors. Based on the safety data from that phase of the study, the recommended phase 2 dose of mocetinostat was 70 mg three times weekly with 1,500 mg of durvalumab on day 1 of each 28-day cycle.

Study subjects were patients with mNSCLC who had received at least one platinum-based doublet and whose most recent treatment prior to enrollment was with a checkpoint inhibitor, or who were immunotherapy naive.

The findings show promising clinical efficacy and safety, and enrollment in the study, which began in June 2016, is currently ongoing in the United States, he said.

Dr. Patel is an advisory board member for Nektar Therapeutics and has received research funding from Merck.

SOURCE: Patel M et al. SITC 2018, Abstract 027.

WASHINGTON – Adding pembrolizumab to weekly low-dose, cisplatin-based chemoradiotherapy shows promise for the treatment of locally advanced, human papillomavirus–associated head and neck squamous cell carcinoma, according to Steven F. Powell, MD.

Sharon Worcester/MDedge News

Of 34 patients with a mean age of 59 years and stage III-IVb disease enrolled as part of an expansion cohort following a prior study demonstrating the safety of the regimen, 85% had a complete response (CR) at a median follow-up of 21 months based on imaging or salvage surgery, and an additional 2 patients had no clinical evidence of disease, Dr. Powell reported in a late-breaking oral abstract session at the annual meeting of the Society for Immunotherapy of Cancer.

About 80% of the patients had intermediate-risk disease, which is “higher risk than your standard HPV-related cancers,” said Dr. Powell of Sanford Cancer Center, Sioux Falls, S.D.

“On posttreatment imaging ... we showed a 62% complete response rate based on [RECIST 1.1 CT criteria], with 11 patients having a partial response and 2 felt to have a partial response based on CT imaging. Looking at Hopkins criteria [for PET scans] alone – 78% of our patients had a complete response,” he said.

Of the patients with a partial response based on either criteria, 11 were negative for disease on PET and 1 that was positive based on Hopkins criteria underwent neck dissection and had only inflammatory tissue; these 12 patients were also considered to have had a CR.

Additionally, of the two patients with progressive disease, one had a positive PET scan, but all biopsies were negative for ongoing disease, thus that patient was also considered to have a CR, for the overall CR rate of 85%, Dr. Powell said.

Two of the four other patients with a partial response were found at surgery to have “nothing to biopsy or resect,” so it was felt that they had a complete response clinically, and the remaining two had partial responses locoregionally and had residual disease, including residual disease at the primary site in one patient, and nodal disease in one patient.

It is important to consider the challenges of PET imaging in this study, he noted, explaining that in one patient with progressive disease, a posttreatment PET appeared to show bone and dermal metastases, but biopsies of all the areas showed that those were granulomatous disease – most likely sarcoidosis that was not present prior to the treatment.

“This ended up resolving over a year and the PET scan became negative, so I think this highlights that as we move into the curative intent setting we need to be very careful that with PET scanning we need to confirm with biopsy [in patients treated with immuno-oncology] therapies,” Dr. Powell said.

As for survival, the early data are “very encouraging,” with only one patient progressing to date (progression-free survival, 97.1%), but he cautioned that follow-up is “still only 23 months.”

The patient who progressed developed distant metastases and died from their disease, he said.

Treatment in this study included 40 mg/m² of cisplatin weekly (six planned doses), 200 mg of pembrolizumab every 3 weeks (eight planned doses) and radiation therapy at 2 Gy once daily for 35 fractions (total of 70 Gy). The primary efficacy endpoint was complete response at 100 days after completion of chemoradiotherapy (CRT).

“Looking at safety ... we did not see any new safety signals. We had two dose discontinuations due to immune-related adverse events, which resolved on their own without therapy. Two patients stopped early due to protocol reasons,” Dr. Powell said, noting that the discontinuation rate was comparable with that seen in pembrolizumab monotherapy studies.

Standard therapy compliance was also good, with the chemotherapy goal dose reached in 88% of patients. The CRT dose was reached in all patients with no major delays in treatment.

“So adding CRT did not impact the safety of giving standard therapy,” he said.

Enrollment in this ongoing study was completed as of August, and data for the HPV-negative cohort should be available sometime in 2019. Several correlative research projects are also underway, he said.

