Thoracic Leaders Examine Novel Treatment Options in Mesothelioma

Joshua M. Bauml, MD

In a special OncLive video program, The Board, Joshua M. Bauml, MD, assistant professor of medicine, Perelman School of Medicine, University of Pennsylvania, led a discussion regarding key abstracts that were presented during the 2020 ASCO Virtual Scientific Program in mesothelioma.

Bauml was joined by:

• Paul Bunn, MD: Distinguished Professor of Medicine-Medical Oncology, James Dudley Chair in Cancer Research, University of Colorado School of Medicine
• Stephen Liu, MD: associate professor of medicine, Division of Hematology and Oncology, Georgetown University Medical Center
• Gilberto De Lima Lopes, MD: associate professor of clinical oncology and associate director of global oncology, Sylvester Comprehensive Cancer Center, University of Miami Health System
• Sandip P. Patel, MD: associate professor of medicine, Moores Cancer Center, University of California San Diego Health
• Jonathan W. Riess, MD, MS: associate professor of medicine, Division of Hematology and Oncology, University of California Davis Comprehensive Cancer Center,
• Mark A. Socinski, MD: executive medical director, AdventHealth Cancer Center
• Viola W. Zhu, MD, PhD: medical oncologist/hematologist, Chao Family Comprehensive Cancer Center, University of California, Irvine
• David R. Spigel, MD: chief scientific officer, director, Lung Cancer Research Program, principal investigator, Sarah Cancer Research Institute

During the discussion, these experts discussed 2 key trials presented during the Virtual Scientific Program, whether immunotherapy has a place in the frontline management of patients with mesothelioma, and potential future additions to the mesothelioma landscape.

Durvalumab Combo Data Pave Way for Phase 3 Study

The results of the phase 2 PrE0505 study (NCT02899195) demonstrated promising findings with the combination of durvalumab (Imfinzi), cisplatin, and pemetrexed as first-line treatment for patients with unresectable malignant pleural mesothelioma (MPM).

Results revealed a median overall survival (OS) of 20.4 months with the regimen (95% CI, 13.0-28.5; one-sided P = .0014).¹ At 24 months, the OS rate was 44.2% (95% CI, 30.2-57.3).

Eligible patients had to have unresectable MPM, no prior therapy, an ECOG performance score (PS) of 0 or 1, and a baseline tumor specimen.

A total of 55 patients received 1120 mg of durvalumab, 500 mg/m² of pemetrexed, and 75 mg/m² of cisplatin every 3 weeks for 6 cycles. Upon stable disease (SD) or partial response (PR), patients received 1120 mg of durvalumab every 3 weeks until disease progression.

Histologic subtypes included epithelioid (n = 41), sarcomatoid (n = 7), biphasic (n = 6), and desmoplastic (n = 1). Additionally, regarding patient demographics, the majority of patients were male (n = 45), with a median age of 68 years.

The median progression-free survival (PFS) was 6.7 months, with a 10.9% PFS rate at 24 months.

Additionally, 56.4% of patients achieved a PR and 40% had SD. One patient developed progressive disease, and 1 patient discontinued treatment before the first assessment.

Regarding safety, all-grade treatment-emergent adverse effects (TEAEs) included fatigue, nausea, anemia, constipation, dyspnea, cough, decreased appetite, diarrhea, vomiting, hypomagnesemia, and rash. Grade 3/4 TRAEs included fatigue (n = 4), anemia (n = 14), decreased appetite (n = 1), and hypomagnesemia (n = 1).

Although no grade 3/4 adverse effects (AEs) of special interest were reported, grade 1/2 AEs of special interest included hypothyroidism (n = 7), rash (n = 5), pruritus (n = 3), aspartate aminotransferase (AST) elevation (n = 3), hyperthyroidism (n = 3), dermatitis (n = 2), neuropathy (n = 2), alanine aminotransferase (ALT) elevation, (n = 1), increased lipase (n = 1), and pneumonitis (n = 1).

Correlative analyses did not reveal a relationship between survival and PD-L1 status or tumor mutational burden, though additional analyses are ongoing.

Additionally, the phase 3 DREAM3R study (NCT04334759) is planned. Despite these data, the discussants were not completely sold on the idea of bringing immunotherapy into the frontline setting.

