The FDA approval of pembrolizumab for patients with TMB >10 mut/Mb: was it a wise decision? No

There are 12 reasons why the US FDA's approval of pembrolizumab for patients with ≥10 mutations/megabase (mut/Mb) progressing on one prior line without satisfactory alternatives is an unwise decision.1.There is nothing logical about the cut off of 10 mut/Mb. The underlying data from KEYNOTE-158 suggest the cut off is arbitrary and capricious. Below 10 mut/Mb, pembrolizumab's response rate (RR) is 6.7%. From 10 to 13 mut/Mb, the RR is 12.5%, and above 13 mut/Mb, the RR is 37%1Food and Drug AdministrationHighlights of prescribing information: KEYTRUDA.https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/125514s068lbl.pdfGoogle Scholar (numerator/denominators not reported). The current approval sanctions a cut point (10 mut/Mb) that does not separate responders from non-responders. Moreover, tumor mutational burden (TMB), so far, has failed to show predictive value for overall survival across cancers.2Addeo A. Banna G.L. Weiss G.J. Tumor mutation burden—from hopes to doubts.JAMA Oncol. 2019; 5: 934-935Crossref PubMed Scopus (46) Google Scholar, 3Hellmann M.D. Paz-Ares L. Bernabe Caro R. et al.Nivolumab plus ipilimumab in advanced non-small-cell lung cancer.N Engl J Med. 2019; 381: 2020-2031Crossref PubMed Scopus (574) Google Scholar, 4Iams W.T. Porter J. Horn L. Immunotherapeutic approaches for small-cell lung cancer.Nat Rev Clin Oncol. 2020; 17: 300-312Crossref PubMed Scopus (50) Google Scholar2.We do not know if patients live longer or better. The goal of cancer drugs is improving overall survival, quality of life or both. Given that the approval for pembrolizumab for TMB >10 mut/Mb lacks a control arm, we do not know if that is achieved. RR is a poor surrogate for survival,5Haslam A. Hey S.P. Gill J. Prasad V. A systematic review of trial-level meta-analyses measuring the strength of association between surrogate end-points and overall survival in oncology.Eur J Cancer. 2019; 106: 196-211Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar and several PD-1/PD-L1 Ab (including pembrolizumab) drug approvals were made on the basis of RRs in uncontrolled studies, but later failed to improve survival in randomized trials.6Gill J. Prasad V. A reality check of the accelerated approval of immune-checkpoint inhibitors.Nat Rev Clin Oncol. 2019; 16: 656-658Crossref PubMed Scopus (12) Google Scholar Caution and randomized trials are warranted.3.Patients who want survival benefits are not satisfied, nor are patients happy with responses. Patients have different appetites for risk and uncertainty.7Tao D. Schott S. Prasad V. The tradeoff of cancer drug regulatory policy: faster approvals for one means less knowledge for another.Am J Med. 2019; 132: e509-e511Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar Some desire randomized trials assessing survival gains, while others may be happy with evidence of responses. Here, there is no proof of survival or quality-of-life benefit. Alternatively, if one thinks responses are sufficient, one must explain why 12.5% is a permitted chance to take, while 6.7% is not. Remember, the FDA did not approve Pembrolizumab for patients with <10mut/Mb, despite 6.7% having responses. Neither patients wanting better evidence nor those tolerant of risk will be satisfied with this approval.4.The cut off has fallen from prior publications, which means more prescriptions and more profits. TMB in KEYNOTE-158 was provided by Foundation Medicine's assay, which was approved as a companion diagnostic.8Center for Drug Evaluation and ResearchFDA approves pembrolizumab for adults and children with TMB-H solid tumors. FDA.https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-pembrolizumab-adults-and-children-tmb-h-solid-tumorsDate: June 17, 2020Date accessed: June 29, 2020Google Scholar Until recently, a cut off of >20 mut/Mb had been used in reports by this company as ‘high TMB,’ where it was associated with a 46% RR9Goodman A.M. Kato S. Bazhenova L. et al.Tumor mutational burden as an independent predictor of response to immunotherapy in diverse cancers.Mol Cancer Ther. 2017; 16: 2598-2608Crossref PubMed Scopus (855) Google Scholar for PD-1/PD-L1 drugs. Lowering the cut off to 10 mut/Mb means a lower RR, but more prescriptions.5.Overall survival was longer in the TMB-low cohort, i.e. where the drug was not approved. The median overall survival for patients with <10 mut/Mb was 13.0 months (95% CI, 11.5–14.6) while it was 11.7 months (95% CI, 8.2–19.1) among patients with TMB ≥10 mut/mb. Landmark analyses support this paradox—survival is longer where the drug was not approved. Although these cohorts are not randomly generated and covariate imbalance may exist, this finding raises concern that the cut point is irrational and does not denote a group with clear long-term benefit.6.The data supporting drug approval are weaker than you think. The FDA excludes patients with microsatelite instability (MSI)-high from their calculation of TMB RRs for good reason. We already have an approval for pembrolizumab in MSI-high tumors. Now, we want to know the RR in microsatelite stable (MSS)/TMB-high tumors. However, bizarrely, the FDA does not extend this logic to tumor types that already have PD-1 or PD-L1 Ab approvals. Specifically, the three most common cancers—small cell lung cancer [34 patients (pts)], cervical cancer (16 pts), and endometrial cancer (15 pts) account for 64% of 102 patients for which approval is based, but all three cancers already have approvals for pembrolizumab as a single agent or in combination.10Center for Drug Evaluation and ResearchFDA approves pembrolizumab for advanced cervical cancer with disease progression during or after chemotherapy. FDA.https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-advanced-cervical-cancer-disease-progression-during-or-after-chemotherapyDate: February 9, 2019Date accessed: June 30, 2020Google Scholar, 11Office of the FDA CommissionerFDA takes first action under new international collaboration with Australia and Canada designed to provide a framework for concurrent review of cancer therapies, approving treatment for patients with endometrial carcinoma. FDA.https://www.fda.gov/news-events/press-announcements/fda-takes-first-action-under-new-international-collaboration-australia-and-canada-designed-provideDate: March 24, 2020Date accessed: June 30, 2020Google Scholar, 12Antonia S.J. López-Martin J.A. Bendell J. et al.Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (CheckMate 032): a multicentre, open-label, phase 1/2 trial.Lancet Oncol. 2016; 17: 883-895Abstract Full Text Full Text PDF PubMed Scopus (720) Google Scholar, 13Center for Drug Evaluation and ResearchFDA approves pembrolizumab for metastatic small cell lung cancer. FDA.https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-metastatic-small-cell-lung-cancerDate: December 20, 2019Date accessed: June 30, 2020Google Scholar Just 37 pts (with anal, vulvar, neuroendocrine, salivary, and thyroid mesothelioma) and 8 responses support the use of TMB among cancers where it is not used. These data are insufficient to sanction widespread use of a costly medication.7.We know nothing about prostate cancer, for instance. No patients with prostate cancer >10 mut/Mb are included in data supporting approval, but ∼5% of prostate cancer meets this threshold.14Chung J.H. Dewal N. Sokol E. et al.Prospective comprehensive genomic profiling of primary and metastatic prostate tumors.JCO Precis Oncol. 2019; : 1-23Google Scholar Roughly one in three such patients are MSS, and some will be treated based on this approval. Yet, there are no data documenting the RR for these patients. The TMB approval ensures unproven extrapolations to tumors for which no data has been provided.8.An agnostic approval, but tumor seems to matter. The sample size is too small to rule in or rule out a meaningful interaction by tissue. Notably, the RR ranges from 0/1 (0%) in mesothelioma to 1/14 (7%) in anal cancer up to 2/2 for thyroid cancer (100%), among cancers without prior pembrolizumab approval. Much larger samples are needed to prove or disprove that all tissues respond similarly at the same TMB score.15Prasad V. Kaestner V. Mailankody S. Cancer drugs approved based on biomarkers and not tumor type—FDA approval of pembrolizumab for mismatch repair-deficient solid cancers.JAMA Oncol. 2018; 4: 157-158Crossref PubMed Scopus (57) Google Scholar9.Low regulatory standards did not considerably speed this drug to market. A common argument from those who favor the use of uncontrolled, surrogate endpoint studies for drug approvals is that it ‘speeds drugs to market.’ This claim is overstated. In an analysis of 188 approvals, Chen et al. find that the acceptance of surrogate endpoints speeds drugs to market by 11 months against a background of 7.3 years of drug development, and this diminishes in later lines of therapies.16Chen E.Y. Joshi S.K. Tran A. Prasad V. Estimation of study time reduction using surrogate end points rather than overall survival in oncology clinical trials.JAMA Intern Med. 2019; 179: 642-647Crossref PubMed Scopus (33) Google Scholar In the current approval 50% of responders have been followed for >24 months. This time—spent documenting duration of response—could instead have been spent on running randomized trials and assessing survival.10.Costs matter. Pembrolizumab earned 11.9 billion dollars in 2019, and is priced variably throughout the world.17MerckMerck announces fourth-quarter and full-year 2019 financial results.https://investors.merck.com/news/press-release-details/2020/Merck-Announces-Fourth-Quarter-and-Full-Year-2019-Financial-Results/default.aspxDate accessed: June 29, 2020Google Scholar Given the crushing price of cancer medicines,18Prasad V. De Jesús K. Mailankody S. The high price of anticancer drugs: origins, implications, barriers, solutions.Nat Rev Clin Oncol. 2017; 14: 381-390Crossref PubMed Scopus (136) Google Scholar society has an obligation to know if those dollars are a wise use of health care resources. We simply do not know that here.11.Accurate cost effectiveness cannot be calculated until you study efficacy. The simple fact is many countries will not pay for this approval until it has been shown to be cost effective. Those calculations cannot be reliably carried out based on retrospective uncontrolled studies documenting response rate. We need prospective randomized trials to quantify survival gains (or decrements) to know (i) is this drug effective and (ii) is it cost effective over alternatives.12.Patients and oncologists do not just want options, they want good options. Some physicians praise every drug approval—no matter how toxic or how low the RR—as ‘providing another option’. However, this attitude confuses options with good options. We want good options—drugs that improve outcomes beyond available therapies. If one merely desires unfettered choice, one should lobby for the FDA and EMA to be dissolved. In fact, a world without drug regulation would have the most options. However, life would be poor, nasty, brutish, and short. For these 12 reasons, the approval of pembrolizumab for tumors with >10 mut/Mb after one prior line of therapy is unwise. This work was funded by Arnold Ventures (no grant number).

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