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Although mesothelioma continues to be a very difficult disease to treat and one with a poor prognosis, new and emerging therapeutic developments hold the promise of extending survival for appropriately selected patients.
Following years of little to no movement, encouraging advances in treatment have been seen on the immunotherapy front. Immune checkpoint inhibitors have demonstrated acceptable safety and promising efficacy in the treatment of unresectable malignant pleural mesothelioma (MPM), including an overall survival advantage over standard-of-care first-line chemotherapy. Beyond systemic therapy, the development of new radiation techniques to complement current, more conservative surgical approaches is likewise encouraging, though further randomized clinical trial data is awaited to determine the potential impact on survival.
Longer survival would be good news for the estimated 3,000 individuals diagnosed with MPM each year in the United States. Overall, the outlook for patients with this rare cancer remains unfavorable, with a 5-year survival rate of about 11%, according to data from the U.S. Surveillance, Epidemiology and End Results (SEER) Program.
One factor underlying that grim survival statistic is a relative lack of investment in the development of drugs specific to rare cancers, as compared to more common malignancies, said Anne S. Tsao, MD, professor and director of the mesothelioma program at the University of Texas MD Anderson Cancer Center in Houston.
On the plus side, the wave of research for more common cancers has yielded a number of agents, including the immune checkpoint inhibitors such as nivolumab, ipilimumab, pembrolizumab, and durvalumab, that hold promise in rare tumor types as well.
“I think that mesothelioma has benefited from that, because these all are agents that have been developed for other solid tumors that are then brought into mesothelioma,” Dr. Tsao said in an interview. “So there’s always a lag time, but nevertheless, of course we are thrilled that we have additional treatment options for these patients.”
Checkpoint inhibitors
Multiple checkpoint inhibitors have received Food and Drug Administration approval for the treatment of non–small cell lung cancer (NSCLC) over the past few years. Because many mesothelioma doctors also treat NSCLC, bringing those agents into the mesothelioma sphere was not a very difficult jump, Dr. Tsao said.
Checkpoint inhibitors got a foothold in mesothelioma, much like in NSCLC, by demonstrating clear benefit in the salvage setting, according to Dr. Tsao.
Pembrolizumab, nivolumab, and avelumab were evaluated in phase 1b/2 clinical trials and real-world cohorts that demonstrated response rates of around 20%, median progression-free survival of 4 months, and median overall survival (OS) around 12 months in patients with previously treated MPM.
Although results of those early-stage studies had to be interpreted with caution, they nonetheless suggested a slight edge for these checkpoint inhibitors over historical data, according to the authors of a recent article in Cancer Treatment Reviews.1 On the basis of phase 1 and 2 data, current clinical practice guidelines from the National Comprehensive Cancer Network2 list pembrolizumab and the combination of nivolumab and ipilimumab as options for MPM patients who have received previous therapy. Phase 3 trials have also been launched, including PROMISE-meso, which is comparing pembrolizumab to single-agent chemotherapy in advanced, pretreated MPM3, and CONFIRM, which pits nivolumab against placebo in relapsed MPM.4
On the front lines
Encouraging results in previously treated MPM led to the evaluation of checkpoint inhibitors as first-line therapy. Notably, the FDA approved nivolumab given with ipilimumab for the treatment of patients with unresectable MPM in October 2020, making that combination the first immunotherapy regimen to receive an indication in this disease.
The FDA approval was based on prespecified interim analysis of CheckMate 743, a phase 3 study that included 605 patients randomly allocated to nivolumab plus ipilimumab or to placebo.
At the interim analysis, median OS was 18.1 months for nivolumab plus ipilimumab, versus just 14.1 months for placebo (hazard ratio, 0.74; 96.6% confidence interval, 0.60-0.91; P = 0.0020), according to results of the study published in the Lancet.5 The 2-year OS rate was 41% for the immunotherapy combination and 27% for placebo. Grade 3-4 treatment-related adverse events were seen in 30% of the immunotherapy-treated patients and 32% of the chemotherapy-treated patients.
The magnitude of nivolumab-ipilimumab benefit appeared to be largest among patients with non-epithelioid MPM subtypes (sarcomatoid and biphasic), owing to the inferior impact of chemotherapy in these patients, with a median OS of just 8.8 months, according to investigators.
That’s not to say that immunotherapy didn’t work for patients with epithelioid histology. The benefit of nivolumab-ipilimumab was consistent for non-epithelioid and epithelioid patient subsets, with median OS of 18.1 and 18.7 months, respectively, results of subgroup analysis showed.
