Checkpoint Inhibitors in Lung Cancer: When One Drug Isn't Enough

Understanding how T cells recognize and attack tumors is fundamental to grasping why checkpoint inhibitors work—and why they sometimes don't. During a Case-Based Roundtable event in Cleveland, Ohio, Neal Ready, MD, Duke Cancer Center, discussed this and the implications for the treatment of patients with non­–small cell lung cancer (NSCLC).

As Ready explained, the process begins deep inside the tumor, where cancer cells, due to their genetic instability, produce abnormal proteins encoded by mutated DNA that the body does not recognize as "self." These proteins, known as neoantigens, are released when cancer cells break down and die.

Professional antigen-presenting cells—monocytes and macrophages—engulf these proteins, digest them into short peptide fragments of roughly 8 to 20 amino acids, and display them on the cell surface via the major histocompatibility complex. Those peptide-MHC complexes are then presented to T cells in the lymph node.

As Ready explained, "T cells have been programmed with a T cell receptor to recognize certain peptides from the day we are born, and from the day we are born, those T cells are just waiting to see their peptide."

When circumstances are favorable—meaning the right peptide is presented and the immune environment is permissive—those T cells become activated, travel through the bloodstream back to the tumor, and attack. But two major checkpoints can block this process at distinct anatomical steps, Ready explained.

The first checkpoint, CTLA-4, operates in the lymph node. When inflammation is high, T cells upregulate CTLA-4, which binds to the B7 molecule on the antigen-presenting cell. Because CTLA-4 has a higher affinity for B7 than the activating receptor CD28, it effectively outcompetes the positive signal and blocks T cell activation before it begins. The second checkpoint, PD-1, operates at the tumor site. Once T cells arrive in the tumor, cancer cells or surrounding stromal cells may express PD-L1, which binds to PD-1 on the T cell and shuts it down.

This is precisely where checkpoint inhibitor drugs intervene. CTLA-4 inhibitors such as ipilimumab (Yervoy) and tremelimumab (Imjudo) use antibodies to block CTLA-4 and allow T-cell activation to proceed. PD-1 inhibitors like nivolumab (Opdivo), pembrolizumab (Keytruda), and cemiplimab (Libtayo) block the PD-1 receptor, while the PD-L1 inhibitors atezolizumab (Tecentriq) and durvalumab (Imfinzi) block the ligand side of that interaction.

"Typically, we're using PD-1 inhibitors in almost all of our stage IV lung cancer patients now," Ready noted, "unless they have an actionable alteration or some bad autoimmune disease."

The central clinical question Ready posed is when a second checkpoint blockade—specifically adding anti-CTLA-4 to anti-PD-1 therapy—provides meaningful benefit. PD-L1 expression on the tumor is a key guiding biomarker. High PD-L1 expression generally indicates that the tumor is already immune-inflamed, meaning T cells have successfully made their way into the tumor and the main barrier is the PD-1/PD-L1 interaction. In that setting, blocking CTLA-4 as well adds little. This was confirmed by KEYNOTE-598 (NCT03302234), a randomized phase 3 trial in patients with PD-L1 scores of 50 or greater, which compared pembrolizumab with or without ipilimumab. The trial was negative.¹

However, in patients with low PD-L1 scores, the story is different. "If your PD-L1 score is really low, your problem is you don't have T cells in the tumor," Ready explained. "You need to get T cells into the tumor." In this context, blocking CTLA-4 may help unlock T-cell activation in the lymph node and get those cells moving toward the tumor in the first place. Combination anti–PD-1/CTLA-4 therapy provides an approved option with survival comparable to chemotherapy for patients who cannot or prefer not to receive cytotoxic treatment. Ready described patients who decline chemotherapy for personal reasons, such as fear of hair loss, nausea, or prior negative experiences in family members, as candidates for this approach.

Ready continued that certain tumor genotypes reinforce the rationale for dual checkpoint blockade. Mutations in STK11 and KEAP1 are associated with immune resistance independent of PD-L1 score, often producing tumors with very few tumor-infiltrating lymphocytes—what immunologists call "immune-cold" tumors. These mutations frequently co-occur with KRAS alterations, often in current or former smokers. Randomized trial data suggest that combining PD-1 and CTLA-4 blockade in STK11-positive tumors improves the likelihood of generating an immune response compared to PD-1 inhibition alone.

Ready shared a striking case from CheckMate 012 (NCT01454102),² the phase 1 trial that established the dosing regimen for nivolumab plus ipilimumab. A patient enrolled in 2014 (before PD-L1 testing was available in clinical practice) presented with a 6-cm primary tumor, a 10-cm liver metastasis, a pathologic fracture of the left femur, and numerous other metastases. He had refused chemotherapy because his mother had received it for lung cancer, suffered severe adverse effects, and died within months. Enrolled in the trial, he received nivolumab-ipilimumab. "He is still progression free," Ready said.

On the question of PD-L1 concordance, Ready explained that the biomarker is not a simple binary switch like an EGFR mutation. Concordance between primary tumor and nearby lymph node PD-L1 testing is roughly 75 to 80% and between primary tumor and distant metastasis, about 60 to 70%. There are patients with PD-L1 scores of 100 who do not respond, and there are low expressers who do. Still, at the high end of the spectrum, outcomes are generally excellent. Cemiplimab single-agent data in patients with PD-L1 scores of 90 to 100, followed out for 5 to 6 years, have not yet reached median survival—a remarkable benchmark for a disease where stage IV lung cancer once carried a median survival measured in months.

The field has moved from a time when immunotherapy was experimental and PD-L1 testing didn't exist, to one in which the nuanced interplay of tumor biology, genomics, and immune environment guides treatment decisions for nearly every patient with advanced lung cancer.

This is part 1 of a 2-part series. Read part 2. here.

DISCLOSURES: Ready has disclosed a consulting or advisory role with Bristol-Myers Squibb, Novartis, Merck, Abbvie, Celgene, Merck Serono, AstraZeneca, G1 Therapeutics, Jazz Pharmaceuticals, and Remeron and research funding from Bristol-Myers Squibb and Merck.

REFERENCES

1. Boyer M, Şendur MAN, Rodríguez-Abreu D, et al. Pembrolizumab Plus Ipilimumab or Placebo for Metastatic Non-Small-Cell Lung Cancer With PD-L1 Tumor Proportion Score ≥ 50%: Randomized, Double-Blind Phase III KEYNOTE-598 Study. J Clin Oncol. 2021 Jul 20;39(21):2327-2338. doi: 10.1200/JCO.20.03579. Epub 2021 Jan 29. PMID: 33513313.

2. Hellmann MD, Rizvi NA, Goldman JW, et al. Nivolumab plus ipilimumab as first-line treatment for advanced non-small-cell lung cancer (CheckMate 012): results of an open-label, phase 1, multicohort study. Lancet Oncol. 2017 Jan;18(1):31-41. doi: 10.1016/S1470-2045(16)30624-6. Epub 2016 Dec 5. PMID: 27932067; PMCID: PMC5476941.