The findings thus far show that pembrolizumab can be safely given with CRT in both HPV-positive and HPV-negative disease, with “encouraging response and progression-free survival in predominantly higher-risk patients,” Dr. Powell said.

“It is important to know that PET may pose challenges as we move into big phase 3, randomized trials, and I would strongly recommend biopsy to confirm PET findings,” he said, adding that it will be “interesting to see how this pans out in high-risk disease.

“I’m hopeful that our correlative research will help guide how we time therapy and how we move ahead in this field,” he said.

The Merck Investigator Studies Program provided grant support for this study. Dr. Powell has received research funding (to his institution) from Bristol-Myers Squibb, Genentech, Incyte, Merck, Novartis, and Pfizer.

WASHINGTON – Adding pembrolizumab to weekly low-dose, cisplatin-based chemoradiotherapy shows promise for the treatment of locally advanced, human papillomavirus–associated head and neck squamous cell carcinoma, according to Steven F. Powell, MD.

Sharon Worcester/MDedge News

Of 34 patients with a mean age of 59 years and stage III-IVb disease enrolled as part of an expansion cohort following a prior study demonstrating the safety of the regimen, 85% had a complete response (CR) at a median follow-up of 21 months based on imaging or salvage surgery, and an additional 2 patients had no clinical evidence of disease, Dr. Powell reported in a late-breaking oral abstract session at the annual meeting of the Society for Immunotherapy of Cancer.

About 80% of the patients had intermediate-risk disease, which is “higher risk than your standard HPV-related cancers,” said Dr. Powell of Sanford Cancer Center, Sioux Falls, S.D.

“On posttreatment imaging ... we showed a 62% complete response rate based on [RECIST 1.1 CT criteria], with 11 patients having a partial response and 2 felt to have a partial response based on CT imaging. Looking at Hopkins criteria [for PET scans] alone – 78% of our patients had a complete response,” he said.

Of the patients with a partial response based on either criteria, 11 were negative for disease on PET and 1 that was positive based on Hopkins criteria underwent neck dissection and had only inflammatory tissue; these 12 patients were also considered to have had a CR.

Additionally, of the two patients with progressive disease, one had a positive PET scan, but all biopsies were negative for ongoing disease, thus that patient was also considered to have a CR, for the overall CR rate of 85%, Dr. Powell said.

Two of the four other patients with a partial response were found at surgery to have “nothing to biopsy or resect,” so it was felt that they had a complete response clinically, and the remaining two had partial responses locoregionally and had residual disease, including residual disease at the primary site in one patient, and nodal disease in one patient.

It is important to consider the challenges of PET imaging in this study, he noted, explaining that in one patient with progressive disease, a posttreatment PET appeared to show bone and dermal metastases, but biopsies of all the areas showed that those were granulomatous disease – most likely sarcoidosis that was not present prior to the treatment.

“This ended up resolving over a year and the PET scan became negative, so I think this highlights that as we move into the curative intent setting we need to be very careful that with PET scanning we need to confirm with biopsy [in patients treated with immuno-oncology] therapies,” Dr. Powell said.

As for survival, the early data are “very encouraging,” with only one patient progressing to date (progression-free survival, 97.1%), but he cautioned that follow-up is “still only 23 months.”

The patient who progressed developed distant metastases and died from their disease, he said.

Treatment in this study included 40 mg/m² of cisplatin weekly (six planned doses), 200 mg of pembrolizumab every 3 weeks (eight planned doses) and radiation therapy at 2 Gy once daily for 35 fractions (total of 70 Gy). The primary efficacy endpoint was complete response at 100 days after completion of chemoradiotherapy (CRT).

“Looking at safety ... we did not see any new safety signals. We had two dose discontinuations due to immune-related adverse events, which resolved on their own without therapy. Two patients stopped early due to protocol reasons,” Dr. Powell said, noting that the discontinuation rate was comparable with that seen in pembrolizumab monotherapy studies.

Standard therapy compliance was also good, with the chemotherapy goal dose reached in 88% of patients. The CRT dose was reached in all patients with no major delays in treatment.

“So adding CRT did not impact the safety of giving standard therapy,” he said.

Enrollment in this ongoing study was completed as of August, and data for the HPV-negative cohort should be available sometime in 2019. Several correlative research projects are also underway, he said.