According to Dr. Tsao, those results reflect the extremely poor prognosis and pressing need for effective therapy early in the course of treatment for patients with non-epithelioid histology.
“You have to get the most effective therapy into these patients as quickly as you can,” she explained. “If you can get the more effective treatment and early, then you’ll see a longer-term benefit for them.”
Role of the PD-L1 biomarker
Despite this progress, one key hurdle has been determining the role of the PD-L1 biomarker in mesothelioma. In NSCLC, PD-L1 is often used to determine which patients will benefit from immune checkpoint inhibitors. In mesothelioma, the correlations have been more elusive.
Among patients in the CheckMate 743 study treated with nivolumab plus ipilimumab, OS was not significantly different for those with PD-L1 expression levels of less than 1% and those with 1% or greater, investigators said. Moreover, PD-L1 expression wasn’t a stratification factor in the study.
“When looking at all of the studies, it appears that the checkpoint inhibitors can truly benefit a certain percentage of mesothelioma patients, but we can’t pick them out just yet,” Dr. Tsao said.
“So our recommendation is to offer [checkpoint inhibitor therapy] at some point in their treatment, whether it’s first, second, or third line,” she continued. “They can get some benefit, and even in those if you don’t get a great response, you can still get disease stabilization, which in and of itself can be highly beneficial.”
Future directions
Immune checkpoint inhibitor–based combination regimens and cellular therapy represent promising directions forward in MPM research. There are several notable phase 3 trials of checkpoint inhibitors plus chemotherapy and targeted therapy going forward, plus intriguing data emerging on the potential role of chimeric antigen receptor (CAR) T-cell therapy in this setting.
One phase 3 trial to watch is IND277, which is comparing pembrolizumab plus cisplatin/pemetrexed chemotherapy to cisplatin/pemetrexed alone; that trial has enrolled 520 participants and has an estimated primary completion date in July 2022, according to the ClinicalTrials.gov website. Another is BEAT-Meso, a comparison of atezolizumab plus bevacizumab and chemotherapy against bevacizumab and chemotherapy, which has an estimated enrollment of 400 participants and primary completion date of January 2024. A third trial of interest is DREAM3R, which compares durvalumab plus chemotherapy followed by durvalumab maintenance to standard chemotherapy followed by observation. That study should enroll 480 participants and has an estimated primary completion date of April 2025.
CAR T-cell therapy, while best known for its emerging role in the treatment of hematologic malignancies, may also have a place in mesothelioma therapy one day. In a recently published report, investigators described a first-in-human phase I study of a mesothelin-targeted CAR T-cell therapy given in combination with pembrolizumab. Among 18 MPM patients who received pembrolizumab safely, median OS from time of CAR T-cell infusion was 23.9 months and 1-year OS was 83%, according to investigators.6An OS of nearly 24 months is “very encouraging” and compares favorably with historical results with systemic therapy in this difficult-to-treat disease, said Jacques P. Fontaine, MD, a thoracic surgeon and section head of mesothelioma research and treatment center at Moffitt Cancer Center in Tampa, Fla.
“It’s huge, but you have to take into account that this [OS] is still less than 2 years,” Dr. Fontaine said in an interview. “There’s still a lot of work to be done.”
Radiotherapy making an IMPRINT
Meanwhile, new developments in the multimodality treatment of resectable MPM are progressing and have the potential to extend survival among patients who undergo lung-sparing surgery.
Less aggressive intervention is increasingly the preferred approach to surgery in this patient population. That shift is supported by studies showing that lung-sparing pleurectomy-decortication (P/D) resulted in less morbidity and potentially better survival outcomes than extrapleural pneumonectomy (EPP), according to Andreas Rimner, MD, associate attending physician and director of thoracic radiation oncology research at Memorial Sloan Kettering Cancer Center in New York.
However, it is more challenging to deliver radiotherapy safely in patients who have undergone P/D as compared with patients who have undergone EPP, according to Dr. Rimner.
“When there’s no lung in place [as in EPP], it’s pretty simple – you just treat the entire empty chest to kill any microscopic cells that may still be left behind,” he said in an interview. “But now we have a situation where both lungs are still in place, and they are very radiation sensitive, so that’s not an easy feat.”
Driven by the limitations of conventional radiation, Dr. Rimner and colleagues developed a novel technique known as hemithoracic intensity-modulated pleural radiation therapy (IMPRINT) that allows more precise application of radiotherapy.
