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NSCLC: New First-Line Option
First-line Checkpoint Inhibitor Therapy in Metastatic NSCLC: A New Option for Our Patients

Released: October 27, 2016

Expiration: October 26, 2017

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New data presented at the ESMO annual meeting earlier this month (October 2016) on first-line immune checkpoint therapy in patients with advanced NSCLC generated quite a bit of excitement among attendees. Three of these agents are approved in advanced NSCLC after progression on previous systemic platinum-based chemotherapy: Atezolizumab and nivolumab are approved for patients with NSCLC independent of PD-L1 expression, and pembrolizumab is approved for patients with NSCLC whose tumors are at least 1% PD-L1 positive by an FDA-approved IHC test. Given that the antitumor activity of chemotherapy is much greater in the first-line setting than in the second-line setting, the results of the first-line studies presented at ESMO were both uncertain and eagerly anticipated.

KEYNOTE‑024: Pembrolizumab vs Platinum-Based Chemotherapy in Newly Diagnosed PD-L1–Positive NSCLC
The phase III KEYNOTE‑024 trial compared pembrolizumab vs investigator’s choice of a platinum‑based doublet chemotherapy in patients with newly diagnosed metastatic NSCLC and PD-L1 expression on at least 50% of cells in their tumor biopsy sample. A threshold of 50% PD-L1 expression has been validated in the second‑line setting and encompasses approximately 25% to 30% of patients with newly diagnosed NSCLC. Requiring high-level tumor PD‑L1 expression served to enhance the likelihood of a response in this trial by selecting for the subset of patients with lung cancer most likely to benefit from checkpoint inhibitor therapy. Patients excluded from KEYNOTE-024 included those with EGFR mutations or ALK translocations, as well as organ/tissue transplant recipients, patients with an active autoimmune disease requiring treatment within 2 years of enrollment, and patients with untreated brain metastases.

The results of the KEYNOTE‑024 trial were strongly positive. The primary endpoint of PFS was significantly improved, with a median PFS of 10.3 months with pembrolizumab vs 6.0 months with chemotherapy (HR: 0.50; P < .001). The secondary endpoint of OS was also significantly improved with pembrolizumab (80% vs 72% at 6 months; HR: 0.60; P = .005), as was the objective response rate (45% vs 28%). Particularly remarkable was that nearly 10% of patients (6 out of 63) achieved a CR with pembrolizumab vs 1 out of 41 with chemotherapy. In addition to improved efficacy, toxicity with pembrolizumab was significantly lower than with chemotherapy, with fewer treatment-related adverse events of both any grade (73% vs 90%) and grade ≥ 3 (27% vs 53%). With a high bar set by the activity of standard of care chemotherapy in the first‑line setting, the data reported for pembrolizumab at ESMO and published in parallel in The New England Journal of Medicine are truly tremendous and resulted in the US FDA rapidly approving first-line therapy with pembrolizumab in PD-L1–positive (≥ 50% staining) metastatic NSCLC on October 24, 2016.

CheckMate 026: Nivolumab vs Platinum-Based Chemotherapy in Newly Diagnosed PD-L1–Positive NSCLC
The phase III CheckMate 026 trial compared nivolumab vs investigator’s choice of platinum-based chemotherapy in patients with newly diagnosed, PD-L1–positive NSCLC. Similar to KEYNOTE-024, CheckMate 026 required PD-L1 selection but at a lower PD-L1 expression threshold. The PD-L1 expression cutoff for this trial was at least 1% of tumor cells in biopsy specimens, with a primary endpoint of PFS in patients with a 5% PD-L1 expression cutoff, which is found in approximately 50% of NSCLC diagnoses.

CheckMate 026 was a negative trial with no significant difference in outcomes between nivolumab and chemotherapy. Overall, median PFS with nivolumab was 4.2 months vs 5.9 months with chemotherapy (HR: 1.15; P = .025). However, even patients with a higher PD-L1 expression cutoff of 50% did not show an improvement in median PFS, although this study was not powered to look at that threshold. As expected, nivolumab was less toxic than chemotherapy, with fewer treatment-related adverse events, whether any grade (18% vs 71%) or serious (51% vs 92%).

