A recent expert panel discussion has highlighted critical patient factors that should guide treatment selection for patients with metastatic non-small cell lung cancer (NSCLC) who test negative for PD-L1 expression, providing new insights into optimizing immunotherapy combinations in this challenging patient population.
The virtual Case-Based Roundtable meeting, moderated by Neal E. Ready, MD, professor of medicine at Duke Cancer Institute, focused on a 66-year-old former smoker with metastatic adenocarcinoma and PD-L1 expression less than 1%. The case involved a patient with significant disease burden, including a 4.2 cm right upper lobe mass, mediastinal lymphadenopathy, and bone metastases.
Timing of Treatment Initiation
The expert panel reached consensus that waiting for PD-L1 results is generally appropriate before initiating therapy. "Since a PD-L1 is an immunohistochemistry test that most places can get in-house, and usually you can get it within a few days, it generally does make sense to wait for it, because it can help direct treatment," Ready explained.
Rajesh Balaj, MD, noted that PD-L1 results typically arrive quickly: "We get these results in house, so PD-L1 comes very quick." However, Giri Raval, MD, emphasized the importance of clinical judgment: "If the PD-L1 is pending, unless I'm concerned about some visceral crisis, I'm in no rush to treat."
Treatment Approaches for PD-L1 Negative Disease
When PD-L1 expression is less than 1%, the panel discussed two primary approaches: chemotherapy plus single-agent immunotherapy versus dual immunotherapy with or without chemotherapy. The CheckMate 9LA regimen, which combines nivolumab plus ipilimumab with two cycles of chemotherapy, emerged as a preferred option for many panelists.
Michael Humeniuk, MD, advocated for the dual immunotherapy approach: "I'm a heavy user of [nivolumab, ipilimumab, and chemotherapy], so in most cases, I give chemotherapy and immunotherapy together. I don't really care what the PD-L1 is because the CheckMate 9LA regimen works for all PD-L1."
The rationale for reduced chemotherapy cycles was particularly compelling. Humeniuk explained: "I can get them through 2 cycles of chemotherapy, because by the time they get 3 and 4, they're getting neutropenic fevers, they're getting neuropathies, or getting all the other chemotherapy toxicities on top of the immunotherapy."
Patient Selection Criteria for Dual Immunotherapy
Ready outlined specific patient characteristics that favor dual immunotherapy over single-agent approaches. Key factors include smoking history, tumor differentiation, and mutational status. "Those would be patients who are smokers, patients who have a poorly differentiated cancer, any squamous cell cancer in a smoker, or a tumor that has a high total mutational burden," Ready stated.
The panel emphasized that these factors increase the likelihood of tumor neoantigens, making CTLA-4 inhibition more beneficial. "Is this the kind of case where there's a good chance that those peptides are present, so it makes sense to inhibit CTLA-4?" Ready asked, highlighting the mechanistic rationale.
Impact of Specific Mutations
The discussion revealed important insights about specific genetic alterations that influence treatment selection. Gary Thomas, MD, identified KEAP1 and STK11 mutations as particularly relevant: "Aren't the mutations KEAP1 and STK11 particularly sensitive to this dual IO approach?"
Ready confirmed this observation, explaining that approximately 30% of adenocarcinomas harbor KRAS mutations, with a significant percentage co-mutated with either STK11 or KEAP1. "The KRAS compound mutations with STK11 and KEAP1 are really immune resistant," he noted. "There are pretty good data from the larger trials suggesting that dual IO has the potential to overcome that resistant genotype."
Contrasting Approaches Across Cancer Types
Jennifer Atlas, MD, who specializes in melanoma and cutaneous cancers, highlighted important differences between lung cancer and other malignancies: "This is always a struggle for me when I see these patients with lung cancer, because I know PD-L1 status matters so much more in [NSCLC]. We don't use it to decide our treatment decisions in melanoma."
This observation underscored the cancer-specific nature of biomarker utility and treatment selection strategies.
Clinical Trial Evidence
The panel referenced multiple clinical trials supporting their treatment recommendations. The CheckMate 9LA trial demonstrated efficacy across all PD-L1 expression levels, while CheckMate 227 provided long-term survival data for dual immunotherapy approaches.
Notably, the KEYNOTE-598 trial, which tested pembrolizumab with or without ipilimumab in high PD-L1 expressing tumors, was negative, suggesting that dual immunotherapy may be most beneficial in the PD-L1 negative population.
Practical Considerations
The panel acknowledged that treatment selection involves balancing efficacy with tolerability. Balaj noted his continued preference for chemotherapy plus single-agent immunotherapy based on experience: "Most people are able to tolerate 4 cycles of carboplatin-based treatment... we use growth factor support quite heavily, so it's not been that much of a problem."
However, others emphasized the potential advantages of the dual immunotherapy approach, particularly in reducing chemotherapy exposure while maintaining or improving efficacy.
The expert discussion provides valuable guidance for oncologists treating PD-L1 negative NSCLC patients, emphasizing the importance of comprehensive patient assessment including smoking history, tumor characteristics, and mutational status in optimizing treatment selection.