In a phase 2 study published in 2016, IMPRINT was found to be safe, with an acceptable rate of radiation pneumonitis (30% grade 2 or 3), according to investigators.7
Subsequent studies have demonstrated encouraging clinical outcomes, including a 20.2-month median OS for IMPRINT versus 12.3 months for conventional adjuvant radiotherapy in a retrospective study of 209 patients who underwent P/D between 1975 and 2015.8 Those findings led to the development of a phase 3 trial known as NRG-LU006 that is evaluating P/D plus chemotherapy with or without adjuvant IMPRINT in an estimated 150 patients. The study has a primary endpoint of OS, and an estimated primary completion date in July 2025, according to ClinicalTrials.gov.
Dr. Rimner said he’s optimistic about the prospects of this study, particularly with recently published results of a phase 3 study in which Italian investigators demonstrated an OS benefit of IMPRINT over palliative radiation in patients with nonmetastatic MPM.9
“That’s more data and rationale that shows there is good reason to believe that we are adding something here with this radiation technique,” said Dr. Rimner.
Dr. Fontaine, the thoracic surgeon and mesothelioma research head at Moffitt Cancer Center, said he’s hoping to see a substantial impact of IMPRINT on disease-free survival (DFS) once results of NRG-LU006 are available.
“I think DFS plays a role that we’ve underestimated over the last few years for sure,” he said.
For a patient with MPM, a short DFS can be anxiety provoking and may have negative impacts on quality of life, even despite a long OS, he explained.
“In terms of your outlook on life, how many times you have to go see a doctor, and how you enjoy life, there’s a big difference between the two,” he said.
Dr. Tsao provided disclosures related to Ariad, AstraZeneca, BMS, Boehringer Ingelheim, Eli Lilly, EMD Serono, Epizyme, Genentech, Huron, Merck, Millennium, Novartis, Polaris, Roche, Seattle Genetics, SELLAS Life Sciences Group, and Takeda. Dr. Fontaine reported no relevant disclosures. Dr. Rimner reported disclosures related to Bristol-Myers Squibb, GE Healthcare, Varian Medical Systems, and Boehringer Ingelheim.
References
1. Parikh K et al. Cancer Treat Rev. 2021 Sept 1;99:102250.
2. National Comprehensive Cancer Network (NCCN) Guidelines. Malignant Pleural Mesothelioma. Version 2.2021, published 2021 Feb 16. Accessed 2021 Aug 30. https://www.nccn.org/professionals/physician_gls/pdf/mpm.pdf
3. Popat S et al. Ann Oncol. 2020;31(12):1734-45.
4. Fennell D et al. Journal of Thoracic Oncology. 2021 Mar 1;16(3):S62.
5. Baas P et al. [published correction appears in Lancet. 2021 Feb 20;397(10275):670]. Lancet. 2021 Jan 30;397(10272):375-86.
6. Adusumilli PS et al. Cancer Discov. 2021 Jul 15;candisc.0407.2021.
7. Rimner A et al. J Clin Oncol. 2016;34(23):2761-8.
8. Shaikh F et al. J Thorac Oncol. 2017;12(6):993-1000.
9. Trovo M et al. Int J Radiat Oncol Biol Phys. 2021;109(5):1368-76.
Although mesothelioma continues to be a very difficult disease to treat and one with a poor prognosis, new and emerging therapeutic developments hold the promise of extending survival for appropriately selected patients.
Following years of little to no movement, encouraging advances in treatment have been seen on the immunotherapy front. Immune checkpoint inhibitors have demonstrated acceptable safety and promising efficacy in the treatment of unresectable malignant pleural mesothelioma (MPM), including an overall survival advantage over standard-of-care first-line chemotherapy. Beyond systemic therapy, the development of new radiation techniques to complement current, more conservative surgical approaches is likewise encouraging, though further randomized clinical trial data is awaited to determine the potential impact on survival.
Longer survival would be good news for the estimated 3,000 individuals diagnosed with MPM each year in the United States. Overall, the outlook for patients with this rare cancer remains unfavorable, with a 5-year survival rate of about 11%, according to data from the U.S. Surveillance, Epidemiology and End Results (SEER) Program.
One factor underlying that grim survival statistic is a relative lack of investment in the development of drugs specific to rare cancers, as compared to more common malignancies, said Anne S. Tsao, MD, professor and director of the mesothelioma program at the University of Texas MD Anderson Cancer Center in Houston.
