Controversies in Thoracic Oncology

Abstract

Over the past decade, there has been dramatic progress in the treatment of lung cancer, fueled by advancements in genomics and immunotherapy. A number of targetable oncogenes have been identified in NSCLC, starting with EGFR. There are currently seven oncogene products, ALK, BRAF, EGFR, RET, ROS1, MET, and NTRK, against which targeted kinase inhibitors are approved for use in the United States, and elsewhere. On the immunotherapy front, the programmed cell death protein 1/programmed death-ligand 1 inhibitors atezolizumab, durvalumab, nivolumab, and pembrolizumab are approved for NSCLC, and cemiplimab is under review by the U.S. Food and Drug Administration. As illustrated in Table 1, there are multiple approved agents for indications such as EGFR-mutant and ALK-rearranged NSCLC. With the other oncogene targets, there are two agents approved in most cases, and multiple other agents with potentially comparative efficacy are in clinical trials. Figure 1 is a treatment algorithm for NSCLC, illustrating the number of available choices for first-line immunotherapy in NSCLC in the United States, in addition to the numerous choices for molecularly targeted therapies described above.Table 1Targeted Therapeutic Agents for First-Line Treatment of NSCLCGeneTherapeutic AgentsALKAlectinib, brigatinib, ceritinib, crizotinib, lorlatinib, ensartinibBRAF V600EDabrafenib plus trametinib, vemurafenib, dabrafenibEGFROsimertinib, erlotinib, afatinib, gefitinib, dacomatinib, erlotinib plus ramucirumab, icotinib (PRC)MET exon 14Capmatinib, tepotinib, amivantamab, savlotinibNTRKLarotrectinib, entrectinibRETSelpercatinib, pralsetinibROS-1Crizotinib, entrectinib, ceritinib, lorlatinib, talotrectinib, brigatinib, cabozantinib, repotrectinibHER2Poziotinib, mobocertinib, DS-8201a, tarloxotinibNRGTarloxotinibNote: Bold, underlined font: approved by the U.S. FDA. Bold font: not approved but used off-label in the United States. Normal font: investigational.FDA, Food and Drug Administration; PRC, People’s Republic of China. Open table in a new tab Note: Bold, underlined font: approved by the U.S. FDA. Bold font: not approved but used off-label in the United States. Normal font: investigational. FDA, Food and Drug Administration; PRC, People’s Republic of China. A problematic situation in oncology, which is particularly amplified in thoracic oncology, is that of redundancy in clinical trials. A number of phase 3 trials have been conducted where the novel agent or combination has been compared with the old standard of care even though an approved new standard is available. An example is the first-line treatment of NSCLC, where pembrolizumab monotherapy was approved on the basis of KEYNOTE-024. The results of KEYNOTE-024 were presented at the European Society for Medical Oncology congress in late 2016, and yet a number of other programmed cell death protein 1/programmed death-ligand 1 inhibitors (atezolizumab, avelumab, durvalumab, nivolumab, and cemiplimab), activated or continued clinical trials for the same indication with comparisons against chemotherapy. Clearly from the purely scientific standpoint, the critical question to be answered would be if these agents were equivalent or superior to single-agent pembrolizumab in the same patient population. Because of secular trends in supportive care and differences in patient populations in different trials, it is generally agreed that comparisons of results across different phase 3 trials are not valid, and this practice is discouraged. Given this background, the lack of head-to-head comparisons of novel agents has produced a plethora of possible regimens, with little guidance on the optimal regimen, for health care providers. In other situations, accelerated approval has been based on surrogate end points such as progression-free survival, with no overall survival data available. Where survival data are presented, they tend to be immature, and not helpful in decision-making. There are, therefore, currently a number of situations where controversies exist regarding the ideal therapeutic choice for a given indication in lung cancer, particularly in NSCLC. Starting with this issue of the journal, we are introducing a new series—“Controversies in Thoracic Oncology.” These will be “Pro and Con” opinion pieces from experts dealing with topics that are open to debate. The first topic in this series is “Osimertinib as standard of care for the adjuvant therapy of stage IB-IIIA EGFR-mutant NSCLC.” We hope readers find this series of interest, and we welcome suggestions on topics for future debate.