“Anecdotally, as a single agent, I’ve seen great, durable responses [with immunotherapy in mesothelioma],” said Riess. “I know the data with single-agent immunotherapy are controversial, especially in the PD-L1–high patient population. So, this is all debatable, but anecdotally, I have seen good activity.”

The experts also raised the question in the context of a recent press release announcing that a study evaluating combination of nivolumab (Opdivo) and ipilimumab (Yervoy) in the frontline setting met its OS endpoint.²

Ramucirumab Slated to Become a Second-Line Option

The Italian RAMES study³ was a randomized phase 2 trial evaluating gemcitabine with or without the monoclonal antibody ramucirumab (Cyramza) as a second-line regimen for patients with advanced MPM.

Notably, OS was 13.8 months with gemcitabine plus ramucirumab compared with 7.5 months with gemcitabine plus placebo (HR, 0.71; 95% CI, 0.59-0.85; P = .057). Moreover, at 12 months, the OS rate was 56.5% versus 33.9%, respectively.

“I am really excited about this study because I had anticipated that immunotherapy plus chemotherapy would become a first-line treatment [for patients with mesothelioma] in the future,” said Zhu, who added that she is a proponent of bringing immunotherapy up front.

The study randomized patients to receive 21-day cycles of 1000 mg/m² of intravenous (IV) gemcitabine plus placebo (n = 81) versus 10 mg/kg of IV ramucirumab (n = 80) until progressive disease or unacceptable toxicity.

Eligible patients had to have an EGOG PS between 0 and 2, a histologically confirmed diagnosis of MPM, documented progressive disease on first-line chemotherapy, among other criteria. Patients who had received more than 1 prior line of chemotherapy, VEGF inhibitor therapy, among other criteria, were excluded from the trial.

Both arms included patients with similar baseline characteristics. Patients received a median of 4 cycles of gemcitabine/placebo and 8 cycles of gemcitabine/ramucirumab.

Subgroup analyses revealed no correlation between OS and PFS with first-line chemotherapy or histology (epithelioid/non-epithelioid).

Additionally, the median duration of response was 8.4 months with ramucirumab versus 5.4 months with placebo. Disease control rates were 72.50% and 51.86%, respectively. Median PFS was 6.2 months versus 3.3 months, respectively (P = .260).

Regarding safety, grade 3 or higher AEs in the placebo arm included anemia (n = 4), neutropenia (n = 1), febrile neutropenia (n = 1), thrombocytopenia (n = 1), fatigue (n = 3), diarrhea (n = 1), and increased AST/ALT (n = 2). Comparatively, grade 3 or higher AEs in the ramucirumab arm included neutropenia (n = 3), thrombocytopenia (n = 2), nausea/vomiting (n = 1), fatigue (n = 4), and increased AST/ALT (n = 2).

Any-grade AEs of special interest included hypertension, proteinuria, bleeding, and thromboembolism, all of which were observed more frequently with ramucirumab versus placebo. Grade 3/4 proteinuria and thromboembolism were also reported in the ramucirumab arm.

From these findings, investigators concluded that ramucirumab in combination with gemcitabine offers a novel treatment option for patients with MPM in the second-line setting.

“There is not a lot out there [in the mesothelioma space],” said Liu. “If I was in a setting where I was giving gemcitabine, I would not hesitate to give gemcitabine/ramucirumab based on this study.”

However, the general consensus of The Board was that larger, phase 3 data are needed to push ramucirumab toward an FDA approval in this setting.

Looking to the future, Patel offered a potential outlook for what the treatment landscape of mesothelioma may look like.

“In 1 or 2 years, the mesothelioma space will look more like the NSCLC space, at least in the frontline setting,” said Patel. “In that sense, we would have the combination of nivolumab and ipilimumab as an option, chemotherapy plus PD-1/PD-L1 inhibitors, and then angiogenesis inhibitors plus chemotherapy with/without an immunologic, if that quadruplet comes across.”

References:

1. Forde MP, Sun Z, Anagnosto 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. doi:10.1200/JCO.2020.38.15_suppl.9003
2. Bristol Myers Squibb announces positive topline result from pivotal phase 3 trial evaluating Opdivo (nivolumab) plus Yervoy (ipilimumab) vs. chemotherapy in previously untreated malignant pleural mesothelioma. April 20, 2020. Accessed August 5, 2020. bit.ly/2XsdQje.
3. 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. doi:10.1200/JCO.2020.38.15_suppl.9004