On the plus side, the wave of research for more common cancers has yielded a number of agents, including the immune checkpoint inhibitors such as nivolumab, ipilimumab, pembrolizumab, and durvalumab, that hold promise in rare tumor types as well.
“I think that mesothelioma has benefited from that, because these all are agents that have been developed for other solid tumors that are then brought into mesothelioma,” Dr. Tsao said in an interview. “So there’s always a lag time, but nevertheless, of course we are thrilled that we have additional treatment options for these patients.”
Checkpoint inhibitors
Multiple checkpoint inhibitors have received Food and Drug Administration approval for the treatment of non–small cell lung cancer (NSCLC) over the past few years. Because many mesothelioma doctors also treat NSCLC, bringing those agents into the mesothelioma sphere was not a very difficult jump, Dr. Tsao said.
Checkpoint inhibitors got a foothold in mesothelioma, much like in NSCLC, by demonstrating clear benefit in the salvage setting, according to Dr. Tsao.
Pembrolizumab, nivolumab, and avelumab were evaluated in phase 1b/2 clinical trials and real-world cohorts that demonstrated response rates of around 20%, median progression-free survival of 4 months, and median overall survival (OS) around 12 months in patients with previously treated MPM.
Although results of those early-stage studies had to be interpreted with caution, they nonetheless suggested a slight edge for these checkpoint inhibitors over historical data, according to the authors of a recent article in Cancer Treatment Reviews.1 On the basis of phase 1 and 2 data, current clinical practice guidelines from the National Comprehensive Cancer Network2 list pembrolizumab and the combination of nivolumab and ipilimumab as options for MPM patients who have received previous therapy. Phase 3 trials have also been launched, including PROMISE-meso, which is comparing pembrolizumab to single-agent chemotherapy in advanced, pretreated MPM3, and CONFIRM, which pits nivolumab against placebo in relapsed MPM.4
On the front lines
Encouraging results in previously treated MPM led to the evaluation of checkpoint inhibitors as first-line therapy. Notably, the FDA approved nivolumab given with ipilimumab for the treatment of patients with unresectable MPM in October 2020, making that combination the first immunotherapy regimen to receive an indication in this disease.
The FDA approval was based on prespecified interim analysis of CheckMate 743, a phase 3 study that included 605 patients randomly allocated to nivolumab plus ipilimumab or to placebo.
At the interim analysis, median OS was 18.1 months for nivolumab plus ipilimumab, versus just 14.1 months for placebo (hazard ratio, 0.74; 96.6% confidence interval, 0.60-0.91; P = 0.0020), according to results of the study published in the Lancet.5 The 2-year OS rate was 41% for the immunotherapy combination and 27% for placebo. Grade 3-4 treatment-related adverse events were seen in 30% of the immunotherapy-treated patients and 32% of the chemotherapy-treated patients.
The magnitude of nivolumab-ipilimumab benefit appeared to be largest among patients with non-epithelioid MPM subtypes (sarcomatoid and biphasic), owing to the inferior impact of chemotherapy in these patients, with a median OS of just 8.8 months, according to investigators.
That’s not to say that immunotherapy didn’t work for patients with epithelioid histology. The benefit of nivolumab-ipilimumab was consistent for non-epithelioid and epithelioid patient subsets, with median OS of 18.1 and 18.7 months, respectively, results of subgroup analysis showed.
According to Dr. Tsao, those results reflect the extremely poor prognosis and pressing need for effective therapy early in the course of treatment for patients with non-epithelioid histology.
“You have to get the most effective therapy into these patients as quickly as you can,” she explained. “If you can get the more effective treatment and early, then you’ll see a longer-term benefit for them.”
Role of the PD-L1 biomarker
Despite this progress, one key hurdle has been determining the role of the PD-L1 biomarker in mesothelioma. In NSCLC, PD-L1 is often used to determine which patients will benefit from immune checkpoint inhibitors. In mesothelioma, the correlations have been more elusive.
Among patients in the CheckMate 743 study treated with nivolumab plus ipilimumab, OS was not significantly different for those with PD-L1 expression levels of less than 1% and those with 1% or greater, investigators said. Moreover, PD-L1 expression wasn’t a stratification factor in the study.
“When looking at all of the studies, it appears that the checkpoint inhibitors can truly benefit a certain percentage of mesothelioma patients, but we can’t pick them out just yet,” Dr. Tsao said.
“So our recommendation is to offer [checkpoint inhibitor therapy] at some point in their treatment, whether it’s first, second, or third line,” she continued. “They can get some benefit, and even in those if you don’t get a great response, you can still get disease stabilization, which in and of itself can be highly beneficial.”