The findings thus far show that pembrolizumab can be safely given with CRT in both HPV-positive and HPV-negative disease, with “encouraging response and progression-free survival in predominantly higher-risk patients,” Dr. Powell said.

“It is important to know that PET may pose challenges as we move into big phase 3, randomized trials, and I would strongly recommend biopsy to confirm PET findings,” he said, adding that it will be “interesting to see how this pans out in high-risk disease.

“I’m hopeful that our correlative research will help guide how we time therapy and how we move ahead in this field,” he said.

The Merck Investigator Studies Program provided grant support for this study. Dr. Powell has received research funding (to his institution) from Bristol-Myers Squibb, Genentech, Incyte, Merck, Novartis, and Pfizer.

WASHINGTON – Adding pembrolizumab to weekly low-dose, cisplatin-based chemoradiotherapy shows promise for the treatment of locally advanced, human papillomavirus–associated head and neck squamous cell carcinoma, according to Steven F. Powell, MD.

Sharon Worcester/MDedge News

Of 34 patients with a mean age of 59 years and stage III-IVb disease enrolled as part of an expansion cohort following a prior study demonstrating the safety of the regimen, 85% had a complete response (CR) at a median follow-up of 21 months based on imaging or salvage surgery, and an additional 2 patients had no clinical evidence of disease, Dr. Powell reported in a late-breaking oral abstract session at the annual meeting of the Society for Immunotherapy of Cancer.

About 80% of the patients had intermediate-risk disease, which is “higher risk than your standard HPV-related cancers,” said Dr. Powell of Sanford Cancer Center, Sioux Falls, S.D.

“On posttreatment imaging ... we showed a 62% complete response rate based on [RECIST 1.1 CT criteria], with 11 patients having a partial response and 2 felt to have a partial response based on CT imaging. Looking at Hopkins criteria [for PET scans] alone – 78% of our patients had a complete response,” he said.

Of the patients with a partial response based on either criteria, 11 were negative for disease on PET and 1 that was positive based on Hopkins criteria underwent neck dissection and had only inflammatory tissue; these 12 patients were also considered to have had a CR.

Additionally, of the two patients with progressive disease, one had a positive PET scan, but all biopsies were negative for ongoing disease, thus that patient was also considered to have a CR, for the overall CR rate of 85%, Dr. Powell said.

Two of the four other patients with a partial response were found at surgery to have “nothing to biopsy or resect,” so it was felt that they had a complete response clinically, and the remaining two had partial responses locoregionally and had residual disease, including residual disease at the primary site in one patient, and nodal disease in one patient.

It is important to consider the challenges of PET imaging in this study, he noted, explaining that in one patient with progressive disease, a posttreatment PET appeared to show bone and dermal metastases, but biopsies of all the areas showed that those were granulomatous disease – most likely sarcoidosis that was not present prior to the treatment.

“This ended up resolving over a year and the PET scan became negative, so I think this highlights that as we move into the curative intent setting we need to be very careful that with PET scanning we need to confirm with biopsy [in patients treated with immuno-oncology] therapies,” Dr. Powell said.

As for survival, the early data are “very encouraging,” with only one patient progressing to date (progression-free survival, 97.1%), but he cautioned that follow-up is “still only 23 months.”

The patient who progressed developed distant metastases and died from their disease, he said.

Treatment in this study included 40 mg/m² of cisplatin weekly (six planned doses), 200 mg of pembrolizumab every 3 weeks (eight planned doses) and radiation therapy at 2 Gy once daily for 35 fractions (total of 70 Gy). The primary efficacy endpoint was complete response at 100 days after completion of chemoradiotherapy (CRT).

“Looking at safety ... we did not see any new safety signals. We had two dose discontinuations due to immune-related adverse events, which resolved on their own without therapy. Two patients stopped early due to protocol reasons,” Dr. Powell said, noting that the discontinuation rate was comparable with that seen in pembrolizumab monotherapy studies.

Standard therapy compliance was also good, with the chemotherapy goal dose reached in 88% of patients. The CRT dose was reached in all patients with no major delays in treatment.

“So adding CRT did not impact the safety of giving standard therapy,” he said.

