Alexander M. Castellino, PhD

June 01, 2015

CHICAGO — The standard of care for mesothelioma has not changed for a decade, but it should now, say experts.

The call for change was prompted by the results showing that bevacizumab (Avastin, Genentech) added to the current standard of care (SOC) pemetrexed and cisplatin — provides significantly longer overall survival (OS) vs the SOC when used first-line in patients with malignant pleural mesothelioma.

The new data come from the French Cooperative Thoracic Intergroup (IFCT) MAPS study, reported at an oral session at the American Society of Clinical Oncology (ASCO) 2015 annual meeting.

The triplet of pemetrexed, cisplatin, and bevacizumab is a new treatment paradigm for pleural mesothelioma patients eligible for bevacizumab not amenable to curative surgery, concluded lead author Gerard Zalcman, MD. Discussing these data at a Highlights of the Day session, Natasha Leighl, MD, from Princess Margaret Cancer Centre, Toronto, Canada, said that these data were "practice changing" for patients with mesothelioma.

The last time practice changes were seen for patients with mesothelioma was over 10 years ago (in 2003) when pemetrexed added to cisplatin became the global standard of care based on data from EMPHACIS, noted Anna Nowak, PhD, of the Sir Charles Gairdner Hospital in Perth, Western Australia, who acted as discussant for the paper.

The MAPS Study

MAPS was a phase 2/3 IFCT-sponsored, open-label, multicenter study, which randomized (1:1) patients with malignant pleural mesothelioma to receive pemetrexed and cisplatin at the standard doses on day 1 every 3 weeks for six cycles (control arm: n = 225) or triplet therapy with bevacizumab, pemetrexed, and cisplatin (experimental arm: n = 223).

Bevacizumab was given at a dose of 15 mg/kg also on day 1 of each cycle for six cycles. After six cycles, patients on the experimental arm continued to receive bevacizumab alone until disease progression.

Eligibility criteria included histologically proven malignant mesothelioma not amenable to curative therapy. No crossover was allowed in the study. Phase 2 study endpoint of disease control rate at 6 months was met and reported at the ASCO 2012 Annual Meeting. Data for the phase 3 primary endpoint of OS were presented at this meeting.

The arms were well balanced for patient demographics and disease characteristics. Patients were mostly males (75%) with a median age of 65 years. Disease histology was predominantly epithelioid (80%). Approximately 75% of patients in each study arm received the six cycles of treatment.

Efficacy and Safety of the Triplet-Drug Combination

Median follow-up was 39.4 months. For the primary endpoint, median OS was significantly higher in patients on the experimental arm receiving triplet therapy (18.8 vs 16.1 months; hazard ratio [HR], 0.76; 95% confidence interval [CI], 0.61 - 0.94; P = .0126). Median progression-free survival (PFS) also followed a similar trend — significantly higher in patients on the experimental arm receiving triplet therapy (9.6 vs 7.5 months; HR, 0.61; 95% CI, 0.50 - 0.75; P < .0001).

Second-line therapy was reported for 73% of patients in the control arm and 62% of patients in the experimental arm; interestingly, 11 patients in the experimental arm received off-protocol therapy with bevacizumab.

Nonhematologic adverse events significantly higher with triplet therapy were creatinine elevations (39% vs 28%), hypertension (56% vs 1%; grade 3/4: 23% vs 0%), arterial and venous thromboembolic events (7% vs 1%; grade 3/4: 6% vs 1%), and hemorrhage (41% vs 7%).

Dr Leighl commented that there were no new emerging signals with respect to bevacizumab toxicities. In the setting of mesothelioma, the toxicities were similar to those seen in other disease settings where bevacizumab has been used.

MAPS was well designed, adequately powered, and appropriately stratified, Dr Nowak indicated. Patients enrolled had mesothelioma with a range of histologies, and bevacizumab was added on a chemotherapy backbone, which was a standard of care. Importantly, no crossover was allowed between the arms, and none occurred, she noted.

Implications for Clinical Practice

Dr Leighl indicated that adding bevacizumab to the SOC is both statistically and clinically significant, and she predicted that this trial along with previous evidence will change clinical practice. "But it is expensive and will cause financial toxicity," she added.

However, in her discussion, Dr Nowak was more circumspect. "The results of the MAPS trial were eagerly awaited," she said. With the statistically significant improvement in OS and PFS, does it constitute a new standard of care? She was cautious in endorsing it as a new standard of care, predominantly because it appeared that long-term OS may be an issue when one looked at the "tail end" of the OS curves.

In addition, although Dr Zalcman provided data indicating that quality of life was similar across the two arms, there was little information on patient symptom improvement such as pain and weight loss, Dr Nowak indicated.

"Its [triplet combination] uptake may vary with geography particularly when the data are considered in the context of health economics and effectiveness," Dr Nowak said.

"We cannot know if efficacy will translate into effectiveness," she said. Dr Nowak pointed out that because the trial was conducted in the academic setting, it may underrepresent the general population of patients with mesothelioma. In addition, racial minorities are underrepresented in the study, as are the elderly — all important considerations when translating these data to practice in the community setting.

"Regimens and doses vary from the label when introduced in the community setting particularly where carboplatin is more often used with pemetrexed," she indicated.

"Demand for a new standard of care will exist irrespective of the cost," Dr Nowak said. "It may be a new standard of care for some and not others," she added. Where central agencies make decisions on access to care as in the United Kingdom and Australia, cost-effectiveness data become important.

American Society of Clinical Oncology (ASCO) 2015 Annual Meeting: Abstract 7500. Presented May 30, 2015. Abstract

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