Future directions
Immune checkpoint inhibitor–based combination regimens and cellular therapy represent promising directions forward in MPM research. There are several notable phase 3 trials of checkpoint inhibitors plus chemotherapy and targeted therapy going forward, plus intriguing data emerging on the potential role of chimeric antigen receptor (CAR) T-cell therapy in this setting.
One phase 3 trial to watch is IND277, which is comparing pembrolizumab plus cisplatin/pemetrexed chemotherapy to cisplatin/pemetrexed alone; that trial has enrolled 520 participants and has an estimated primary completion date in July 2022, according to the ClinicalTrials.gov website. Another is BEAT-Meso, a comparison of atezolizumab plus bevacizumab and chemotherapy against bevacizumab and chemotherapy, which has an estimated enrollment of 400 participants and primary completion date of January 2024. A third trial of interest is DREAM3R, which compares durvalumab plus chemotherapy followed by durvalumab maintenance to standard chemotherapy followed by observation. That study should enroll 480 participants and has an estimated primary completion date of April 2025.
CAR T-cell therapy, while best known for its emerging role in the treatment of hematologic malignancies, may also have a place in mesothelioma therapy one day. In a recently published report, investigators described a first-in-human phase I study of a mesothelin-targeted CAR T-cell therapy given in combination with pembrolizumab. Among 18 MPM patients who received pembrolizumab safely, median OS from time of CAR T-cell infusion was 23.9 months and 1-year OS was 83%, according to investigators.6An OS of nearly 24 months is “very encouraging” and compares favorably with historical results with systemic therapy in this difficult-to-treat disease, said Jacques P. Fontaine, MD, a thoracic surgeon and section head of mesothelioma research and treatment center at Moffitt Cancer Center in Tampa, Fla.
“It’s huge, but you have to take into account that this [OS] is still less than 2 years,” Dr. Fontaine said in an interview. “There’s still a lot of work to be done.”
Radiotherapy making an IMPRINT
Meanwhile, new developments in the multimodality treatment of resectable MPM are progressing and have the potential to extend survival among patients who undergo lung-sparing surgery.
Less aggressive intervention is increasingly the preferred approach to surgery in this patient population. That shift is supported by studies showing that lung-sparing pleurectomy-decortication (P/D) resulted in less morbidity and potentially better survival outcomes than extrapleural pneumonectomy (EPP), according to Andreas Rimner, MD, associate attending physician and director of thoracic radiation oncology research at Memorial Sloan Kettering Cancer Center in New York.
However, it is more challenging to deliver radiotherapy safely in patients who have undergone P/D as compared with patients who have undergone EPP, according to Dr. Rimner.
“When there’s no lung in place [as in EPP], it’s pretty simple – you just treat the entire empty chest to kill any microscopic cells that may still be left behind,” he said in an interview. “But now we have a situation where both lungs are still in place, and they are very radiation sensitive, so that’s not an easy feat.”
Driven by the limitations of conventional radiation, Dr. Rimner and colleagues developed a novel technique known as hemithoracic intensity-modulated pleural radiation therapy (IMPRINT) that allows more precise application of radiotherapy.
In a phase 2 study published in 2016, IMPRINT was found to be safe, with an acceptable rate of radiation pneumonitis (30% grade 2 or 3), according to investigators.7
Subsequent studies have demonstrated encouraging clinical outcomes, including a 20.2-month median OS for IMPRINT versus 12.3 months for conventional adjuvant radiotherapy in a retrospective study of 209 patients who underwent P/D between 1975 and 2015.8 Those findings led to the development of a phase 3 trial known as NRG-LU006 that is evaluating P/D plus chemotherapy with or without adjuvant IMPRINT in an estimated 150 patients. The study has a primary endpoint of OS, and an estimated primary completion date in July 2025, according to ClinicalTrials.gov.
Dr. Rimner said he’s optimistic about the prospects of this study, particularly with recently published results of a phase 3 study in which Italian investigators demonstrated an OS benefit of IMPRINT over palliative radiation in patients with nonmetastatic MPM.9
“That’s more data and rationale that shows there is good reason to believe that we are adding something here with this radiation technique,” said Dr. Rimner.
Dr. Fontaine, the thoracic surgeon and mesothelioma research head at Moffitt Cancer Center, said he’s hoping to see a substantial impact of IMPRINT on disease-free survival (DFS) once results of NRG-LU006 are available.
“I think DFS plays a role that we’ve underestimated over the last few years for sure,” he said.
