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NSCLC: A Look Ahead
Immunotherapy and Targeted Therapy in NSCLC: Where Are We Going in 2018?

Released: December 28, 2017

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Advances in the treatment of advanced NSCLC have been evolving at a steady pace during the past decade, most notably the advent and continued development of immunotherapy and targeted therapy. Here is what I am most looking forward to in 2018 that I believe will contribute to the continued growth of our understanding of how best to use these agents in our patients with advanced NSCLC.

Should We Be Treating Our Newly Diagnosed Advanced NSCLC Patients With a Chemo/Immunotherapy Combination?
In 2017, the combination regimen of carboplatin/pemetrexed/pembrolizumab was FDA approved for the first-line treatment of metastatic nonsquamous NSCLC regardless of PD-L1 expression based on the results from cohort G of the phase II KEYNOTE-021 trial. KEYNOTE-021 cohort G showed a significant improvement in both ORR across the spectrum of PD-L1 expression and PFS, but no difference in OS, with the addition of pembrolizumab to carboplatin/pemetrexed vs chemotherapy alone in 123 patients with newly diagnosed advanced, nonsquamous NSCLC. Because this was a rather limited data set to justify a new treatment strategy, we anxiously await the results of the large phase III KEYNOTE-189 trial of platinum plus pemetrexed chemotherapy with or without pembrolizumab to clarify whether combination chemoimmunotherapy without PD-L1 selection is how we should be treating many of our newly diagnosed patients.

Several other trials evaluating combination chemoimmunotherapy in the first-line treatment of advanced NSCLC using different immune checkpoint inhibitors (eg, atezolizumab, nivolumab, and durvalumab) are also expected to report in 2018. For example, results from the IMpower trial series evaluating the potential value of atezolizumab combined with chemotherapy have already started coming out. At the ESMO Immuno-Oncology 2017 Conference, early results from the phase III IMpower 150 trial of just over 1200 patients with newly diagnosed metastatic nonsquamous NSCLC demonstrated an improved PFS with atezolizumab combined with carboplatin/paclitaxel plus bevacizumab vs chemotherapy plus bevacizumab (8.3 vs 6.8 months, respectively; HR: 0.62; 95% CI: 0.52-0.74; P < .0001); mature OS data from this important trial should be available in the first half of 2018. In the next 6-12 months we can also expect to see phase III results from IMpower 130 of atezolizumab plus carboplatin/nab-paclitaxel vs chemotherapy alone in patients with advanced nonsquamous NSCLC, IMpower 131 of atezolizumab plus carboplatin and either paclitaxel or nab-paclitaxel vs carboplatin/nab-paclitaxel in advanced squamous NSCLC, and—similar to KEYNOTE-189—IMpower 132 of cisplatin or carboplatin plus pemetrexed with or without atezolizumab in advanced nonsquamous NSCLC.

Results from the atezolizumab trials, and those with nivolumab and durvalumab, should give us a much better sense during the next 1-2 years of how broadly the principles of combining immune checkpoint inhibitors with chemotherapy should be applied and whether it should be the first-line strategy for many or most of our patients or more narrowly selected for particular patients. It is also going to be important to refine our understanding of PD-L1 as a biomarker of immunotherapy benefit, with or without chemotherapy, especially for immune checkpoint inhibitors other than pembrolizumab.

What About Frontline Combination Immunotherapy for Advanced NSCLC?
In 2018, we are poised to learn a great deal about the potential incremental benefit of combining PD-L1 and CTLA-4 inhibitors for the treatment of newly diagnosed advanced NSCLC. Insight into the utility of nivolumab plus ipilimumab combination therapy will be provided by the single-arm phase II CheckMate 568 trial of this combination and the large, randomized phase III CheckMate 227 trial comparing nivolumab monotherapy, nivolumab plus ipilimumab, or nivolumab plus platinum-doublet chemotherapy vs platinum-doublet chemotherapy, with a focus on OS and not just PFS. Similarly, although the phase III MYSTIC trial, which randomized patients newly diagnosed with metastatic or advanced NSCLC to durvalumab plus tremelimumab, durvalumab monotherapy, or standard-of-care platinum doublet chemotherapy, did not meet its primary endpoint of improved PFS with the immunotherapy combination vs chemotherapy, it will report additional primary endpoints in 2018, including OS data for the combination and durvalumab alone. The phase III NEPTUNE trial is comparing durvalumab plus tremelimumab to any of several standard-of-care doublet chemotherapy regimens, while the phase III POSEIDEN trial is evaluating durvalumab monotherapy or durvalumab plus tremelimumab combined with chemotherapy vs chemotherapy alone. The results of these trials will help to clarify the following questions: Is there a clear incremental benefit to immunotherapy combinations? If so, will it be limited to a definable subset of patients? Will the tolerability be feasible enough to adopt in a broad community setting? Will the benefits outweigh the cost increase of combining 2 immunotherapy agents, when we are already struggling with the challenge of paying for one agent through the course of treatment given on an ongoing basis until either disease progression or intolerable toxicity?

