New Options Spark Sequencing and Biomarker Trials in Mesothelioma

Anne S. Tsao, MD

Now that a new standard of care has been established in frontline mesothelioma, clinical trials are needed to evaluate optimal sequencing with checkpoint inhibitors in the salvage setting and determine whether biomarkers of response to immunotherapy could further tailor treatment to individual patients, said Anne S. Tsao, MD, during a virtual presentation at the 18th Annual Winter Lung Cancer Conference, a program hosted by the Physicians Education Resource® (PER®), LCC.

Nivolumab/Ipilimumab Marks a New Frontline Standard for Patients With Mesothelioma

Mesothelioma is a complex disease that has a latency period of 20 to 50 years from the time of environmental exposure, with the main causative agent being asbestos, explained Tsao. The primary sites of disease include the pleura, peritoneum, testicle, and pericardium. Additionally, 3 main histologic subtypes can arise, including epithelioid, biphasic, and sarcomatoid.

Historically, mesothelioma was largely chemotherapy resistant, but combinations proved to be more effective, and a current standard of care in the United States is cisplatin plus pemetrexed (Alimta). Then, bevacizumab (Avastin) was added to the combination after demonstrating improved overall survival (OS) compared with cisplatin/pemetrexed alone across all evaluable subpopulations with unresectable malignant pleural mesothelioma in the phase 3 MAPS trial.¹

“[Chemotherapy plus bevacizumab] is not currently FDA approved, but is commonly used in the United States, as well as various places in Europe and Asia,” explained Tsao, a professor, section chief, and program chair of the Department of Thoracic/Head and Neck Medical Oncology in the Division of Cancer Medicine, as well as the director of the Department of Mesothelioma Program at The University of Texas MD Anderson Cancer Center.

In 2020, a new standard of care was introduced to the frontline setting with the findings of the phase 3 CheckMate-743 trial. The study showed an improvement in OS and progression-free survival (PFS) with the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) versus cisplatin or carboplatin plus pemetrexed in patients with unresectable pleural mesothelioma.²

At a median follow up of 29.7 months, the median OS was 18.1 months with nivolumab/ipilimumab versus 14.1 months with chemotherapy (HR, 0.74; 95% CI, 0.60-0.91; P = .002). The 2-year OS rates were 41% and 27%, respectively, and the 2-year PFS rates were 16% and 7%, respectively.

The OS and PFS was improved with the immunotherapy combination, irrespective of disease histology; however, patients with non-epithelioid mesothelioma (25% of the total population) derived a greater OS benefit (HR, 0.47; 95% CI, 0.35-0.63) compared with the epithelioid subgroup (HR, 0.93; 95% CI, 0.68-1.28).

“If a patient has biphasic or sarcomatoid [disease], we need to consider giving them ipilimumab and nivolumab in the frontline setting,” said Tsao. “The magnitude of benefit from CheckMate-743 was significant, and we do see remarkable responses with high duration of response [with the immunotherapy combination].”

When broken down by PD-L1 expression status, which patients were not stratified for, patients with PD-L1 expression of 1% or greater appeared to derive more benefit from nivolumab/ipilimumab versus patients with a PD-L1 expression of less than 1%.

“We do need additional investigation into predictive biomarkers for immunotherapy. As of right now, we do not use biomarkers in mesothelioma to predict whether or not somebody should be receiving immunotherapy,” added Tsao.

In October 2020, the FDA approved nivolumab at 360 mg every 3 weeks plus ipilimumab at 1 mg/kg every 6 weeks for the frontline treatment of adult patients with unresectable malignant pleural mesothelioma, according to findings from a prespecified interim analysis of the CheckMate-743 trial.³

Ongoing Studies Set the Stage for Additional Frontline Advances

Multiple studies are ongoing to identify additional combination regimens that confer activity in frontline mesothelioma, Tsao said.