For a patient with MPM, a short DFS can be anxiety provoking and may have negative impacts on quality of life, even despite a long OS, he explained.
“In terms of your outlook on life, how many times you have to go see a doctor, and how you enjoy life, there’s a big difference between the two,” he said.
Dr. Tsao provided disclosures related to Ariad, AstraZeneca, BMS, Boehringer Ingelheim, Eli Lilly, EMD Serono, Epizyme, Genentech, Huron, Merck, Millennium, Novartis, Polaris, Roche, Seattle Genetics, SELLAS Life Sciences Group, and Takeda. Dr. Fontaine reported no relevant disclosures. Dr. Rimner reported disclosures related to Bristol-Myers Squibb, GE Healthcare, Varian Medical Systems, and Boehringer Ingelheim.
References
1. Parikh K et al. Cancer Treat Rev. 2021 Sept 1;99:102250.
2. National Comprehensive Cancer Network (NCCN) Guidelines. Malignant Pleural Mesothelioma. Version 2.2021, published 2021 Feb 16. Accessed 2021 Aug 30. https://www.nccn.org/professionals/physician_gls/pdf/mpm.pdf
3. Popat S et al. Ann Oncol. 2020;31(12):1734-45.
4. Fennell D et al. Journal of Thoracic Oncology. 2021 Mar 1;16(3):S62.
5. Baas P et al. [published correction appears in Lancet. 2021 Feb 20;397(10275):670]. Lancet. 2021 Jan 30;397(10272):375-86.
6. Adusumilli PS et al. Cancer Discov. 2021 Jul 15;candisc.0407.2021.
7. Rimner A et al. J Clin Oncol. 2016;34(23):2761-8.
8. Shaikh F et al. J Thorac Oncol. 2017;12(6):993-1000.
9. Trovo M et al. Int J Radiat Oncol Biol Phys. 2021;109(5):1368-76.
Although mesothelioma continues to be a very difficult disease to treat and one with a poor prognosis, new and emerging therapeutic developments hold the promise of extending survival for appropriately selected patients.
Following years of little to no movement, encouraging advances in treatment have been seen on the immunotherapy front. Immune checkpoint inhibitors have demonstrated acceptable safety and promising efficacy in the treatment of unresectable malignant pleural mesothelioma (MPM), including an overall survival advantage over standard-of-care first-line chemotherapy. Beyond systemic therapy, the development of new radiation techniques to complement current, more conservative surgical approaches is likewise encouraging, though further randomized clinical trial data is awaited to determine the potential impact on survival.
Longer survival would be good news for the estimated 3,000 individuals diagnosed with MPM each year in the United States. Overall, the outlook for patients with this rare cancer remains unfavorable, with a 5-year survival rate of about 11%, according to data from the U.S. Surveillance, Epidemiology and End Results (SEER) Program.
One factor underlying that grim survival statistic is a relative lack of investment in the development of drugs specific to rare cancers, as compared to more common malignancies, said Anne S. Tsao, MD, professor and director of the mesothelioma program at the University of Texas MD Anderson Cancer Center in Houston.
On the plus side, the wave of research for more common cancers has yielded a number of agents, including the immune checkpoint inhibitors such as nivolumab, ipilimumab, pembrolizumab, and durvalumab, that hold promise in rare tumor types as well.
“I think that mesothelioma has benefited from that, because these all are agents that have been developed for other solid tumors that are then brought into mesothelioma,” Dr. Tsao said in an interview. “So there’s always a lag time, but nevertheless, of course we are thrilled that we have additional treatment options for these patients.”
Checkpoint inhibitors
Multiple checkpoint inhibitors have received Food and Drug Administration approval for the treatment of non–small cell lung cancer (NSCLC) over the past few years. Because many mesothelioma doctors also treat NSCLC, bringing those agents into the mesothelioma sphere was not a very difficult jump, Dr. Tsao said.
Checkpoint inhibitors got a foothold in mesothelioma, much like in NSCLC, by demonstrating clear benefit in the salvage setting, according to Dr. Tsao.
Pembrolizumab, nivolumab, and avelumab were evaluated in phase 1b/2 clinical trials and real-world cohorts that demonstrated response rates of around 20%, median progression-free survival of 4 months, and median overall survival (OS) around 12 months in patients with previously treated MPM.
