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In 2004, the lung cancer community met EGFR, the first targeted oncogenic alteration in non-small cell lung cancer (NSCLC). After that, the flood gates opened with "unprecedented progress in identifying and targeting new molecular alterations. Almost two decades of experience have allowed scientists to elucidate the biological function of oncogenic drivers and understand and often overcome the molecular basis of acquired resistance mechanisms," noted authors of a 2024 review.

But most patients with NSCLC "still lack targetable genomic alterations, making platinum-based chemotherapy the longstanding mainstay for treatment," explained Martin Reck, MD, PhD, of the German Center for Lung Research in Grosshansdorf, Germany, and Nikolaj Frost, MD, of Charite-Universitatsmedizin Berlin, in an review.

"Pemetrexed-based platinum doublet chemotherapy has been a cornerstone in the pre-immune checkpoint inhibitor (ICI) era for nonsquamous NSCLC," Reck and Frost wrote, adding that, of course, the advent of "ICIs has substantially improved the survival of patients with lung cancer over the past decade."

Reck would certainly know as he led the seminal trial that tested (Keytruda) versus platinum-based chemotherapy in patients with with a PD-L1 tumor proportion score of at least 50% and no sensitizing EGFR or ALK alterations.

In the current review, Reck and Frost offered several main messages:

• "ICI-based treatments stand as the current first-line standard of care for suitable patients with non-oncogenic addicted NSCLC."

• While PD-L1 expression correlates with how effective ICI is, high expression does not guarantee a "robust immune response."

• Dual checkpoint inhibition may be the best bet in patients with squamous NSCLC and/or groups with PD-L1-negative NSCLC.

• The future focus lies in identifying predictive markers to guide optimal, individual treatment strategies.

Besides Keynote-024, Reck and Frost name-checked several other major NSCLC trials in the review. But how have chemo-ICI regimens played in the real world? Vamsidhar Velcheti, MD, of NYU Perlmutter Cancer Center in New York City, and colleagues shared their experiences in a at the 2024 ASCO annual meeting. Below are highlights from Velcheti's presentation.

What was the impetus for this study?

Velcheti: Treatment with platinum-based chemotherapy and anti-PD-1 and PD-L1 regimens improves outcomes for some patients with metastatic NSCLC. However, many patients who initially respond become resistant. Effective treatment options for advanced, metastatic NSCLC are lacking, and the role of immunotherapy is not well characterized for these patients.

This study examined real-world treatment patterns and long-term outcomes in patients with NSCLC who have previously been treated with platinum-based chemotherapy and anti-PD-1 and anti-PD-L1 regimens.

What are some of the study details?

Velcheti: The study used the nationwide Flatiron Health electronic health record-derived database. Patient records were divided into one of three cohorts, depending on the sequence of the treatments received.

Cohort 1 received platinum-based chemotherapy and anti-PD-1 or anti-PD-L1 in combination in a single line. Cohort 2a received platinum-based chemotherapy followed by anti-PD-1 or anti-PD-L1. Cohort 2b received anti-PD-1 or anti-PD-L1 followed by platinum-based chemotherapy.

The first line of subsequent treatment following platinum-based chemotherapy and anti-PD-1 and anti-PD-L1 was defined as the index treatment. The start of the index treatment was defined as the index date. A total of 1,793 patients were included in the analysis. Of these, most were in cohort 1, which included 73.5% of patients.

What were some of the main findings?

Velcheti: Among all patients, the median duration of follow-up from the index date was 7.8 months, with a range of 0 to 65 months. Patients in cohort 2a were most likely to have an earlier index year. A diagnosis of metastatic stage 4 NSCLC was the most common across all cohorts. In cohort 2b, 78.1% of patients had PD-L1 ≥50%. Cohort 1 and cohort 2a had a lower percentage, with 19.9% and 17.9% of patients having PD-L-1 ≥50%, respectively.

Among all patients, the most common index-treatment categories were chemotherapy plus targeted therapy and chemotherapy as monotherapy. Docetaxel plus ramucirumab [Cyramza] and docetaxel monotherapy were the most common index treatments.

Among all patients, median progression-free survival [PFS] from the time of starting index treatment was 5.29 months. Rates were similar across cohorts. Among all patients, median overall survival [OS], from the time of starting index treatment, was 11.2 months. The rates were again similar across cohorts.

What are some of the take-home messages?

Velcheti: The study found that patients most frequently received platinum-based chemotherapy and anti-PD-L1 and anti-PD1 together in a single line. There was a broad range of index treatments for use following platinum-based chemotherapy and anti-PD1 and anti-PD-L1 regimens -- most commonly, docetaxel with or without ramucirumab.

Across all three cohorts, short median PFS and OS durations underscored a significant unmet need among patients previously treated with platinum-based chemotherapy and anti-PD-1 and anti-PD-L1. Continued development of novel agents is warranted to address this unmet need.

Read the review here and expert commentary about it here.