Enrollment in this ongoing study was completed as of August, and data for the HPV-negative cohort should be available sometime in 2019. Several correlative research projects are also underway, he said.

The findings thus far show that pembrolizumab can be safely given with CRT in both HPV-positive and HPV-negative disease, with “encouraging response and progression-free survival in predominantly higher-risk patients,” Dr. Powell said.

“It is important to know that PET may pose challenges as we move into big phase 3, randomized trials, and I would strongly recommend biopsy to confirm PET findings,” he said, adding that it will be “interesting to see how this pans out in high-risk disease.

“I’m hopeful that our correlative research will help guide how we time therapy and how we move ahead in this field,” he said.

The Merck Investigator Studies Program provided grant support for this study. Dr. Powell has received research funding (to his institution) from Bristol-Myers Squibb, Genentech, Incyte, Merck, Novartis, and Pfizer.

WASHINGTON – Fecal microbiota transplantation (FMT) shows promise for the treatment of refractory immune checkpoint inhibitor–associated colitis, according to Yinghong Wang, MD.

In two patients who developed severe, refractory, immune-mediated colitis (IMC), FMT led to recovery, Dr. Wang of M.D. Anderson Cancer Center, Houston, reported at the annual meeting of the Society for Immunotherapy of Cancer.

Patient 1 was a woman with renal cell cancer who developed grade 2+ IMC within 1 month of initiation of treatment with combined ipilimumab and nivolumab. Infectious etiology was ruled out, and her symptoms and ulcers persisted despite 3 months of treatment with corticosteroids, two doses of infliximab, and one dose of vedolizumab.

A single FMT delivered via colonoscopy led to complete symptom resolution within 10 days, and a repeat colonoscopy showed “very nice healing of inflammation and ulcers,” Dr. Wang said.

Patient 2 was a man with prostate cancer who developed grade 2+ IMC 3 months after receiving two doses of ipilimumab. Infectious etiologies were ruled out, and like patient 1, his symptoms and mucosal ulcerations persisted despite 5 months of immunosuppression with corticosteroids, two doses of infliximab, and three doses of vedolizumab. He underwent two FMTs via colonoscopy.

“The first fecal transplant achieved partial response, and the second fecal transplant achieved complete clinical response, and this remission was sustained for a total of 8 months,” Dr. Wang said.

Immune checkpoint inhibitor–related IMC is typically treated with immunosuppressive therapy that is associated with significant morbidity, including a possible adverse impact on the antitumor effects of checkpoint inhibitors, Dr. Wang said.

However, studies have suggested that “the microbiome in healthy people potentially plays a very important and synergistic role for tumor regression in combination with immunotherapy,” and animal models also suggest that patients who develop IMC have differential bacterial signatures in their gut microbiome, she said.

“Based on that preliminary information, we performed fecal transplant as a compassionate treatment for cases refractory to all immunosuppression in June 2017 at M.D. Anderson,” she said.

Stool microbiome analyses showed successful engraftment of donor microbiome in recipient stool samples, and microbiome taxonomy showed increases in specific Escherichia species that “we think potentially play a role in this colitis recovery,” she said.

“Fecal transplant is safe and effective based on our preliminary study,” she said, adding that restoration of a healthy microbiome seems to reverse IMC. “Future large-scale studies are needed to evaluate this finding.”

Dr. Wang reported having no disclosures.

SOURCE: Wang Y et al. SITC 2018, Abstract P194.

WASHINGTON – Fecal microbiota transplantation (FMT) shows promise for the treatment of refractory immune checkpoint inhibitor–associated colitis, according to Yinghong Wang, MD.

In two patients who developed severe, refractory, immune-mediated colitis (IMC), FMT led to recovery, Dr. Wang of M.D. Anderson Cancer Center, Houston, reported at the annual meeting of the Society for Immunotherapy of Cancer.

Patient 1 was a woman with renal cell cancer who developed grade 2+ IMC within 1 month of initiation of treatment with combined ipilimumab and nivolumab. Infectious etiology was ruled out, and her symptoms and ulcers persisted despite 3 months of treatment with corticosteroids, two doses of infliximab, and one dose of vedolizumab.

A single FMT delivered via colonoscopy led to complete symptom resolution within 10 days, and a repeat colonoscopy showed “very nice healing of inflammation and ulcers,” Dr. Wang said.