Immunotherapy for Unresectable Stage III NSCLC
In late 2017, the very important early results from the phase III PACIFIC trial of durvalumab monotherapy vs placebo as consolidation after chemoradiation for unresectable stage III NSCLC were reported at ESMO and published in the New England Journal of Medicine. PACIFIC demonstrated a profound and sustained PFS benefit with durvalumab vs placebo (median PFS: 16.8 vs 5.6 months, respectively; HR: 0.52; P < .001) that is likely to lead to a change in the standard of care in 2018. I expect we will see an FDA approval and I am also quite hopeful that we will see this impressive PFS benefit translate into a significant OS improvement in the stage III setting.

Tumor Mutational Burden as an Emerging Biomarker for Immunotherapy Benefit
In addition to refining our understanding of PD-L1 as a biomarker, I think it will be important in 2018 to make an effort toward developing new biomarkers of immunotherapy benefit, with tumor mutational burden emerging as a leading candidate: Preliminary studies suggest that patients with a high tumor mutational burden are especially likely to benefit from immunotherapy. For example, an exploratory analysis of the phase III CheckMate-026 trial evaluating first-line nivolumab vs standard-of-care chemotherapy suggested that in patients with high tumor mutational burden nivolumab improves ORR and PFS vs doublet chemotherapy. In the CheckMate 032 trial, efficacy of nivolumab with or without ipilimumab was also enhanced in patients with recurrent small-cell lung cancer and high tumor mutational burden. Although these are still early days, the converging evidence from multiple trials could eventually amount to a critical mass and a tipping point of using tumor mutational burden in clinical practice to select patients best suited to receive immunotherapy strategies.

Continued Advances in Targeted Therapy for Advanced NSCLC With Actionable Biomarkers
One of the most anticipated advances in targeted therapies for NSCLC in 2018 will be the reporting of mature OS data from the phase III FLAURA trial. FLAURA, which was presented at ESMO 2017, demonstrated a statistically and clinically significant improvement in PFS for first-line osimertinib vs standard of care in patients with advanced or metastatic EGFR-mutant NSCLC (18.9 vs 10.2 months, respectively; HR: 0.46; P < .0001) that, I believe, is remarkable enough to change our standard of care. Translation of the PFS improvement into a similarly improved OS should make it even more compelling to transition osimertinib into the first-line setting for essentially all patients with advanced NSCLC and an activating EGFR mutation rather than deferring it until the second line for just EGFR T790M mutation–positive patients. If osimertinib in the first-line setting leads to better outcomes for more of our patients with NSCLC than the current standard of care, especially with its greater intracranial activity, I encourage clinicians to not worry about losing osimertinib as a second-line option.

In ALK-positive disease, we expect to see the first-line results from a phase III trial of brigatinib vs crizotinib, with other agents (eg, ensartinib, lorlatinib) also being tested as potential first line therapy vs crizotinib in coming years. However, with the first-line standard of care clearly moving toward alectinib over crizotinib based on the highly positive results from the global phase III ALEX trial that was presented at ASCO 2017 (median PFS: not reached vs 11.1 months, respectively; P < .001), their role in standard of care for newly diagnosed advanced NSCLC will remain a subject of debate. In the second-line setting, the anticipated FDA approval of lorlatinib in the first half of 2018 will undoubtedly change the landscape for ALK-positive disease given its demonstrated efficacy even in patients who have previously received 2-3 different ALK inhibitors. With the entrance of additional ALK inhibitors into the therapeutic landscape for advanced ALK-positive NSCLC and with more choices to consider, we will be faced with the enviable challenge of figuring out how to best use them sequentially through the course of care to achieve the optimal balance of efficacy and tolerability, a question I suspect will take us into the next few years to answer.

Let me know which development you think will be the mostly likely to have an impact on your NSCLC practice in 2018. Please leave a comment below.