Beyond PD-L1: Refining First-Line Treatment Decisions in Metastatic NSCLC

In this episode of OncLive On Air, Aditya Juloori, MD, a radiation oncologist and associate professor at the University of Chicago in Illinois, was joined by David Carbone, MD, PhD, a thoracic medical oncologist and director of the Thoracic Oncology Center at The Ohio State University in Columbus. Together, they explored how factors beyond PD-L1 expression, including histology, co-occurring genomic alterations, brain metastases, and patient fitness, can inform first-line regimen selection for patients with driver-negative metastatic non–small cell lung cancer (NSCLC).

Dr Carbone began by explaining that immunotherapy has transformed the treatment landscape, with frontline regimens now producing an overall 5-year survival rate of approximately 20% and potentially curing a subset of patients. However, he noted that this benefit is not evenly distributed. Patients with PD-L1–negative disease tend to fare worse than those with PD-L1–positive tumors, and outcomes are particularly poor for patients with PD-L1–negative squamous disease. In the 5-year data from the phase 3 KEYNOTE-407 trial (NCT02775435), survival curves for this subgroup had fully converged with the control arm, and the 5-year survival rate among patients with PD-L1–negative nonsquamous disease in the phase 3 KEYNOTE-189 trial (NCT02578680) was below 10%.

Drs Carbone and Juloori emphasized that dual checkpoint inhibition has emerged as an important option for these higher-risk populations. Dr Carbone highlighted that the CheckMate 9LA regimen (NCT03215706) of nivolumab (Opdivo) plus ipilimumab (Yervoy) with 2 cycles of chemotherapy produced a 5-year survival rate exceeding 20% in PD-L1–negative and squamous subsets, making it his preferred approach for patients with PD-L1–negative squamous disease. For PD-L1–negative nonsquamous tumors, he weighs additional factors such as brain metastases and STK11 or KEAP1 alterations. Although dual immunotherapy carries a higher risk of immune-related adverse effects, he noted that outcomes in CheckMate 9LA remained favorable even among patients who discontinued a component of therapy, underscoring the effectiveness of proactive toxicity management. He added that the chemotherapy-free regimen evaluated in the phase 3 CheckMate 227 trial (NCT02477826) demonstrated similar efficacy, and that many patients value receiving only 2 cycles of chemotherapy.

The conversation also explored the management of patients with baseline brain metastases. Dr Juloori explained that in both CheckMate 227 and CheckMate 9LA, the benefit of dual immunotherapy was at least as large in patients with brain metastases as in those without. This may reflect the ability of CTLA-4 blockade to convert immunologically cold intracranial tumors, which tend to have fewer activated cytotoxic T cells and tertiary lymphoid structures, into more inflamed ones. He cited a phase 2 trial of ipilimumab, nivolumab, and chemotherapy that reported an intracranial response rate of approximately 50%. For patients with multiple asymptomatic brain metastases, Dr Juloori described starting the 9LA regimen with close monthly brain imaging to assess early intracranial response, an approach that can defer whole-brain radiation therapy and help preserve performance status and eligibility for subsequent therapies. He noted that some of his patients have avoided radiation for more than a year with sustained complete responses.

Turning to genomic modifiers, Dr Carbone described STK11 and KEAP1 alterations as markers of immunologically cold, often PD-L1–negative tumors that may require more than standard chemotherapy plus pembrolizumab (Keytruda). The prospective phase 2 TRITON trial (NCT06008093) of durvalumab (Imfinzi) plus tremelimumab-actl (Imjudo) in STK11-, KEAP1-, or KRAS-mutant disease was limited by low accrual, but multiple studies support dual immunotherapy activity in these subsets. He cautioned, however, that mutation status is an imperfect surrogate for STK11 function, noting that his laboratory has identified mutant tumors that retain function and wild-type tumors that have lost it. As a result, he would still favor single-agent immunotherapy for a patient with high PD-L1 expression and an isolated STK11 mutation.

Dr Carbone also addressed how to apply trial data to patients who are older, frail, or have reduced performance status. He suggested that limiting chemotherapy exposure may be particularly beneficial in these populations, while noting that patients with interstitial lung disease or active autoimmune conditions requiring aggressive immunosuppression may be poor candidates for dual immunotherapy. He added that age alone should not preclude more intensive treatment in patients with good performance status and organ function. Both experts expressed a preference for nivolumab plus ipilimumab over durvalumab plus tremelimumab, citing stronger supporting data, particularly in squamous disease.

Looking ahead, Dr Carbone noted that emerging tools, including serum proteomic assays and SMARCA4 status, may eventually be incorporated into treatment algorithms, though their role in the dual immunotherapy and PD-L1–negative settings remains undefined. Drs Carbone and Juloori concluded that while clinicians often must rely on incomplete data and cross-trial comparisons, decisions should remain grounded in the available evidence as the field works toward more precise tools for moving beyond PD-L1.