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Advanced NSCLC Trials Demonstrate Potential of First-Line Immunotherapy

CHICAGO (GenomeWeb) – Results presented at the American Society of Clinical Oncology annual meeting here this week are highlighting the possibility of using immune checkpoint inhibitors as a first-line therapy in advanced or metastatic non-small cell lung cancer (NSCLC), though the molecular features marking the cases that may benefit most from immunotherapy alone or in combination with chemotherapy are still being hammered out.

At an ASCO plenary session on Sunday, for example, Gilberto Lopes of the University of Miami's Sylvester Comprehensive Cancer Center presented data from Keynote-042, a Phase III open-label trial comparing survival outcomes in 1,274 advanced or metastatic NSCLC cases randomized to receive either platinum-based chemotherapy or monotherapy with pembrolizumab (Merck's Keytruda).

The trial was open to individuals with NSCLC tumors that did not contain sensitizing EGFR mutations or ALK translocations, Lopes noted, but had at least 1 percent PD-L1 expression, defined on a tumor proportion score (TPS).

Results from the Phase III Keynote-024 trial, reported in the New England Journal of Medicine in late 2016, put the cutoff for significant survival benefits in immune checkpoint-targeted tumors at 50 percent or higher expression of PD-L1, which is part of the same pathway targeted by pembrolizumab.

In the Keynote-042 trial, the median overall survival time across 637 cases randomized to the pembrolizumab arm was 16.7 months, compared to a median of 12.1 months in the chemotherapy arm, which involved up to six rounds of treatment with paclitaxel, carboplatin, or pemetrexed.

These results suggest the anti-PD-1 checkpoint immunotherapy conferred some benefit as a front-line monotherapy, even for advanced NSCLC cases with relatively low levels of PD-L1, Lopes said during an ASCO press briefing over the weekend.

As he showed during the plenary presentation at ASCO on Sunday, the overall survival benefit in the pembrolizumab arm was further enhanced in the group of tumors with 50 percent or greater PD-L1 TPS, stretching to a median of 20 months versus 12.2 months in the chemotherapy-treated group.

Individuals with a more modest PD-L1 tumor expression of at least 20 percent had median overall survival times of 17.7 months in the pembrolizumab arm and 13 months in the chemotherapy arm.

The objective response rate in the checkpoint inhibitor-treated, high-PD-L1 group was nearly 40 percent, compared to 32 percent after chemotherapy treatment, dipping to 33 percent and 29 percent objective response rate, respectively, in pembrolizumab- or chemotherapy-treated tumors with slightly lower PD-L1 expression of at least 20 percent.

Across the complete set of tumors with 1 percent or higher PD-L1 expression, pembrolizumab and chemotherapy were neck and neck at around 27 percent. Likewise, the team did not see a significant difference in progression-free survival in the pembrolizumab and chemotherapy arms, Lopes reported, in part due to an uptick in progression-free survival for NSCLC patients with lower PD-L1 expression.

The Keynote-042 team parsed the Phase III data in several other ways as well, considering everything from individuals' geography — in or outside of East Asia — to squamous or non-squamous histology.

At Saturday's press briefing, MD Anderson Cancer Center oncologist John Heymach suggested that the Keynoe-042 findings might more than double the population of NSCLC patients who may receive pembrolizumab as a first-line therapy, provided the US Food and Drug Administration modifies the label accordingly.

During a discussion of the abstract at Sunday's plenary, meanwhile, Leena Gandhi of the NYU Perlmutter Cancer Center argued that the higher response in patients with higher PD-L1 expression warrants caution in pursuing pembrolizumab monotherapy rather than combination therapy, which appears to be effective for NSCLC tumors that have 1 to 49 percent PD-L1 expression as well as for PD-L1-negative tumors.

A related discussion spilled over into a post-plenary session, in which oncologists dug into the potential clinical implications of available clinical trial data on checkpoint inhibitor monotherapy or combination therapy in advanced lung cancer patients, including other data presented at the conference.

Likewise, those investigators are continuing to tease out the most effective PD-L1 expression cutoff for immune checkpoint inhibitor monotherapy in lung cancer — part of an ongoing discussion around potential biomarkers for immunotherapy response in trials for a range of cancer types, as underlined by presentations at ASCO and this year's American Association for Cancer Research annual conference, held here in April.

Over the course of the ASCO conference, attendees had the opportunity to take in findings from several combination immunotherapy and chemotherapy trials.

On Sunday, for example, Luis Paz-Ares, medical oncology chair at the University Hospital 12 de Octubre in Madrid, presented an interim analysis from the Keynote-407 Phase III trial of chemotherapy with or without pembrolizumab in 559 individuals with metastatic squamous NSCLC.

For that study, researchers stratified the patients into groups with PD-L1 expression above or below 1 percent TPS, Paz-Ares reported, though there appeared to be a survival benefit when adding pembrolizumab to chemotherapy across the PD-L1 expression groups.

Robert Jotte, a medical oncology and hematology researcher at the Rocky Mountain Cancer Centers, shared early results from Impower131, a Phase III trial of the PD-L1-targeting drug atezolizumab (Tecentriq from Genentech) in combination with chemotherapy for advanced squamous NSCLC cases lacking EGFR or ALK alterations.

Based on interim data available from 683 patients from two treatment groups in that study, the addition of the checkpoint inhibitor appears to have a benefit across tumor PD-L1 expression groups, Jotte noted. Even so, the progression-free survival and objective response rates documented so far were enhanced in the tumor subset with higher levels of PD-L1.

Commenting on the Impower131 study during a press briefing, David Graham, medical director of the Levine Cancer Institute, said the result "dramatically broadens the group of patients with squamous NSCLC who can benefit from the addition of immunotherapy to chemotherapy as front-line treatment." 

"We previously thought that you needed a high level of PD-L1 expression to get the best results in immunotherapy," he added, but in the large, randomized Impower131 trial "the benefit of immunotherapy was seen across all groups."

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