CheckMate 9LA Data Push Toward Dual Checkpoint Blockade in PD-L1–Negative NSCLC

For patients with metastatic non–small cell lung cancer (NSCLC) with no targetable driver alteration and whose tumors express little or no PD-L1, the standard chemoimmunotherapy backbone leaves a persistent gap. Roughly one-quarter to one-third of newly diagnosed patients fall into this biomarker-negative subgroup, and their long-term survival on single-agent checkpoint inhibition plus chemotherapy lags well behind that of patients with higher PD-L1 expression. Whether adding a CTLA-4 inhibitor closes that gap enough to justify its added toxicity has remained an open, practical question for community oncologists.

In a virtual Case-Based Roundtable event for oncologists in the Los Angeles area, Millie Das, MD, a thoracic medical oncologist who serves as chief of oncology at the VA Palo Alto Health Care System and clinical professor of medicine at Stanford University, reviewed long-term data on dual checkpoint inhibition plus chemotherapy in advanced NSCLC. Das emphasized that patients with PD-L1 expression below 1% derive the least durable benefit from standard chemoimmunotherapy and represent the population with the clearest signal for benefit from an added CTLA-4 inhibitor.

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CASE SUMMARY

• A 68-year-old former smoker presents with progressive fatigue, blood-streaked cough, unintentional weight loss, and right shoulder pain.
• Imaging revealed a 4.2-cm spiculated right upper lobe mass with mediastinal lymphadenopathy and sclerotic bone metastases.
• Biopsy confirmed adenocarcinoma
• Molecular testing negative for EGFR and ALK; PD-L1 expression by immunohistochemistry was below 1%
  

Before any data were reviewed, participants split their initial treatment preferences roughly evenly between pembrolizumab (Keytruda) plus platinum/pemetrexed and ipilimumab (Yervoy) plus nivolumab (Opdivo) plus platinum/pemetrexed, with smaller shares choosing cemiplimab (Libtayo)-based, durvalumab (Imfinzi)/tremelimumab (Imjudo)-based, or dual-checkpoint-only regimens. Several oncologists said the patient’s relatively young age and preserved performance status supported escalating to a dual checkpoint approach, while others pointed to co-occurring STK11 or KEAP1 mutations, which were not present in this case but are common in PD-L1–negative disease, as a rationale for adding a CTLA-4 inhibitor when they do appear.

One participant asked why the NCCN guidelines list dual checkpoint regimens only as “other recommended” options rather than “preferred.”¹ Das explained that NCCN’s preferred designations track the largest randomized evidence base in all-comer, not biomarker-defined, populations, and that the trial data specific to PD-L1–negative patients, where dual checkpoint blockade appears to separate itself most, are not what drive the guideline hierarchy.

Das then walked through the supporting evidence. In KEYNOTE-189 (NCT02578680), 5-year overall survival (OS) in the PD-L1 < 1% subgroup favored pembrolizumab plus chemotherapy over chemotherapy alone (9.6% vs 5.3%; HR, 0.55; 95% CI, 0.39-0.76).² CheckMate 9LA (NCT03215706), which paired nivolumab and ipilimumab with just 2 cycles of chemotherapy, showed a starker separation at 6-year follow-up in this same biomarker-negative subgroup: median OS of 17.7 months vs 9.8 months (HR, 0.64; 95% CI, 0.49-0.84), with 20% of patients alive at 6 years compared with 7% on chemotherapy alone.³ Response rates and duration of response were also higher with the dual checkpoint regimen (overall response rate, 38% vs 25%; median duration of response, 13.0 vs 5.6 months, respectively). By contrast, POSEIDON (NCT03164616), which combined durvalumab and tremelimumab with 4 cycles of chemotherapy before dropping tremelimumab after the fifth dose, showed a narrower gap in the PD-L1–negative subgroup at 5 years (median OS, 12.7 vs 11.0 months; HR, 0.81; 95% CI, 0.62–1.05).⁴

Robert Hsu, MD, an oncologist who said he has used multiple regimens, noted a key practical distinction. “I think the nice part about CheckMate 9LA is it’s 2 cycles of [chemotherapy,” he said, adding that he has occasionally extended patients to 4 cycles when disease burden seemed to warrant it. He also pointed out that the 2 regimens diverge in how long patients stay on CTLA-4 therapy, continuing every 6 weeks in CheckMate 9LA vs stopping after the fifth dose in POSEIDON. Other participants echoed a preference for the CheckMate 9LA backbone, reasoning that its 2-cycle chemotherapy design makes the contribution of the CTLA-4 inhibitor easier to isolate than in POSEIDON’s 4-cycle design, where it is harder to know how much of the observed benefit comes from the additional chemotherapy.

The added efficacy comes with added toxicity that participants said they must counsel patients about carefully. In CheckMate 9LA, treatment discontinuation due to treatment-related adverse events occurred in 22% of patients on the dual checkpoint regimen vs 9% on chemotherapy alone, and serious treatment-related adverse events were more frequent (30% vs 18%); treatment-related deaths were rare and similar between arms.³ Among 5-year survivors, immune-mediated toxicities such as thyroid dysfunction, colitis, hepatitis, and pneumonitis occurred but largely resolved with standard management.⁵ Participants also flagged nonclinical barriers such as insurance denials, restricted formularies, and the administrative burden of peer-to-peer appeals, which can limit access to dual checkpoint regimens even when the data support them.

After reviewing the long-term follow-up data, every participant who voted said they would now recommend ipilimumab, nivolumab, and platinum/pemetrexed for this patient, a complete shift from the even split recorded before the case discussion began. The 6-year survival tail, more than any single toxicity or access consideration, appeared to be what moved the room.

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DISCLOSURES: Das has served as a consultant or on advisory board for Sanofi/Genzyme, Regeneron, Janssen, Gilead, Bristol Myers Squibb, Catalyst Pharmaceuticals, Novocure, Guardant, EMD Serono, Natera, Merus, AbbVie, Daiichi Sankyo; and has received research funding from Merck, Genentech, CellSights, Novartis, and Varian.

REFERENCES

1. Clinical Practice Guidelines in Oncology. Non-small cell lung cancer; version 5.2026. NCCN. Accessed July 2026. https://tinyurl.com/mvcepk5f 

2. Garassino MC, Gadgeel S, Speranza G, et al. Pembrolizumab Plus Pemetrexed and Platinum in Nonsquamous Non-Small-Cell Lung Cancer: 5-Year Outcomes From the Phase 3 KEYNOTE-189 Study. J Clin Oncol. 2023;41(11):1992-1998. doi:10.1200/JCO.22.01989

3. Carbone DP, Ciuleanu TE, Cobo M, et al. Nivolumab plus ipilimumab with chemotherapy as first-line treatment of patients with metastatic non-small-cell lung cancer: final, 6-year outcomes from CheckMate 9LA. ESMO Open. 2025;10(6):105123. doi:10.1016/j.esmoop.2025.105123

4. Johnson ML, Cho BC, Luft A, et al. Durvalumab with or without tremelimumab in combination with chemotherapy as first-line therapy for metastatic non-small-cell lung cancer: the phase III POSEIDON study. J Clin Oncol. 2023;41(6):1213-1227. doi:10.1200/JCO.22.00975

5. Reck M, Ciuleanu TE, Schenker M, et al. Five-year outcomes with first-line nivolumab plus ipilimumab with 2 cycles of chemotherapy versus 4 cycles of chemotherapy alone in patients with metastatic non-small cell lung cancer in the randomized CheckMate 9LA trial. Eur J Cancer. 2024;211:114296. doi:10.1016/j.ejca.2024.114296