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WCLC 2019 Data

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My Thoughts on New Findings in Lung Cancer From WCLC 2019

Physicians: Maximum of 0.40 AMA PRA Category 1 Credit™

Released: September 26, 2019

Expiration: September 25, 2020

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At the 2019 World Conference on Lung Cancer (WCLC) in Barcelona, Spain, many exciting findings were reported that are informing practice and, in some instances, have the potential to change how we practice. In this commentary, I share my thoughts on some of the key studies presented at WCLC 2019.

Non-Small-Cell Lung Cancer
 Several important advances in non-small-cell lung cancer (NSCLC) treatment were reported at WCLC 2019, including those on immune checkpoint inhibitors and novel targeted agents.

KEYNOTE‑024: 3-Year Update
KEYNOTE‑024 was a phase III trial that compared pembrolizumab with first-line platinum-based chemotherapy in patients with advanced NSCLC and high PD-L1 expression (tumor proportion score ≥ 50). Based on the initial results from this trial, pembrolizumab was approved by the FDA and is now part of standard first-line therapy for patients with advanced NSCLC. At WCLC 2019, extended follow-up survival data from KEYNOTE-024 were reported. In this analysis, the 3‑year OS rate was 43.7% with pembrolizumab vs 24.9% with chemotherapy. Median OS were 26.3 months and 14.2 months, respectively. These data further demonstrate that pembrolizumab results in durable long-term survival in this biomarker-selected patient population (PD-L1 expression ≥ 50), and further validate the effectiveness of first-line pembrolizumab monotherapy in patients with advanced NSCLC and high PD-L1 expression.

CheckMate 017 and 057: 5-Year Outcomes
 Gettinger and colleagues presented a combined analysis of long‑term survival data from the phase III CheckMate 017 and 057 clinical trials of nivolumab vs docetaxel in patients with advanced NSCLC who progressed on platinum-based chemotherapy. CheckMate 017 enrolled patients with nonsquamous histology whereas CheckMate 057 enrolled patients with squamous histology. These trials demonstrated improved OS with nivolumab vs docetaxel, and as a result, nivolumab was approved by the FDA in previously treated advanced NSCLC.

The long-term results from CheckMate 017 and 057 presented at WCLC 2019 showed a 5-year OS rate of 13.4% with nivolumab vs 2.6% with docetaxel (HR: 0.68). This is consistent with previous reports, where approximately 15% to 20% of patients with advanced NSCLC achieved long‑term survival with nivolumab. No new safety signals were observed with longer follow-up. These results provide confirmation of durable benefits in a subset of NSCLC patients; further efforts are required to increase the number of patients that will benefit from immune checkpoint inhibition.

LIBRETTO‑001: Updated Results
 In addition to immune checkpoint inhibitors, I also want to discuss a couple of key studies of targeted therapies for patients with oncogene-addicted advanced NSCLC. RET fusion–positive disease consists of 1% to 2% of all patients with nonsquamous NSCLC. Selpercatinib (LOXO‑292) is a highly selective, oral RET inhibitor being evaluated in patients with RET fusion–positive NSCLC. At WCLC 2019, updated results were reported from the phase I/II LIBRETTO-001 study of selpercatinib in patients with RET fusion–positive advanced NSCLC. Remarkably, the ORR was 68% with a median duration of response of 20.3 months. Notably, in patients who had not received previous systemic therapy, the ORR was even higher at 85%. Selpercatinib was well tolerated with few grade 3/4 adverse events. Most adverse events were grade 1/2 in severity, including dry mouth, diarrhea, and increased liver enzymes.

Based on these data, it is anticipated that selpercatinib will be approved by the FDA for patients with RET fusion–positive advanced NSCLC. Currently, there are no FDA-approved options for this patient subpopulation although there are other RET inhibitors such as BLU-667 being investigated besides selpercatinib. The potential approval would represent a major step forward in providing effective targeted therapy for RET fusion–positive patients.

Phase I Trial of AMG 510: Updated Results
 Updated results from another important and exciting study were presented that will benefit patients with advanced NSCLC and the KRASG12C mutation, which is found in approximately 11-14% of patients with NSCLC. AMG 510 is an oral inhibitor of KRASG12C that is being investigated in various solid tumors. At WCLC 2019, Govindan and colleagues presented updated phase I results from 23 evaluable patients who were treated with AMG 510. The ORR was 54% and the disease control rate was 100% in the 13 patients who received the target dose of 960 mg/day. The drug appeared to be well tolerated; multiple ongoing clinical trials are evaluating the efficacy of AMG 510 in expanded groups of patients with NSCLC.

