On July 27, AstraZeneca (AZ) disappointed their investors and many immuno-oncology watchers with the results of their MYSTIC trial combining two immunotherapies targeting PD-L1 (durvalumab/Imfinzi) and CTLA-4 (tremelimumab) in newly diagnosed Stage-IV lung cancer patients. The AZ combination therapy failed to show a benefit compared to chemotherapy in a primary endpoint of “Progression-free Survival (PFS).” Results on the additional primary endpoint, “Overall Survival (OS),” won’t be available until sometime in the first half of 2018. Currently, only Merck’s Keytruda (pembrolizumab) is approved as a first line treatment (as a monotherapy and in combination with chemotherapy) in non-small cell lung cancer (NSCLC).
Just a few days later, the company got better news on Imfinzi when the U.S. Food and Drug Administration awarded a “breakthrough therapy” designation to the AZ drug based on positive interim results in its Phase 3 PACIFIC trial. PACIFIC is a randomized, double-blind, multicenter, placebo-controlled, clinical trial of durvalumab in patients with locally-advanced, unresectable non-small cell lung cancer (NSCLC) whose disease has not progressed following platinum-based chemotherapy and radiation. The PACIFIC patients’ disease was at an earlier stage than those patients participating in the MYSTIC trial. While AZ has not yet released results of the study, which will be presented at a future medical meeting, the PD-L1 inhibitor significantly improved progression-free survival (PFS) compared with placebo.
We think the jury is still out with respect to the success or lack thereof of the Imfinzi/tremelimumab combination. In addition, another PD-1 + CTLA-4 combination, Opdivo + Yervoy has shown promising results in first-line NSCLC. There are a number of questions yet to be answered:
- Could the combination’s lack of success in PFS be linked to the time it takes for the combination to have an effect, especially given that delayed benefit has been seen in other IO trials? That remains an open question until the data on OS becomes available.
- Could the disappointing PFS data be related to the trial design and the selectivity of patient inclusion/exclusion criteria? It is very difficult to compare results between trials of different drug combinations when such studies are differently designed and encompass different patient populations. Are trials controlling sufficient variables, both in their design and the in the selected patient population?
- Are the PD-1 / PD-L1s more different than we had previously thought? John Carroll of Endpoints reports that, according to Regeneron, PD-1 may be a much better target than PD-L1 for immuno-oncology. The two companies have been collaborating on the development of an antibody against PD-1 (REGN2810) that they are currently studying as a monotherapy for multiple cancers – including cutaneous squamous cell carcinoma (CSCC), basal cell carcinoma (BCC) and non-small cell lung cancer (NSCLC) – as well as in combination with REGN3767, another investigational immunotherapy targeting the checkpoint inhibitor LAG-3 (lymphocyte-activation gene 3). But with others, like Roche, committed to PD-L1, the jury remains out as to the relative value of the two targets.
Ultimately — and especially given the positive results to date with Imfinzi in the PACIFIC lung cancer trial — we think it’s much too early to read anything much into these initial MYSTIC trial results. Moreover, we have seen each of the various IO therapies to date failing in at least one trial while succeeding in others. Trial failures by one IO therapy have furthermore not precluded successes by others in the same indication. We look forward to seeing how this story develops over time.