October 2, 2020, saw the first U.S. Food and Drug Administration approval of a drug combination for malignant pleural mesothelioma in 16 years, since the combination cisplatin and pemetrexed was approved for this indication in 2004. During the intervening years, we have witnessed numerous negative clinical trials of drug combinations for this disease, mostly phase II, but also several randomized phase III trials that failed to fulfill the early promise of those regimens. The nearest we ever came to a treatment advance during those years was with the addition of bevacizumab to chemotherapy. And although the MAPS trial of cisplatin, pemetrexed, and bevacizumab was a positive study, demonstrating a modest, but statistically significant survival advantage over chemotherapy alone, this combination is not FDA approved.1
The CheckMate 743 study randomly assigned 605 participants with unresectable malignant pleural mesothelioma and no previous anticancer therapy to either nivolumab and ipilimumab for up to 2 years, or up to six cycles of combination chemotherapy with pemetrexed plus either cisplatin or carboplatin. The results showed a statistically significant improvement in the primary endpoint of OS, with the median OS of 14.1 months for patients who received chemotherapy, versus 18.1 months for those who received dual immunotherapy (HR 0.74, p = 0.002). This result was released early as the outcome of a planned interim analysis, and there is little doubt that it represents a substantial clinical advance for these patients.2
However, it is particularly important to drill down into the more nuanced results of CheckMate 743 to help us understand the drivers of this outcome. Malignant pleural mesothelioma comprises multiple histologic subtypes, the most well-recognized being epithelioid, sarcomatoid, and biphasic.3 The very poor prognosis of sarcomatoid mesothelioma, in particular, is well-recognized; with a median OS of around 7.5 months in many cohorts, sarcomatoid or non-epithelioid histology appears as a prognostic indicator in multiple prognostic systems.4 ,5 In CheckMate 743, patients with non-epithelioid histology were the outright winners in benefiting from this combination. Median OS of patients with non-epithelioid disease was 8.8 months (95% CI[7.4-10.2]) for those receiving chemotherapy versus 16.5 months (95% CI[14.9-20.5]) for those receiving dual immunotherapy (HR 0.46, 95% CI[0.31-0.69]), an extraordinary outcome that should immediately make this combination the standard of care for these patients. However, the corollary of this result is the observation that the key driver of the outcomes for the trial as a whole is this subgroup of patients. Patients with epithelioid disease did not derive a statistically significant or clinically meaningful benefit from combination immunotherapy (HR 0.86, 95% CI[0.69-1.08]), with a median OS of 18.1 months (95% CI[12.2-22.8]) for those receiving chemotherapy compared with 18.7 months (95% CI[16.9-22.0]) for those receiving dual immunotherapy.2
What is the underlying biologic driver of this result? It is likely that some patients with epithelioid disease did benefit from combination immunotherapy—but how can we identify these individuals up front? While extensive biomarker studies on CheckMate 743 samples are underway, the only information publicly available to date is an analysis of the impact of PD-L1 expression on outcomes. The data presented used a PD-L1 cut point of 1%; however, in subset analyses, the impact of PD-L1 expression on outcomes is less pronounced than the impact of the histologic subtype.2 We already know that PD-L1 expression is higher in sarcomatoid mesothelioma than in other subtypes.6 Hence, it would be more informative to delineate data from a sensitivity analysis of different PD-L1 cut points, in particular to gain some understanding of the impact of PD-L1 expression on outcomes in the epithelioid subgroup, because these are the patients for whom we will have the greatest challenge making therapeutic recommendations from this point forward.
A key take-home message from CheckMate 743 is that, although this combination of ipilumumab and nivolumab affords a spectacular advance for patients with sarcomatoid and biphasic disease, we must be a bit more measured (or nuanced) regarding outcomes for those with epithelioid disease. Those with epithelioid histology who did not achieve a therapeutic benefit experienced disease progression more rapidly on the combination of ipilimumab and nivolumab. Therefore, we must gain a better understanding of the biology of response and nonresponse, and understand how we can make more nuanced predictions as to who will most likely benefit from this combination.
How to integrate this information into the next generation of clinical trials is a major challenge. The era of studying epithelioid and non-epithelioid mesothelioma together in first-line clinical trials has probably passed. At the very least, histology needs to be a stratification factor in future phase III trials. The ATOMIC study was the first randomized phase III trial in mesothelioma to study only the non-epithelioid histologic subset, driven by a strong biologic rationale and supporting early-phase data.7 Ipilimumab and nivolumab should now be the control arm for upcoming studies in this histologic subset. Although the number of patients with mesothelioma is small, oncology treatment trials in many cancer types have moved toward identifying and treating patients with uncommon subsets of disease. This results from CheckMate 743 makes it more important than ever to obtain histologic as opposed to cytologic diagnoses in mesothelioma, to be more confident of pathologic subtype and to preserve the opportunity to examine tissue biomarkers.8
For epithelioid disease, it can be readily argued that standard chemotherapy with platinum-based agents and pemetrexed remains an acceptable control arm and standard of care. The combination of chemotherapy and immunotherapy has been a successful strategy in NSCLC and other malignancies, and in mesothelioma, because of the success of CM-743, we have a narrowing window of opportunity to test the addition of checkpoint blockade to chemotherapy in randomized clinical trials. Current clinical trials include the Canadian Cancer Trials Group study I227, as well as DREAM3R and BEAT-Meso. Results from DREAM9 and PrE0505 strongly support the possible benefits of chemotherapy plus immunotherapy in all mesothelioma subtypes. Because patients with epithelioid disease gain little benefit from ipilimumab plus nivolumab, we should be working hard to complete these clinical trials.
Finally, what are the implications of CM743 with respect to second-line treatment of mesothelioma? Experience with other cancers has shown us that single-agent checkpoint blockade is unlikely to benefit patients for whom dual immunotherapy has previously failed.10 What options do we have? Dual platinum-based chemotherapy is likely to be used in the community but unlikely to be studied systematically post immunotherapy. Can we evaluate combining single-agent checkpoint blockade with chemotherapy in the second-line setting, capitalizing on the known biologic synergy of chemotherapy and immunotherapy11 ? Is there a role for continuing checkpoint blockade at failure and adding other modalities? Does oligoprogression pose an opportunity to use radiotherapy and continue checkpoint blockade12 ? Because we are witnessing a major change in the current standard of care, it will be difficult to investigate good answers to these questions in the short term.
In conclusion, CheckMate 743 is the most important practice-changing clinical trial in mesothelioma since 2004, but the data suggest that a minority of patients gain most of the benefit. As a result, we must be careful not to slow our progress toward improving treatment for all patients with mesothelioma.
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