In Squamous NSCLC, Cemiplimab Data Pulled the Room Away From Dual Checkpoint Blockade

This article is part 2 of a 2-part series from a Case-Based Roundtable event. Read part 1 here.

Squamous histology has long been treated as a reason to reach for more aggressive first-line immunotherapy, on the assumption that these tumors respond less robustly to single-agent checkpoint inhibition. But not every checkpoint inhibitor behaves the same way in squamous disease, and trial data presented at a recent event suggest that assumption can lead oncologists toward a regimen that isn't actually the best-supported option for a given patient.

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 (oncology) at Stanford University, presented a second case built around squamous histology to test whether the dual-checkpoint reasoning from a preceding PD-L1–negative, nonsquamous case would hold. It did not extend cleanly.

CASE SUMMARY

• A 62-year-old former smoker presented with voice changes, a persistent cough, and an 11-pound weight loss.
• Imaging showed a 4-cm left upper lobe mass with liver metastases and no brain involvement.
• Final pathology confirmed squamous cell carcinoma.
• PD-L1 expression: 6%
• Next-generation sequencing showed no actionable mutations.

Before reviewing squamous-specific data, half of participants said they would recommend ipilimumab (Yervoy) plus nivolumab (Opdivo) plus platinum/paclitaxel, reasoning by analogy from the PD-L1–negative, non-squamous case discussed earlier in the program. Smaller shares favored cemiplimab (Libtayo) plus chemotherapy, pembrolizumab (Keytruda) plus chemotherapy, or dual checkpoint inhibition without chemotherapy.

Das then presented data that complicated the analogy. In KEYNOTE-407 (NCT02775435), pembrolizumab plus chemotherapy showed essentially no separation from chemotherapy alone in the PD-L1 <1% squamous subgroup at 5-year follow-up (median OS, 15.0 vs 11.0 months; HR, 0.83; 95% CI, 0.61-1.13)¹—a pattern Das said was considerably worse than what the same regimen achieves in nonsquamous, PD-L1–negative disease. POSEIDON (NCT03164616) told a similar story in squamous patients: durvalumab (Imfinzi) plus tremelimumab (Imjudo) plus chemotherapy produced a median OS of 10.4 months vs 10.5 months with chemotherapy alone (HR, 0.85; 95% CI, 0.65-1.10), essentially no benefit.² CheckMate 9LA (NCT03215706), by contrast, showed a real if modest advantage in its squamous subgroup at 6-year follow-up (median OS, 14.5 vs 9.1 months; HR, 0.65; 95% CI, 0.49-0.85; 6-year OS, 14% vs 5%).³

The regimen that stood apart, however, was cemiplimab plus chemotherapy. In EMPOWER-Lung 3 (NCT03409614), the squamous subgroup achieved a median OS of 22.3 months vs 13.8 months with chemotherapy alone⁴—among the longest survival outcomes reported across any regimen in this population, squamous or nonsquamous. "It's making people change to giving that particular I/O," Das said of the finding, adding that she did not have a clean biological explanation for why a single PD-1 inhibitor would outperform combination checkpoint blockade specifically in squamous disease. One participant asked whether the cemiplimab data included patients treated across a narrow enough geographic and demographic range to generalize; Das acknowledged that cross-trial comparisons carry real limitations given differing global trial populations and study designs but said the magnitude of the squamous-specific effect was large enough that it was changing prescribing patterns regardless.

Participants also discussed toxicity trade-offs specific to escalating therapy in a population that, in this case, already carried liver metastases and a modest smoking history. Real-world Flatiron database data shared during the session showed treatment discontinuation rates for adverse events were broadly comparable whether or not a CTLA-4 inhibitor was added, and roughly a quarter of patients across all regimens required hospitalization for adverse events. Several oncologists described managing immune-related toxicities—colitis and hepatitis most commonly, with rarer but more serious events like myocarditis and encephalitis—and discussed emerging options such as abatacept for steroid-refractory immune-related myocarditis, though most agreed the mainstay of management remains corticosteroids and selective use of tocilizumab.

After the squamous-specific data were reviewed, the room's preference shifted markedly—but not toward the dual checkpoint regimen many had initially favored. Support for cemiplimab plus chemotherapy rose to a clear plurality, while the share favoring ipilimumab/nivolumab plus chemotherapy fell by roughly a third and support for pembrolizumab-based therapy also declined. Asked afterward whether the discussion would change their broader approach to adding a CTLA-4 inhibitor in PD-L1–low or negative NSCLC, the large majority of participants said yes.

Taken together with the preceding non-squamous case, the discussion illustrated that the reflex to escalate therapy in PD-L1–negative or low disease cannot be applied uniformly across histologies. Squamous disease appears to reward a specific single-agent PD-1 inhibitor over combination checkpoint blockade, a distinction that has no clear biological explanation yet but carries real implications for a patient sitting in clinic today.

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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:

REFERENCES

1. Novello S, Kowalski DM, Luft A, et al. Pembrolizumab Plus Chemotherapy in Squamous Non-Small-Cell Lung Cancer: 5-Year Update of the Phase III KEYNOTE-407 Study. J Clin Oncol. 2023 Apr 10;41(11):1999-2006. doi: 10.1200/JCO.22.01990.

2. Peters S, Cho BC, Luft AV, et al. Durvalumab With or Without Tremelimumab in Combination With Chemotherapy in First-Line Metastatic NSCLC: Five-Year Overall Survival Outcomes From the Phase 3 POSEIDON Trial. J Thorac Oncol. 2025 Jan;20(1):76-93. doi: 10.1016/j.jtho.2024.09.1381.

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 Jun;10(6):105123. doi: 10.1016/j.esmoop.2025.105123.

4. Makharadze T, Gogishvili M, Melkadze T, et al. Cemiplimab Plus Chemotherapy Versus Chemotherapy Alone in Advanced NSCLC: 2-Year Follow-Up From the Phase 3 EMPOWER-Lung 3 Part 2 Trial. J Thorac Oncol. 2023 Jun;18(6):755-768. doi: 10.1016/j.jtho.2023.03.008.