Although results of those early-stage studies had to be interpreted with caution, they nonetheless suggested a slight edge for these checkpoint inhibitors over historical data, according to the authors of a recent article in Cancer Treatment Reviews.1 On the basis of phase 1 and 2 data, current clinical practice guidelines from the National Comprehensive Cancer Network2 list pembrolizumab and the combination of nivolumab and ipilimumab as options for MPM patients who have received previous therapy. Phase 3 trials have also been launched, including PROMISE-meso, which is comparing pembrolizumab to single-agent chemotherapy in advanced, pretreated MPM3, and CONFIRM, which pits nivolumab against placebo in relapsed MPM.4
On the front lines
Encouraging results in previously treated MPM led to the evaluation of checkpoint inhibitors as first-line therapy. Notably, the FDA approved nivolumab given with ipilimumab for the treatment of patients with unresectable MPM in October 2020, making that combination the first immunotherapy regimen to receive an indication in this disease.
The FDA approval was based on prespecified interim analysis of CheckMate 743, a phase 3 study that included 605 patients randomly allocated to nivolumab plus ipilimumab or to placebo.
At the interim analysis, median OS was 18.1 months for nivolumab plus ipilimumab, versus just 14.1 months for placebo (hazard ratio, 0.74; 96.6% confidence interval, 0.60-0.91; P = 0.0020), according to results of the study published in the Lancet.5 The 2-year OS rate was 41% for the immunotherapy combination and 27% for placebo. Grade 3-4 treatment-related adverse events were seen in 30% of the immunotherapy-treated patients and 32% of the chemotherapy-treated patients.
The magnitude of nivolumab-ipilimumab benefit appeared to be largest among patients with non-epithelioid MPM subtypes (sarcomatoid and biphasic), owing to the inferior impact of chemotherapy in these patients, with a median OS of just 8.8 months, according to investigators.
That’s not to say that immunotherapy didn’t work for patients with epithelioid histology. The benefit of nivolumab-ipilimumab was consistent for non-epithelioid and epithelioid patient subsets, with median OS of 18.1 and 18.7 months, respectively, results of subgroup analysis showed.
According to Dr. Tsao, those results reflect the extremely poor prognosis and pressing need for effective therapy early in the course of treatment for patients with non-epithelioid histology.
“You have to get the most effective therapy into these patients as quickly as you can,” she explained. “If you can get the more effective treatment and early, then you’ll see a longer-term benefit for them.”
Role of the PD-L1 biomarker
Despite this progress, one key hurdle has been determining the role of the PD-L1 biomarker in mesothelioma. In NSCLC, PD-L1 is often used to determine which patients will benefit from immune checkpoint inhibitors. In mesothelioma, the correlations have been more elusive.
Among patients in the CheckMate 743 study treated with nivolumab plus ipilimumab, OS was not significantly different for those with PD-L1 expression levels of less than 1% and those with 1% or greater, investigators said. Moreover, PD-L1 expression wasn’t a stratification factor in the study.
“When looking at all of the studies, it appears that the checkpoint inhibitors can truly benefit a certain percentage of mesothelioma patients, but we can’t pick them out just yet,” Dr. Tsao said.
“So our recommendation is to offer [checkpoint inhibitor therapy] at some point in their treatment, whether it’s first, second, or third line,” she continued. “They can get some benefit, and even in those if you don’t get a great response, you can still get disease stabilization, which in and of itself can be highly beneficial.”
Future directions
Immune checkpoint inhibitor–based combination regimens and cellular therapy represent promising directions forward in MPM research. There are several notable phase 3 trials of checkpoint inhibitors plus chemotherapy and targeted therapy going forward, plus intriguing data emerging on the potential role of chimeric antigen receptor (CAR) T-cell therapy in this setting.
One phase 3 trial to watch is IND277, which is comparing pembrolizumab plus cisplatin/pemetrexed chemotherapy to cisplatin/pemetrexed alone; that trial has enrolled 520 participants and has an estimated primary completion date in July 2022, according to the ClinicalTrials.gov website. Another is BEAT-Meso, a comparison of atezolizumab plus bevacizumab and chemotherapy against bevacizumab and chemotherapy, which has an estimated enrollment of 400 participants and primary completion date of January 2024. A third trial of interest is DREAM3R, which compares durvalumab plus chemotherapy followed by durvalumab maintenance to standard chemotherapy followed by observation. That study should enroll 480 participants and has an estimated primary completion date of April 2025.