Patient 2 was a man with prostate cancer who developed grade 2+ IMC 3 months after receiving two doses of ipilimumab. Infectious etiologies were ruled out, and like patient 1, his symptoms and mucosal ulcerations persisted despite 5 months of immunosuppression with corticosteroids, two doses of infliximab, and three doses of vedolizumab. He underwent two FMTs via colonoscopy.

“The first fecal transplant achieved partial response, and the second fecal transplant achieved complete clinical response, and this remission was sustained for a total of 8 months,” Dr. Wang said.

Immune checkpoint inhibitor–related IMC is typically treated with immunosuppressive therapy that is associated with significant morbidity, including a possible adverse impact on the antitumor effects of checkpoint inhibitors, Dr. Wang said.

However, studies have suggested that “the microbiome in healthy people potentially plays a very important and synergistic role for tumor regression in combination with immunotherapy,” and animal models also suggest that patients who develop IMC have differential bacterial signatures in their gut microbiome, she said.

“Based on that preliminary information, we performed fecal transplant as a compassionate treatment for cases refractory to all immunosuppression in June 2017 at M.D. Anderson,” she said.

Stool microbiome analyses showed successful engraftment of donor microbiome in recipient stool samples, and microbiome taxonomy showed increases in specific Escherichia species that “we think potentially play a role in this colitis recovery,” she said.

“Fecal transplant is safe and effective based on our preliminary study,” she said, adding that restoration of a healthy microbiome seems to reverse IMC. “Future large-scale studies are needed to evaluate this finding.”

Dr. Wang reported having no disclosures.

SOURCE: Wang Y et al. SITC 2018, Abstract P194.

WASHINGTON – Fecal microbiota transplantation (FMT) shows promise for the treatment of refractory immune checkpoint inhibitor–associated colitis, according to Yinghong Wang, MD.

In two patients who developed severe, refractory, immune-mediated colitis (IMC), FMT led to recovery, Dr. Wang of M.D. Anderson Cancer Center, Houston, reported at the annual meeting of the Society for Immunotherapy of Cancer.

Patient 1 was a woman with renal cell cancer who developed grade 2+ IMC within 1 month of initiation of treatment with combined ipilimumab and nivolumab. Infectious etiology was ruled out, and her symptoms and ulcers persisted despite 3 months of treatment with corticosteroids, two doses of infliximab, and one dose of vedolizumab.

A single FMT delivered via colonoscopy led to complete symptom resolution within 10 days, and a repeat colonoscopy showed “very nice healing of inflammation and ulcers,” Dr. Wang said.

Patient 2 was a man with prostate cancer who developed grade 2+ IMC 3 months after receiving two doses of ipilimumab. Infectious etiologies were ruled out, and like patient 1, his symptoms and mucosal ulcerations persisted despite 5 months of immunosuppression with corticosteroids, two doses of infliximab, and three doses of vedolizumab. He underwent two FMTs via colonoscopy.

“The first fecal transplant achieved partial response, and the second fecal transplant achieved complete clinical response, and this remission was sustained for a total of 8 months,” Dr. Wang said.

Immune checkpoint inhibitor–related IMC is typically treated with immunosuppressive therapy that is associated with significant morbidity, including a possible adverse impact on the antitumor effects of checkpoint inhibitors, Dr. Wang said.

However, studies have suggested that “the microbiome in healthy people potentially plays a very important and synergistic role for tumor regression in combination with immunotherapy,” and animal models also suggest that patients who develop IMC have differential bacterial signatures in their gut microbiome, she said.

“Based on that preliminary information, we performed fecal transplant as a compassionate treatment for cases refractory to all immunosuppression in June 2017 at M.D. Anderson,” she said.

Stool microbiome analyses showed successful engraftment of donor microbiome in recipient stool samples, and microbiome taxonomy showed increases in specific Escherichia species that “we think potentially play a role in this colitis recovery,” she said.

“Fecal transplant is safe and effective based on our preliminary study,” she said, adding that restoration of a healthy microbiome seems to reverse IMC. “Future large-scale studies are needed to evaluate this finding.”

Dr. Wang reported having no disclosures.

SOURCE: Wang Y et al. SITC 2018, Abstract P194.