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FDA Investigators Share Insights on First-Line Immunotherapy Regimens in NSCLC

NEW YORK – Research at the US Food and Drug Administration's Center for Drug Evaluation and Research has provided clues for using PD-L1- or PD-1-targeting immune checkpoint inhibitors — by themselves or with chemotherapy — as a first-line treatment for advanced non-small cell lung cancer patients with different molecular tumor features.

The work was presented during a session on metastatic NSCLC at the American Society of Clinical Oncology's annual meeting in Chicago on Friday.

For one of these studies, FDA medical oncologist Oladimeji Akinboro and colleagues retrospectively pooled data on almost 3,200 PD-L1-high advanced or metastatic NSCLC cases and explored how anti-PD-(L)1 checkpoint immunotherapy alone, chemotherapy alone, or a combination of the two in the first-line setting impacted overall survival, progression-free survival, and overall response rates.

They also performed subgroup analyses based on patient age, smoking history, and performance status, Akinboro noted.

The team's analyses hinted that when it comes to cases with high PD-L1 levels, patients receiving first-line immunotherapy may fare as well as those on chemo-immunotherapy, he explained, particularly those in the age 75 and older subgroup.

These results contrast with the team's prior exploratory analyses of advanced NSCLC cases with PD-1 scores in the 1 percent to 49 percent range, who seemed to do best in terms of progression-free and overall survival when they received first-line chemo-immunotherapy as opposed to immunotherapy only, Akinboro noted.

"There may be no difference in the overall survival between chemo-immunotherapy and immunotherapy-only regimens in patients with PD-L1-high advanced non-small cell lung cancer," Akinboro said, noting that "we selected overall survival as a key outcome measure, as it is a composite measure of both efficacy and safety."

At present, he explained, the approved first-line therapy options for advanced NSCLCs that lack specific molecular changes include immunotherapy alone or combined chemo-immunotherapy, which have both been shown to boost overall survival compared to chemotherapy alone.

For the analyses, researchers at the FDA brought together data from a dozen trials used to establish this standard of care, focusing on patients with PD-L1 scores at or above 50 percent based on approved immunohistochemistry staining assays and excluding cases with EGFR or ALK mutations in their tumors.

The team saw a median overall survival of 25 months in the chemotherapy-immunotherapy combination group, which included 455 patients, compared to a median overall survival of 20.9 months for the 1,298 patients treated with immunotherapy alone — a difference that was not statistically significant.

Even so, the chemo-immunotherapy treatment appeared to edge out single-agent immunotherapy when it came to disease progression and response rates. Combination treatment in the first line was linked to a median progression-free survival of 9.6 months and a response rate of 61 percent, while just immunotherapy treatment resulted in a median progression-free survival of 7.1 months with an objective response rate of 43 percent.

Akinboro emphasized that just a fraction of the patients analyzed came from non-European ancestry groups, and just 1 percent of patients were African American in trials that reported ethnicity. He also cautioned that the results are based on retrospective, exploratory analyses done across trials, without taking toxicity and side effects into account and are meant to serve as a spark for future hypotheses and research.

The findings "are not meant to be prescriptive at all," Akinboro said. Rather, he suggested, "they reinforce the importance of shared decision making between patients and their oncologists."

In another analysis presented at the meeting on Friday, FDA investigators performed a similar pooled analysis of immunotherapy- or chemo-immunotherapy-treated advanced NSCLC patients, taking KRAS mutation status into consideration.

KRAS mutations are the most common NSCLC driver, turning up in nearly one-third of tumors from this type, explained Erica Nakajima, a medical oncologist at the FDA, in presenting the findings. One of these mutations, the KRAS G12C, has been found in some 13 percent of NSCLC patients.

Past studies suggested that KRAS-mutated NSCLC may be particularly amenable to immunotherapy treatment, she noted, since KRAS mutations tend to coincide with a history of smoking and high PD-L1 expression.

Nevertheless, comparisons between first-line immunotherapy or chemo-immunotherapy outcomes in patients with or without KRAS mutations are limited, prompting the team to try to tease out such patterns retrospectively in data on almost 8,900 patients evaluated in a dozen trials.

Across the trials, Nakajima noted, just 1,430 patients had their KRAS mutation status reported including 555 individuals with KRAS-mutated tumors and 157 patients with KRAS G12C mutations specifically.

The findings suggested that advanced NSCLC patients with both KRAS-mutated and KRAS-wild type tumors had enhanced overall survival times and objective response rates when their first-line treatments included chemo-immunotherapy rather than immunotherapy alone.

Among patients with documented KRAS mutations, for example, the researchers saw median overall survival of 22.4 months if they received chemo-immunotherapy compared to just over 16 months median overall survival if they got just immunotherapy.

In cases with KRAS wild-type tumors, meanwhile, the median overall survival was 18.7 months and 16.4 months in the pooled chemo-immunotherapy and immunotherapy arms, respectively. These patterns appeared to hold when the team considered KRAS-mutant and -wild type cases in the context of PD-L1-high or -low status.

"For each of the treatment regimens evaluated in our analysis, patients with [KRAS]-wild type and -mutant disease respond similarly," Nakajima said, adding that the limited number of patients with KRAS G12C mutations made it difficult to do analyses in that subgroup.

"Collectively, this data suggests that the optimal control arm for studies of first-line therapy for patients with KRAS-mutant disease may be a checkpoint inhibitor plus chemotherapy," she suggested, adding that "we need additional patients to bolster our data" for patient subgroups defined by both KRAS G12C mutation status and PD-L1 expression levels.

Nakajima also pointed to the importance of performing further research on the potential role of targeted inhibitors rather than immunotherapy as a first-line treatment for KRAS-mutant advanced NSCLC, particularly those with the G12C alteration.

There is currently an FDA-approved treatment, Amgen's Lumakras (sotorasib), for previously treated, locally advanced, or metastatic NSCLC patients with KRAS G12C mutations. But KRAS inhibitors aren't yet available as a front-line option in the metastatic setting.

Discussing findings from Friday's ASCO session, Sukhmani Padda, director of thoracic medical oncology at Cedars-Sinai Medical Center, noted that further research is needed to refine treatments within NSCLC subsets including KRAS-mutated patients with high- or low-PD-L1 expression or more elderly patients who have PD-L1-high expression and appeared to have particularly enhanced benefits from immunotherapy alone.

"Only about 10 percent of the population enrolled were in this [75 years or older] age group," she said. "It's a reminder to us who are designing clinical trials to ensure that our eligibility is modernized and that we're conducting dedicated clinical trials in this population."

Similarly, with KRAS mutation status only available for 16 percent of patients, Padda considered whether this is a biased population. "Given the degree of missingness, how confident can we be in these particular results?" she wondered.