The New Era of First-Line Immunotherapy for Advanced NSCLC

H. Jack West, MD


January 23, 2017

As valuable as it has been to get new approvals for patients with previously treated advanced non–small cell lung cancer (NSCLC), as described recently, the stakes are even higher when a new therapy is approved in the first-line setting. With the presentation[1] and simultaneous publication of the KEYNOTE-024 trial[2] of the PD-1 inhibitor pembrolizumab versus standard doublet chemotherapy in patients with tumors showing high PD-L1 expression, followed by the rapid FDA approval of pembrolizumab for a first-line indication,[3] we have entered a new era. And this is only the beginning of an avalanche of new data and greater understanding of the role of immunotherapy for NSCLC that will follow in the coming months and years.

We have entered a new era.

KEYNOTE-024 enrolled 305 previously untreated advanced NSCLC patients (squamous or nonsquamous) whose tumors expressed high-level (>50%) expression of PD-L1 by the companion diagnostic test for pembrolizumab with the antibody 22C3; this high-level expression is seen in about 30% of patients with advanced NSCLC. Patients with an EGFR mutation or ALK rearrangement were excluded from the trial because they were felt to be far more likely to benefit from the targeted therapies against their driver mutations than either chemotherapy or immunotherapy.

Enrolled patients were randomly assigned either to standard chemotherapy with one of an array of platinum-based chemotherapy doublets, with potential maintenance therapy with pemetrexed for nonsquamous NSCLC patients after the first six cycles of doublet chemotherapy for patients without progression, or to pembrolizumab at a fixed dose of 200 mg IV every 3 weeks, until they developed significant side effects or disease progression. Patients on the chemotherapy arm were eligible to cross over to receive pembrolizumab as second-line therapy.

The primary endpoint of KEYNOTE-024 was progression-free survival (PFS). On the basis of differences in efficacy favoring pembrolizumab, the Data and Safety Monitoring Committee following the trial recommended discontinuing randomization in light of emerging highly significant results. Specifically, the hazard ratio (HR) was 0.50 (P < .001), strongly favoring the pembrolizumab arm, with a median PFS of 10.3 months versus 6.0 months and 1-year PFS of 48% versus 15%, all favoring pembrolizumab over first-line chemotherapy. The response rate also significantly favored pembrolizumab, 45% versus 28% (P < .0011), with the median duration of responses to pembrolizumab not yet reached, compared with a median duration of response of 6.3 months among responders to standard chemotherapy.

Though patients on both arms did well relative to historical controls, overall survival (OS) was also significantly better for the recipients of initial pembrolizumab (HR, 0.60; P < .005); median OS hasn't been reached or reported, and 1-year OS strongly favored initial pembrolizumab (70% vs 54%). Though this survival benefit was seen despite built-in crossover of patients from first-line chemotherapy to pembrolizumab upon progression, only 54% of the progressing patients subsequently received immunotherapy, a disappointing and thus far unexplained result that partially undermines the conclusion that it is clearly more valuable to receive first-line immunotherapy than immunotherapy at some point over the course of a patient's treatment for advanced NSCLC.

As is typical with immunotherapy trials, immunotherapy was associated with a far lower rate of grade 3-4 toxicities (26% vs 51%), though 10% of patients experienced grade 3-4 immune-mediated adverse effects ranging from endocrinopathies to pneumonitis to skin toxicities. There were no grade 5 immune-mediated toxicities.

With the European Society for Medical Oncology (ESMO) presentation, publication in the New England Journal of Medicine, and the new approval for first-line pembrolizumab, we have now established a new standard of care, in which tumors of newly diagnosed patients with advanced squamous or nonsquamous NSCLC should be promptly tested for PD-L1, and for the 30% of patients with high-level expression of PD-L1, single-agent pembrolizumab is the clear leading choice for initial treatment.

For the 30% of patients with high-level expression of PD-L1, single-agent pembrolizumab is the clear leading choice for initial treatment.

However, as noted above, because far too many patients assigned to first-line chemotherapy failed to ever receive immunotherapy, a treatment that has been repeatedly proven to improve survival as a second-line therapy, we cannot conclude that it is critical to receive first-line pembrolizumab rather than initial chemotherapy followed by a reliable transition to immunotherapy at the first evidence of clinically significant progression, or possibly as a maintenance therapy (a strategy for which we still await trial data).

Though we are now ushering in a clear new standard for initial PD-L1 testing and first-line pembrolizumab for the subset of 30% of patients with high-level PD-L1 expression, we should also recognize that the current standard of care remains either standard chemotherapy or driver mutation–associated targeted therapy for the other 70% of patients. Though some provocative data came out looking at chemo concurrent with immunotherapy as first-line therapy,[4] that was only a phase 2 trial, and it did not demonstrate an OS benefit compared with first-line chemo followed by immunotherapy. The KEYNOTE-024 trial also excluded patients with an EGFR mutation or ALK rearrangement, as we've seen disappointing (though still very limited) results with immunotherapy overall in these populations.[5] Finally, the CheckMate-026 trial[6] of nivolumab versus platinum doublet chemotherapy as first-line treatment for advanced NSCLC in a broader population of patients with PD-L1 expression > 5% (using a different assay for PD-L1 expression) failed to show a benefit with nivolumab, a humbling reminder that we cannot extrapolate the favorable results in the subgroup of patients prospectively identifiable as most likely to benefit from immunotherapy to most or all advanced NSCLC patients.

In the meantime, we are still left with many unanswered questions. Why, even in an enriched population, do fewer than half of the patients in the KEYNOTE-024 trial demonstrate an objective response? Can refinements in PD-L1 testing or additional factors help hone optimal patient selection? Will combinations of PD-1 or PD-L1 inhibitors with conventional chemotherapy or other immunotherapy agents lead to better outcomes in selected patients and/or a broadening of the patient population in which first-line immunotherapy will prove superior to our standard therapies up to this point? These and many other questions will almost certainly lead to further evolution of the role of immunotherapy in first-line NSCLC, as we now enter just the beginning of a new era in NSCLC management.


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