The randomized phase 3 DREAMR3 trial (NCT04334759) is evaluating the first-line combination of durvalumab (Imfinzi) plus cisplatin and pemetrexed followed by durvalumab maintenance compared with cisplatin/pemetrexed alone followed by observation in patients with advanced pleural mesothelioma.⁴

“The goal of this study is to see whether we could have another new standard of care and potentially even predict and identify characteristics that might tell us which patients should be receiving chemotherapy and durvalumab as opposed to chemotherapy alone or ipilimumab plus nivolumab,” said Tsao.

The study is building off findings from the phase 2 DREAM trial in which the addition of durvalumab to chemotherapy demonstrated a 6-month PFS rate of 57% and a 48% response rate.⁵ Additionally, the PrE0505 trial reported a 12-month OS rate of 70.4% with the combination in patients with malignant pleural mesothelioma.⁶

Additionally, the ongoing phase 3 BEAT-Meso study (NCT03762018) is evaluating the addition of atezolizumab (Tecentriq) to carboplatin/pemetrexed/bevacizumab versus carboplatin/pemetrexed/bevacizumab alone in patients with unresectable malignant pleural mesothelioma.⁷

Finally, the ongoing phase 2/3 CCTG IFCT trial (NCT02784171) is evaluating the addition of pembrolizumab (Keytruda) to cisplatin plus pemetrexed versus cisplatin plus pemetrexed alone in patients with unresectable malignant pleural mesothelioma.⁸

Immunotherapy Makes Waves in the Salvage Setting, Though Sequencing Trials are Needed

Currently, no standard, FDA-approved, salvage options are available for patients with mesothelioma. Chemotherapy regimens with limited benefit include pemetrexed if it has not been administered as frontline therapy, gemcitabine, vinorelbine, or clinical trials.

Additional options have been evaluated in clinical trials with the goal of introducing other modalities, such as immunotherapy, to the salvage setting.

For example, in patients who progressed on prior platinum/pemetrexed chemotherapy, findings from the phase 3 PROMISE-meso trial showed that pembrolizumab demonstrated similar PFS and OS compared with gemcitabine or vinorelbine and improved overall response rate ([ORR]; 22% with pembrolizumab versus 6% with chemotherapy).⁹

Additionally, the phase 3 CONFIRM trial showed that nivolumab improved OS and PFS compared with placebo in patients with mesothelioma.¹⁰ The results, which were presented during the International Association for the Study of Lung Cancer 2020 World Conference on Lung Cancer, showed no correlation between nivolumab’s activity and PD-L1 status by immunohistochemistry.

“In the United States, we would never do a placebo-controlled trial in the salvage setting,” said Tsao. “[However,] CONFIRM tells us, scientifically, that we need to do sequencing trials because if we are giving checkpoint inhibitor combination therapy frontline, we don’t know precisely whether patients will benefit by getting chemotherapy with or without immunotherapy after, and how we should be sequencing this.”

During the 2020 ASCO Virtual Scientific Program, findings from the phase 2 RAMES trial demonstrated an improvement in OS with gemcitabine plus ramucirumab (Cyramza) versus gemcitabine plus placebo in patients with malignant pleural mesothelioma who progressed on first-line platinum/pemetrexed chemotherapy.¹¹

The 12-month OS rate was 56.5% with ramucirumab versus 33.9% with placebo. Additionally, the median duration of response was 8.4 months and 5.4 months, respectively. The disease control rates were 72.50% and 51.86%, respectively.

“Gemcitabine and ramucirumab may be better than gemcitabine alone in salvage mesothelioma, but this potential survival benefit needs to be weighed against the toxicity of ramucirumab. [The investigators] did see some hypertension and thromboembolism, which is typical of antiangiogenic agents,” Tsao said.

Multiple agents are under investigation for use in the salvage setting of mesothelioma, including TKIs, PARP inhibitors, CAR T-cell therapies, mesothelin inhibitors, dendritic cell vaccines, mTOR inhibitors, and CDK4/6 inhibitors, among others.

Additionally, a number of combination regimens with immunotherapy are being evaluated in ongoing clinical trials to evaluate their efficacy in the salvage setting.

