Emerging Biomarkers and Tumor Heterogeneity Lead the Way in Lung Cancer

Ongoing clinical trials in small cell lung cancer (SCLC) and non–small cell lung cancer (NSCLC) are fueling excitement in the oncology community with research efforts focusing on understanding the biology and heterogeneity of SCLC, and FDA approvals in 2024 in the NSCLC setting. Anne Chiang, MD, PhD, a faculty member at the 25th Annual International Lung Cancer Congress®, sponsored by Physicians’ Education Resource (PER®), LLC, addressed a number of practice-changing trials and regulatory updates in the lung cancer setting, ahead of the conference from July 25 to 27, 2024, in Huntington Beach, California. “We’re starting to understand more about the biology, heterogeneity, and molecular subtypes of SCLC disease that we can potentially exploit,” Chiang, an associate professor and associate cancer center director, clinical initiatives, at the Yale School of Medicine in New Haven, Connecticut, told Targeted Therapies in Oncology, during an interview ahead of the conference.

SCLC Setting

In the SCLC setting, Chiang highlighted the findings¹ from Carl M. Gay, MD, PhD, and colleagues, who looked at patterns of 4 SCLC subtypes that were defined by the transcription factors ASCL1, NEUROD1, and POU2F3 or low expression of all 3 transcription factor signatures accompanied by an inflamed gene signature (SCLC-A, N, P, and I, respectively).¹ The researchers noted that SCLC-I demonstrated greater benefit when immunotherapy was added to chemotherapy, whereas the other subtypes had distinct shortcomings.

These investigators validated these subtypes using RNA sequencing from treatment-naive patients enrolled in the phase 3 IMpower133 trial (NCT02763579).² Results from IMpower133 demonstrated that patients who received atezolizumab (Tecentriq), carboplatin, and etoposide had a median overall survival of 12.3 months compared with 10.3 months in the control group.3 Progression-free survival (PFS) was also statistically improved at 5.2 months in the experimental arm compared with 4.3 months in the control arm.³ In the trial, patients received atezolizumab plus carboplatin and etoposide (n = 201) or placebo plus carboplatin and etoposide (n = 202).

The median follow-up for overall survival (OS) was 22.9 months, with 302 deaths reported. Median OS was 12.3 and 10.3 months with atezolizumab plus carboplatin and etoposide and placebo plus carboplatin/etoposide, respectively (HR, 0.76; 95% CI, 0.60-0.95; P = .0154).⁴

Another biomarker that appears promising is the Schlafen 11 (SLFN11) gene, said Chiang. Findings from the phase 2 S1929 trial conducted by the SWOG Cancer Research Network and presented at the 2023 American Society of Clinical Oncology Annual Meeting showed more improvement in PFS in patients with SLFN11- expressing SCLC who received atezolizumab plus talazoparib (Talzenna) than in patients who received atezolizumab alone.⁵

“As we gain more information, we’ll hopefully disprove the myth that small cell lung cancer is a disease with 1 treatment approach,” Chiang said. “We need to understand better the heterogeneity associated with SCLC in order to use a targeted approach.”

To further our understanding, Chiang recommends talking to the pulmonary team to make sure tissue samples of SCLC tumors are adequate, as sometimes only a limited sample of tissue is obtained by f ine needle aspirate, even though SCLC is characterized by bulky disease. She noted that in NSCLC, adequate tissue samples are needed to determine PD-L1 status for treatment decisions. “If there were a tissue requirement [for SCLC], I think we’d be able to push the field forward.”

Four Approvals

In the early months of 2024, the FDA approved 4 agents in the NSCLC setting: tepotinib (Tepmetko) in patients with MET exon 14 skipping alterations,⁶ osimertinib (Tagrisso) plus chemotherapy based on the FLAURA2 (NCT04035486) data,⁷ amivantamab-vmjw (Rybrevant) plus chemotherapy in patients with exon 20 insertion mutation–positive NSCLC,⁸ and alectinib (Alecensa) as an adjuvant treatment for ALK-positive NSCLC.⁹

“What an exciting year,” Chiang said. In her practice, Chiang has had positive experiences using tepotinib. “It’s a great agent for our patients, but we still need to manage adverse events such as peripheral edema and pleural effusion. But it’s exciting to have a new treatment option for these patients with rare MET exon 14 [skipping] mutations.”

FDA approval for tepotinib was based on findings from the phase 2 VISION trial (NCT02864992) in which investigators reported that the overall response rate among 164 treatment-naive patients was 57% (95% CI, 49%-65%), and 40% of responders had a duration of response of 12 months or longer.⁶

Results from the FLAURA2 trial led to the FDA approval of osimertinib and platinum- based chemotherapy in patients with EGFR exon 19 deletions or exon 21 L959R mutations.⁷ “When discussing whether or not to use this regimen with patients upfront, a key factor will be the difference between coming into the office every 2 to 3 months to monitor scans and side effects of an oral pill vs coming into the office every 3 weeks to receive IV chemotherapy in addition to the osimertinib,” Chiang said.

Amivantamab-vmjw in combination with carboplatin and pemetrexed was approved in the first-line setting for patients with locally advanced or metastatic NSCLC whose tumors harbor EGFR exon 20 insertion mutations.⁸ In the ALINA trial (NCT03456076), 257 patients were randomly assigned to receive alectinib 600 mg orally twice daily or platinum-based chemotherapy following tumor resection.⁹

For the Community Oncologist

For the community oncologist, understanding the biology of the tumors and their treatment response, whether for SCLC or NSCLC, is becoming more important, Chiang said. “To obtain tissue so that we can understand what subtypes or biomarkers are present and to determine how to target effective therapies to those patients is key in both small cell and NSCLC,” Chiang continued. “Moving agents earlier into the neoadjuvant setting, or even into the adjuvant setting, is important to help our patients receive that benefit before the disease has reached the metastatic stage,” she said.

Chiang noted that she is looking forward to the presentations, which will highlight the role of antibody-drug conjugates (ADCs) including, “ADCs and Immunotherapy: Can We Achieve Synergy?”; “Are Biomarkers Important for ADCs in Lung Cancer?”; “ADCs in Driver Mutation-Positive NSCLC: Do We Have a Real Signal?”; and “ADCs in Early-Stage NSCLC: Is This a Good Fit?” They are scheduled for July 27, 2024.