In the Clinic
Based on the results of the KEYNOTE‑024 trial, checkpoint inhibition therapy with pembrolizumab is a new, FDA-approved and NCCN guideline category 1 recommendation for first-line therapy for patients with newly diagnosed metastatic NSCLC that is PD-L1–positive and negative for EGFR and ALK genetic aberrations. Patients with a history of autoimmune disease or other possible contraindications to immune checkpoint inhibitor therapy are not candidates for first-line pembrolizumab. Similar to its use as second-line therapy, first-line pembrolizumab will be administered intravenously at a dose of 2 mg/kg every 3 weeks until disease progression or intolerance, and close monitoring for potential adverse events, including patient education of signs and symptoms to watch for, will be important. For those patients who progress on first‑line pembrolizumab or discontinue due to intolerance, I recommend standard platinum‑based doublet chemotherapy considering tumor histology and patient performance status.

As recommended by the NCCN guidelines, the standard-of-care treatment paradigm is now to test all patients with a new diagnosis of advanced NSCLC for PD‑L1 expression, in addition to EGFR sensitizing mutations, ALK translocations, and ROS rearrangements, to determine whether they are a candidate for first‑line pembrolizumab checkpoint inhibition therapy. The PD-L1 IHC 22C3 pharmDx companion diagnostic assay is specifically approved for use with pembrolizumab. It is a qualitative IHC assay that detects PD-L1 protein in formalin-fixed, paraffin-embedded tumor biopsy samples. It requires 2-3 unstained slides, which should be processed by a CLIA-approved laboratory, whether commercially or in-house at a major academic center. Clearly, this assay requires a tumor core biopsy. PD-L1 expression testing cannot be done on fine-needle aspiration biopsy samples or by cytology.

Looking Ahead
Although it is very exciting to have single-agent pembrolizumab as a new effective frontline therapy option for our patients with PD‑L1–positive NSCLC, there is still room for further improvement. To this end, combining immune checkpoint inhibitor therapy with chemotherapy is being actively investigated. At ESMO and published in parallel in Lancet Oncology, the results of a randomized phase II cohort of the open-label KEYNOTE-021 study comparing carboplatin plus pemetrexed with or without pembrolizumab in advanced nonsquamous NSCLC were also reported. These data demonstrated a high level of response for pembrolizumab plus chemotherapy vs chemotherapy alone (55% vs 29%). Median PFS was also significantly improved with the addition of pembrolizumab (13.0 vs 8.9 months; HR: 0.53; P = .010). However, OS was not. This may be related to crossover to immunotherapy from the chemotherapy‑alone arm, as well as the relatively short follow‑up duration for this trial so far (10.6 months as of the August, 8, 2016, cutoff date). Toxicity for combination therapy was similar to chemotherapy alone. Grade ≥ 3 treatment-related adverse events occurred in 39% of patients receiving pembrolizumab plus chemotherapy and in 26% of patients receiving chemotherapy alone. At this time, I think we need to wait for data from randomized phase III trials to be reported in the next couple of years to see if there is a survival benefit for combining checkpoint inhibitor therapy with chemotherapy, and the magnitude of this potential benefit, before we consider these combination regimens outside of a trial.

Finally, one last point I’d like to mention on the topic of combination immunotherapy. Data on dual checkpoint inhibitor therapy regimens combining PD-1 or PD-L1 inhibitors with a CTLA-4 inhibitor are also on the horizon. The phase III MYSTIC trial evaluating the combination of durvalumab and tremelimumab as first‑line therapy in unselected NSCLC patients will likely be reported sometime during 2017, and the phase III CheckMate 227 trial evaluating the combination of ipilimumab and nivolumab will likely be reported sometime in 2018. I am hopeful that these studies will provide us with evidence supporting the use of some dual checkpoint inhibitor therapy options for our patients in the not too distant future.

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Will you recommend pembrolizumab as a first-line therapy option for patients with PD-L1 positive and EGFR, ALK, ROS-1 negative NSCLC?
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