Ramucirumab Added to Gemcitabine Extends Survival in Previously Treated Malignant Pleural Mesothelioma

Following front-line standard chemotherapy, the combination of ramucirumab (Cyramza) and gemcitabine improved overall survival (OS) in patients with malignant pleural mesothelioma, according to results of the phase 2 RAMES clinical trial.¹

The findings, which were published in The Lancet Oncology, also showed that OS benefit was observed regardless of histological subtype and outcomes seen with frontline platinum-based chemotherapy plus pemetrexed. Ramucirumab plus gemcitabine also demonstrated a favorable safety profile.

“There is a substantial unmet need for new therapies in pretreated malignant pleural mesothelioma. The results of the RAMES study show that the addition of ramucirumab to gemcitabine can provide a notable improvement in overall survival versus gemcitabine alone, suggesting that this combination could be a novel, well-tolerated, and active treatment option in patients with malignant pleural mesothelioma who have progressed on first-line chemotherapy with pemetrexed and platinum,” wrote the study authors led by Carmine Pinto, MD.

Treatment with platinum-based chemotherapy in combination with pemetrexed has been standard of care for patients with MPM that is unresectable since 2004. The survival benefit of frontline combination immunotherapy was first demonstrated in the phase 3 CheckMate 743 (NCT02899299) clinical trial in which frontline nivolumab (Opdivo) plus ipilimumab (Yervoy) led to a significant and clinically meaningful improvement in OS compared with standard-of-care chemotherapy in patients with unresectable MPM.² Later, in the phase 3 CONFIRM study, the co-primary end points of improved OS and progression-free survival (PFS) were met with nivolumab compared with placebo in patients with relapsed disease.³ Further, VEGF inhibitors have been tested in different studies after first-line chemotherapy led investigators to believe that the use of ramucirumab may offer benefit in the second-line setting.¹

RAMES was a multicenter, randomized, double-blind, placebo-controlled, randomized, phase 2 trial conducted in 26 hospitals with the goal of determining the safety and efficacy of ramucirumab and gemcitabine as second-line treatment for advanced MPM. The primary end point of the study is OS, and the secondary end points are PFS, incidence of treatment-emergent adverse events, (AEs) objective response rate (ORR), disease control rate (DCR), predictive molecular markers, and quality of life.

Those eligible for the study were patients who were at least 18 years old with a histologically confirmed disease, a documented disease progression during or after frontline standard chemotherapy, measurable disease per RECIST v1.1, an ECOG performance status of 0 to 2, and adequate bone marrow function.

A total of 165 patients were enrolled in the study and all patients were randomized 1:1 to received either ramucirumab with gemcitabine or gemcitabine and placebo. At baseline, the ramucirumab arm had a median age of 69 years (range, 45-81) with 61% of patients being aged 70 or younger. The majority of patients were male (74%), had an ECOG performance status of 0 (63%), had a histological subtype of epithelioid disease (85%), and had progressed on front-line treatment in less than 6 months (59%). Baseline characteristics were similar in the gemcitabine/placebo arm.

At a median follow-up of 21.9 months (interquartile range, 17.7-28.5), the median OS observed with ramucirumab plus gemcitabine was 13.8 months (70% CI, 12.7-14.4) compared with 7.5 months (505% CI, 6.9-8.9) in the gemcitabine and placebo arm (HR, 0.71; 70% CI, 0.59-0.85; unstratified log-rank test P =.028). At 6 months, the OS rate was 76.0 (70% CI, 70.6%-80.5%) with the addition of ramucirumab compared with 56.5% (70% CI, 50.4%-62.1%) with gemcitabine alone. The 12-month OS observed was 63.9% (70% CI, 57.9%-69.2%) in the experimental arm compared with 33.9% (70% CI, 28.3%-39.5%) in the control arm.

Prolonged PFS was also observed with the addition of ramucirumab to gemcitabine in the study. The median PFS was 6.4 months (70% C, 5.5-7.6) compared with 3.3 months (70% CI, 3.0-3.9) with gemcitabine and placebo (HR, 0.79; 70% CI, 0.66-0.94; un-stratified log-rank test P =.082).

In terms of response to treatment, the ORR in the experimental arm was 6% (95% CI, 2%-14%) versus 10% (95% CI, 4%-19%) in the control arm. No patients in either arm had a complete response, but 65% of the ramucirumab/gemcitabine arm versus 10% of the gemcitabine/placebo arm had a partial response. The DCR achieved with the experimental combination was 73% (70% CI, 66%-78%) compared with 52% (70% CI, 46%-58%). The median DOR observed was 8.4 months (range, 4.2-11.5) with ramucirumab and gemcitabine versus 5.4 months (range, 2.1-17.0) in the gemcitabine and placebo arm.

The most common grade1/2 adverse events (AEs) observed in the experimental arm versus the control arm were neutropenia (14% vs 11%, respectively) and anemia (19% vs 5%). Neutropenia was also the most common grade 3 AEs in both arms occurring in 16% of the ramucirumab-containing arm compared with 11% of the gemcitabine and placebo arm.

Based on the study findings, Pinto et al wrote: “In this new scenario, the combination of gemcitabine plus ramucirumab warrants exploration in a further prospective phase 3 trial stratified according to patient clinical and pathological features and previous treatments, including immune checkpoint inhibitors and antiangiogenics.”

_References:

_{1. Pinto C, Zucali A, Pagano M, et al. Gemcitabine with or without ramucirumab as second-line treatment for malignant pleural mesothelioma (RAMES): a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol. Published online September 6, 2021. doi: 10.1016/S1470-2045(21)00404-6}

_{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 Oncol. 2021;397(10272): P375-386. doi: 10.1016/S0140-6736(20)32714-8}

_{3. Fennell D, Ottensmeier C, Califano R, et al. PS01.11 Nivolumab versus placebo in relapsed malignant mesothelioma: The CONFIRM phase 3 trial. J Thorac Oncol. 2021;16(3): S62.doi: 10.1016/j.jtho.2021.01.323}