COMMENTARY

Jack West, MD: Top Five Lung Cancer Abstracts at ESMO 2017

H. Jack West

Disclosures

September 05, 2017

The European Society for Medical Oncology (ESMO) 2017 Congress is just around the corner, and we can already say with confidence that there will be many provocative presentations, including several that are poised to change practice. At this point, we can only rely on the abstracts and press releases for several of these, but here are my early impressions on the top five presentations in lung cancer for ESMO 2017.

PACIFIC: A double-blind, placebo-controlled phase III study of durvalumab after chemoradiation therapy (CRT) in patients with stage III, locally advanced, unresectable NSCLC.

Befitting its status as the first presentation in Presidential Symposium I, which is focused on lung cancer, the PACIFIC trial has the potential to break the impasse we have faced in locally advanced non–small cell lung cancer (NSCLC) for more than a decade. Over many years of clinical research, we have extended treatment to several additional cycles of chemotherapy, escalated the radiation dose, and have also added targeted therapies, but these approaches have all failed to improve survival after the first 6-7 weeks of concurrent chemoradiation—sometimes even leading to statistically significant harmful effects. We know from a prior press release that the PACIFIC trial met its primary endpoint of prolonging progression-free survival (PFS) with a year of the PD-L1 inhibitor durvalumab compared with placebo for a year.[1] But with a cost in the range of $200,000 for that year of treatment, and patients required to receive treatment for more than a year instead of less than 2 months, I would contend that we need to see durvalumab improve overall survival (OS) to make it a truly compelling new standard of care. At that financial cost and impact on the lives of lung cancer patients, we should expect more than delaying a recurrence. But if it significantly improves OS and actually improves the cure rate in a curable population, the PACIFIC trial could mark one of the most exciting applications of immunotherapy—not just in lung cancer but in all of oncology.

The PACIFIC trial could mark one of the most exciting applications of immunotherapy—not just in lung cancer but in all of oncology.

Osimertinib vs standard of care (SoC) EGFR-TKI as first-line therapy in patients with EGFR mutation-positive advanced NSCLC: FLAURA.

Another study reported in an earlier press release as positive for a significant improvement in the primary endpoint of PFS,[2] the widely anticipated FLAURA trial pits the well-tolerated and highly effective oral third-generation EGFR inhibitor osimertinib against first-generation EGFR inhibitors gefitinib and erlotinib as first-line therapy. To many with significant experience with osimertinib, it is not surprising that osimertinib has superior efficacy in terms of PFS. The key question, however, is whether the absolute difference in PFS—regardless of a statistically significant difference—is sufficient to offset the loss of a second line of EGFR-directed therapy for the 50%-60% of EGFR mutation-positive patients who develop acquired resistance positive for the T790M mutation, for whom osimertinib is an ideal second-line treatment option after what is often a durable response to another EGFR TKI. Of note, osimertinib given first-line would make it available to 100% of EGFR mutation-positive patients rather than just the subset who are tested at acquired resistance and found to be positive for T790M, and osimertinib has the advantage of better central nervous system activity.

Nevertheless, in the absence of a significant improvement in OS, I believe that the clinical significance of the FLAURA trial results will hinge on the magnitude of the difference in PFS between the two arms, regardless of the statistical significance of this comparison.

Results of the phase III IFCT-0302 trial assessing minimal versus CT-scan-based follow-up for completely resected non–small cell lung cancer.

I would like to offer kudos to the French Cooperative Thoracic Intergroup (IFCT), a French consortium that is providing helpful data to guide practice on a question for which our current practices and professional guidelines have been based far more on compelling rationales and judgments than actual data. As we learned from a recent press release from ESMO, the IFCT-0302 trial randomly assigned 1775 patients with completely resected stage I-IIIA NSCLC to either clinical exams and chest x-rays alone or the same along with CT scans of the chest and abdomen, along with bronchoscopies (optional for patients with adenocarcinoma histology). With a long median follow-up of nearly 9 years, there was no difference in OS between the groups. While these data do not imply that it is incorrect to pursue postoperative CT surveillance, particularly along the lines of the annual low-dose chest CT screening that would be indicated for routine screening of high-risk patients, they demonstrate that an approach of CT scan surveillance several times per year, as is commonly recommended and pursued for the first 2-3 years after surgery, does not confer an improvement in survival. These results should be practice-changing, though US-based oncologists may resist, following a "less is more" approach even in the face of compelling data.

Randomized results of fixed duration (1-year) vs continuous nivolumab in patients with advanced non-small cell lung cancer.

The question of how long to continue treating patients responding well on an immune checkpoint inhibitor is a question that practicing oncologists face daily. With only cross-trial comparisons and anecdotal data to guide us, we rely overwhelmingly on our best judgment, biases, and patient preference. The CheckMate 153 trial directly compares a fixed duration of 1 year of the PD-1 inhibitor nivolumab with indefinite ongoing treatment, looking at the incidence of select high-grade treatment-related adverse events as the primary objective. Notably, the trial enrolled 1375 patients who were winnowed down to 218 randomly assigned at the end of a year of nonprogression, highlighting the challenge of asking this question. The incidence of serious toxicities is certainly a major concern, but I hope the results will also provide insight and actual data to inform whether ongoing treatment with an immune checkpoint inhibitor for more than a year improves clinical outcomes or merely adds increased risk for serious immune-mediated toxicities and cost.

Blood-based biomarkers for cancer immunotherapy: Tumor mutational burden in blood is associated with improved atezolizumab efficacy in second-line-plus NSCLC (POPLAR and OAK).

PD-L1 is the predictive biomarker that we focus on in lung cancer and other cancer settings, but we know that it is far from perfect. Neither necessary nor sufficient, it also requires precious tumor tissue that may not be readily available. This retrospective analysis of nearly 800 patients, pooled from the second-line (or later) POPLAR and OAK trials of the PD-L1 inhibitor atezolizumab versus docetaxel, evaluated PFS and OS in patients according to subgroups defined by the level of tumor mutational burden (TMB) in blood using an assay interrogating single nucleotide variants in 397 genes from cell-free DNA in plasma. The exploratory analysis revealed that a high level of TMB on the blood-based assay is highly associated with better PFS and OS on atezolizumab in both the POPLAR and OAK trials, and also that this TMB assay was not correlated with PD-L1 expression by either the SP-142 antibody used with atezolizumab or the more widely used 22C3 assay that is the companion diagnostic for pembrolizumab. Will this usher in a new era of blood-based testing for utility of immune checkpoint inhibitors? Not on its own, but this work adds momentum to the argument of the relevance of TMB, and it sets the stage for ongoing prospective trials of this approach as being quite important for future practice patterns.

Will this usher in a new era of blood-based testing for utility of immune checkpoint inhibitors?

Of course, this is just a preview of a limited collection of high-impact presentations at ESMO 2017. I hope you'll follow Medscape for coverage and commentary as the data are presented. In addition to offering thoughts through Medscape, I'll be relaying key information and my perspective on Twitter. Follow me at @JackWestMD. I'll have a lot of important new content to share from ESMO 2017 in Madrid!

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