This is exciting because so many different strategies have failed in KRAS mutation–positive NSCLC. Now, for the first time, we have seen promising efficacy with a selective KRAS inhibitor in this patient population. If these results are validated in subsequent larger studies, it is likely that AMG 510 will become the first approved targeted agent for KRASG12C mutation–positive NSCLC.

Other Studies of Clinical Interest
 Final OS results from the phase III IMpower131 trial of chemotherapy with or without the PD-L1 antibody atezolizumab as first-line therapy in advanced squamous NSCLC were presented at WCLC 2019. There was no significant median OS difference with the addition of atezolizumab to chemotherapy in the overall patient population although an OS improvement was observed in patients with high PD-L1 expression.

Tumor mutational burden (TMB) has been studied extensively as a potential predictive biomarker for immune checkpoint inhibitors in NSCLC with mixed results. At WCLC 2019, 2 analyses of randomized trials (KEYNOTE‑189 and KEYNOTE 21) comparing the addition of pembrolizumab to first-line chemotherapy in metastatic nonsquamous NSCLC found no significant association between TMB level and efficacy outcomes. However, results from the CheckMate 817 trial of nivolumab plus ipilimumab as first-line therapy for advanced NSCLC in special patient populations including those with poor performance status showed that patients with high TMB appeared to exhibit improved efficacy. At this point, it remains unclear whether TMB will be a clinically useful biomarker to predict efficacy with immune checkpoint inhibitors.

Small Cell Lung Cancer
 Unlike NSCLC, patients with small-cell lung cancer (SCLC) have had few first-line treatment options other than platinum‑based chemotherapy until recently. At WCLC 2018, results from the phase III IMpower133 trial were presented, in which adding atezolizumab to first-line chemotherapy improved both OS and PFS in patients with extensive-stage SCLC. Atezolizumab plus carboplatin/etoposide was subsequently approved by the FDA for first-line treatment of extensive-stage SCLC in March 2019.

CASPIAN: Interim Analysis
At WCLC 2019, results from the phase III CASPIAN trial of combining the PD-L1 antibody durvalumab with first-line chemotherapy in extensive‑stage SCLC were presented. More than 500 patients were randomized to 3 arms: platinum plus etoposide alone, chemotherapy combined with durvalumab, or chemotherapy plus durvalumab and the CTLA-4 antibody tremelimumab. This trial is ongoing, and results from the group who received both durvalumab and tremelimumab are not yet available.

In the current interim analysis of CASPIAN, the addition of durvalumab to chemotherapy resulted in a statistically significant OS improvement (median: 13.0 vs 10.3 months; HR: 0.73; P = .0047). PFS was also improved by adding durvalumab to chemotherapy (12-month PFS rate: 17.5% vs 4.7%; HR: 0.78). Overall, adverse events were consistent with previous reports, and this regimen was generally well tolerated.

Of importance, these results are very similar to those from IMpower133 and provide more evidence that adding an immune checkpoint inhibitor to first-line chemotherapy is an effective strategy that results in OS improvement for patients with extensive‑stage SCLC.

Phase II Trial of Lurbinectedin: Subgroup Analysis
Lurbinectedin is a novel synthetic alkaloid analogue of the DNA-damaging agent trabectedin under development as an anticancer agent for SCLC. It is being investigated as single agent or in combination with other chemotherapy agents. At WCLC 2019, a subgroup analysis of the phase II trial of lurbinectedin in relapsed SCLC showed an ORR of 45% and median OS of 11.9 months in 60 patients who relapsed ≥ 90 days after the last dose of a platinum agent. These results are promising, and lurbinectedin is currently being evaluated in combination with doxorubicin in the phase III ATLANTIS trial. Our hope is that lurbinectedin will continue to show promise, providing a much-needed new treatment option for patients with relapsed SCLC.

Your Thoughts?
What are your thoughts on the new data on lung cancer reported at WCLC 2019? I encourage you to answer the polling question and post your questions and thoughts in the comments box below. 

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Which of the following findings presented at WCLC 2019 do you find most interesting?
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