CAR T-cell therapy, while best known for its emerging role in the treatment of hematologic malignancies, may also have a place in mesothelioma therapy one day. In a recently published report, investigators described a first-in-human phase I study of a mesothelin-targeted CAR T-cell therapy given in combination with pembrolizumab. Among 18 MPM patients who received pembrolizumab safely, median OS from time of CAR T-cell infusion was 23.9 months and 1-year OS was 83%, according to investigators.6An OS of nearly 24 months is “very encouraging” and compares favorably with historical results with systemic therapy in this difficult-to-treat disease, said Jacques P. Fontaine, MD, a thoracic surgeon and section head of mesothelioma research and treatment center at Moffitt Cancer Center in Tampa, Fla.
“It’s huge, but you have to take into account that this [OS] is still less than 2 years,” Dr. Fontaine said in an interview. “There’s still a lot of work to be done.”
Radiotherapy making an IMPRINT
Meanwhile, new developments in the multimodality treatment of resectable MPM are progressing and have the potential to extend survival among patients who undergo lung-sparing surgery.
Less aggressive intervention is increasingly the preferred approach to surgery in this patient population. That shift is supported by studies showing that lung-sparing pleurectomy-decortication (P/D) resulted in less morbidity and potentially better survival outcomes than extrapleural pneumonectomy (EPP), according to Andreas Rimner, MD, associate attending physician and director of thoracic radiation oncology research at Memorial Sloan Kettering Cancer Center in New York.
However, it is more challenging to deliver radiotherapy safely in patients who have undergone P/D as compared with patients who have undergone EPP, according to Dr. Rimner.
“When there’s no lung in place [as in EPP], it’s pretty simple – you just treat the entire empty chest to kill any microscopic cells that may still be left behind,” he said in an interview. “But now we have a situation where both lungs are still in place, and they are very radiation sensitive, so that’s not an easy feat.”
Driven by the limitations of conventional radiation, Dr. Rimner and colleagues developed a novel technique known as hemithoracic intensity-modulated pleural radiation therapy (IMPRINT) that allows more precise application of radiotherapy.
In a phase 2 study published in 2016, IMPRINT was found to be safe, with an acceptable rate of radiation pneumonitis (30% grade 2 or 3), according to investigators.7
Subsequent studies have demonstrated encouraging clinical outcomes, including a 20.2-month median OS for IMPRINT versus 12.3 months for conventional adjuvant radiotherapy in a retrospective study of 209 patients who underwent P/D between 1975 and 2015.8 Those findings led to the development of a phase 3 trial known as NRG-LU006 that is evaluating P/D plus chemotherapy with or without adjuvant IMPRINT in an estimated 150 patients. The study has a primary endpoint of OS, and an estimated primary completion date in July 2025, according to ClinicalTrials.gov.
Dr. Rimner said he’s optimistic about the prospects of this study, particularly with recently published results of a phase 3 study in which Italian investigators demonstrated an OS benefit of IMPRINT over palliative radiation in patients with nonmetastatic MPM.9
“That’s more data and rationale that shows there is good reason to believe that we are adding something here with this radiation technique,” said Dr. Rimner.
Dr. Fontaine, the thoracic surgeon and mesothelioma research head at Moffitt Cancer Center, said he’s hoping to see a substantial impact of IMPRINT on disease-free survival (DFS) once results of NRG-LU006 are available.
“I think DFS plays a role that we’ve underestimated over the last few years for sure,” he said.
For a patient with MPM, a short DFS can be anxiety provoking and may have negative impacts on quality of life, even despite a long OS, he explained.
“In terms of your outlook on life, how many times you have to go see a doctor, and how you enjoy life, there’s a big difference between the two,” he said.
Dr. Tsao provided disclosures related to Ariad, AstraZeneca, BMS, Boehringer Ingelheim, Eli Lilly, EMD Serono, Epizyme, Genentech, Huron, Merck, Millennium, Novartis, Polaris, Roche, Seattle Genetics, SELLAS Life Sciences Group, and Takeda. Dr. Fontaine reported no relevant disclosures. Dr. Rimner reported disclosures related to Bristol-Myers Squibb, GE Healthcare, Varian Medical Systems, and Boehringer Ingelheim.
References
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2. National Comprehensive Cancer Network (NCCN) Guidelines. Malignant Pleural Mesothelioma. Version 2.2021, published 2021 Feb 16. Accessed 2021 Aug 30. https://www.nccn.org/professionals/physician_gls/pdf/mpm.pdf
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8. Shaikh F et al. J Thorac Oncol. 2017;12(6):993-1000.
9. Trovo M et al. Int J Radiat Oncol Biol Phys. 2021;109(5):1368-76.