Thoracic oncologists have been waiting for some positive data from checkpoint inhibitors in advanced mesothelioma for some time and this may have finally come in the form of the investigator-sponsored Maps-2 phase II study, presented at Asco on Monday. The Maps-2 study, which examined Bristol-Myers Squibb's (NYSE:BMY) Opdivo with/without Yervoy in second or third-line patients showed an impressive set of survival curves that may set a new bar for combinations in this patient group.

The median overall survival for the Opdivo/Yervoy combo was not reached but the Kaplan-Meier plot suggests it will, when mature, exceed 12 months, possibly by some margin, with a median progression-free survival for the combo of 5.6 months (see table below). Such figures are considered very impressive in this extremely poor prognosis disease.

Yervoy if you do

Furthermore, survival measures for the combo exceeded single agent Opdivo in all respects, suggesting an additive benefit for the CTLA4 antibody. This was also seen as an important finding, given the disappointing outcome of the Determine trial, which examined Astrazeneca's (NYSE:AZN) CTLA4 antibody, tremelimumab, against placebo in advanced mesothelioma last year.

With 125 patients enrolled, Maps-2 was of a sufficient size to give confidence in the robustness of the data. By contrast, most studies with checkpoint inhibitors in mesothelioma have been small as well as single arm, so outcome measures could be skewed. Compounding the problem is a well recognized difficulty of determining response in a disease where the tumor is located in the lining of the lungs.

A separate study largely of Merck & Co's (NYSE:MRK) Keytruda was also presented at Asco and showed a median overall survival of 8.0 months in advanced mesothelioma. But the study is more notable for the fact it highlighted large differences in response between PD-L1 positive and especially PD-L1 high patients, relative to those with negative expression, albeit based on a small sub-set. This suggests that PD-L1 testing is going to be required in this setting.

Larger studies in mesothelioma tend to be run by co-operative groups and there are two such under way with checkpoint inhibitors: Promise-Meso with Keytruda in first-line disease and Confirm with Opdivo in the third-line setting. Both test these agents as monotherapies.

The positive outcome from Maps-2 does provides some read-across to the Checkmate-743, the only industry-sponsored phase III study in this cancer type, which examines Opdivo/Yervoy combo directly against pemetrexed/cisplatin in the first-line setting.

However, KOLs discussing the data believe that checkpoint inhibitors should be most effective when used for either first-line maintenance or as second-line agents after progression. The scientific consensus in this indication remains that patients should be treated with chemo, potentially with targeted therapy, first line.

Vargatef in first line

This was reinforced by updated survival results presented at Asco with Boehringer Ingelheim's Vargatef from the Lume-Meso phase II trial in first-line mesothelioma. This small study tested pemetrexed/cisplatin with/without Vargatef and showed a trend in overall survival and a significant advantage in terms of PFS. The magnitude of the benefit was similar to that seen with the addition of Avastin to pem/cis in the larger Maps study - run by the same French cooperative group as Maps-2 - which is currently supporting an approval application for the Roche drug.

Boehringer noted the benefit for adding Vargatef was greatest in patients with epithelioid histology, which represent the majority and may become a key target for its kinase inhibitor.

Boehringer is conducting a large phase III study, also called Lume-Meso, designed to support a registration application.

But a hotly awaited readout in mesothelioma this year is that of a large, 248-patient phase II study with Bayer's antibody-drug conjugate anetumab ravtansine in second line, which is due in November. This study is sufficiently large that, if positive, it could support a registration application.

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