Notably, although standard of care practices are not currently influenced by genetics, BAP1 germline mutations, as well as other investigational markers, may play a significant role in treatment selection as more clinical data emerge, concluded Tsao.

References

1. Zalcman G, Mazieres J, Margery J, et al. Bevacizumab for newly diagnosed pleural mesothelioma in the Mesothelioma Avastin Cisplatin Pemetrexed Study (MAPS): a randomised, controlled, open-label, phase 3 trial. Lancet. 2016;387(10026):1405-1414. doi:10.1016/S0140-6736(15)01238-6

2. Baas P, Scherpereel A, Nowak AK, et al. First-line nivolumab plus ipilimumab in unresectable malignant pleural mesothelioma (CheckMate 743): a multicentre, randomised, open-label, phase 3 trial. Lancet. 2021;397(10272):375-386. doi:10.1016/S0140-6736(20)32714-8

3. U.S. Food and Drug Administration approves Opdivo (nivolumab) + Yervoy (ipilimumab) as the first and only immunotherapy treatment for previously untreated unresectable malignant pleural mesothelioma. Bristol Myers Squibb. October 2, 2020. Accessed February 7, 2021. https://bit.ly/2Sn2t9e.

4. DuRvalumab With chEmotherapy as first line treAtment in advanced pleural mesothelioma (DREAM3R). ClinicalTrials.gov. Posted April 6, 2020. Updated February 5, 2021. Accessed February 7, 2021. https://clinicaltrials.gov/ct2/show/NCT04334759.

5. Nowak AK, Lesterhuis WJ, Kok PS, et al. Durvalumab with first-line chemotherapy in previously untreated malignant pleural mesothelioma (DREAM): a multicentre, single-arm, phase 2 trial with a safety run-in. Lancet Oncol. 2020;21(9):1213-1223. doi:10.1016/S1470-2045(20)30462-9

6. Forde PM, Sun Z, Anagnostou V, et al. PrE0505: phase II multicenter study of anti-PD-L1, durvalumab, in combination with cisplatin and pemetrexed for the first-line treatment of unresectable malignant pleural mesothelioma (MPM)—a PrECOG LLC study. J Clin Oncol. 2020;38(suppl 15):9003-9003. doi:10.1200/JCO.2020.38.15_suppl.9003

7. BEAT-meso: bevacizumab and atezolizumab in malignant pleural mesothelioma (BEAT-meso). ClinicalTrials.gov. Posted December 3, 2018. Updated November 30, 2020. Accessed February 7, 2021. https://clinicaltrials.gov/ct2/show/NCT03762018.

8. Pembrolizumab in patients with advanced malignant pleural mesothelioma. ClinicalTrials.gov. Posted May 26, 2016. Updated January 7, 2021. Accessed February 7, 2021. https://clinicaltrials.gov/ct2/show/NCT02784171

9. Popat S, Curioni-Fontecedro A. Dafni U, et al. A multicentre randomised phase III trial comparing pembrolizumab versus single-agent chemotherapy for advanced pre-treated malignant pleural mesothelioma: the European Thoracic Oncology Platform (ETOP 9-15) PROMISE-meso trial. Ann Oncol. 2020;31(12):1734-1745. doi:10.1016/j.annonc.2020.09.009

10. Fennell D, Ottensmeier C, Califano R, et al. Nivolumab versus placebo in relapsed malignant mesothelioma: preliminary results from the CONFIRM phase 3 trial. Presented at: International Association for the Study of Lung Cancer 2020 World Conference on Lung Cancer; January 28-31, 2021; Virtual. Abstract PS01.11.

11. Pagano M, Ceresoli GL, Zucali PA, et al. Randomized phase II study on gemcitabine with or without ramucirumab as second-line treatment for advanced malignant pleural mesothelioma (MPM): results of Italian Rames Study. J Clin Oncol. 2020;38(suppl 15):9004-9004. doi:10.1200/JCO.2020.38.15_suppl.9004