Transcript Related Guidelines

Immunotherapy Doublets 

Sandip P. Patel, MD · University of California at San Diego


August 30, 2021

Key Takeaways:

  • Patients with non-small cell lung cancer (NSCLC) have recently benefited from the use of immunotherapy (IO). 

  • Current trials have focused on doublets (IO-IO) or IO combination with chemotherapy, however the most effective regimen per patient population is not yet understood.

    • Ipilimumab-nivolumab (cytotoxic T-lymphocyte antigen 4 [CTLA-4] + programmed cell death protein-1 [PD-1] inhibitor) combination received Food and Drug Administration (FDA) approval for first-line (1L) metastatic NSCLC with programmed cell death-ligand 1 (PD-L1) expressions at ≥1% without EGFR or ALK mutations (CheckMate-227):

      • Apart from approval, a non-PD-L1 expressing cohort also receiving ipilimumab-nivolumab has demonstrated durable survival.

      • Results potentially indicate that nonexpressors or PD-L1 expression of ˂1% may have greater benefit from the IO-IO doublet than groups with higher expression.

    • In KEYNOTE-598, pembrolizumab-ipilimumab doublet in patients with PD-L1 of ≥50%, with pembrolizumab as control:

      • The doublet did not improve survival.

    • CITYSCAPE is currently evaluating anti-TIGIT therapy for high PD-L1 expression, with encouraging unconfirmed results.

  • Most NSCLC patients are currently treated with a chemo-IO therapy, including PD-1/PD-L1 inhibitors in combination with bevacizumab (IMpower150) or ipilimumab with CTLA-4 (CheckMate-9LA).

  • NSCLC patients who will best benefit from IO-IO or chemo-IO therapies and at what PD-L1 expression level will likely be elucidated with further study.

This transcript has been edited for clarity.

Cancer immunotherapy has revolutionized the treatment of non-small cell lung cancer (NSCLC), and the advent of immunotherapy (IO) doublets—taking advantage of PD-1 (programmed cell death protein-1) and PD-L1 (programmed cell death-ligand 1) inhibitors as the base combined with a second drug—is an active area of research. There are many innovations that have occurred in many clinical trials that inform which patient populations may benefit from a combination approach of immuno-immuno (IO-IO) versus potential chemo-immuno approaches, which is a discussion point for a different day. 

In terms of IO-IO combinations, the main one, the one that's FDA (Food and Drug Administration) approved currently, is CTLA-4 (cytotoxic T-lymphocyte antigen 4) plus PD-1 inhibition, or ipilimumab plus nivolumab, through a CheckMate-227 study.[1,2]This is FDA approved in frontline metastatic NSCLC for patients who do not have an EGFR or ALK mutation, and it's for PD-L1 expression greater than 1%.[1,2] One of the most interesting things about that study, the most interesting cohort for many of us, is actually the PD-L1 nonexpressing cohort in which CTLA-4 plus PD-1—ipilimumab plus nivolumab—performed extraordinarily well with durable survival, though that's not part of the formal FDA approval.

Thinking about the flip side of the coin—we talked about how PD-L1 nonexpressors, PD-L1 less than 1%, may have preferential benefit to ipilimumab plus nivolumab—the KEYNOTE 598 study looked at combining pembrolizumab with ipilimumab for PD-L1 greater than 50%.[3]And this was compared to pembrolizumab as a standard, as the control arm. In that study, there was no survival benefit demonstrated with the addition of ipilimumab to pembrolizumab.[3]

And so, as we think about these patients—patients who are PD-L1 positive greater than 50%—who are likely to benefit from anti-PD-1-directed strategies alone, such as pembrolizumab, though there are clinical trials with novel immunotherapeutics, the most recent being an anti-TIGIT molecule, tiragolumab plus atezolizumab, for high PD-L1, though this study remains in the confirmatory state to confirm the initial promising results from the CITYSCAPE study.[4] And so, I think we'll learn more about what the optimal therapy is outside of a clinical trial for these patients. Will it be integrating an anti-TIGIT antibody? Will it be anti-PD-1 or PD-L1 monotherapy? I think the best is yet to come. 

For the vast majority of patients, chemo-IO approaches remain very reasonable, whether this is with KEYNOTE-189, KEYNOTE-407, IMpower150, CheckMate-9LA.[5,6] These are a variety of different studies that take chemotherapy plus a PD-1 inhibitor or a PD-L1 inhibitor. In the case of IMpower150, it's the addition of bevacizumab, or CheckMate-9LA, and it's the addition of ipilimumab or CTLA-4 inhibitor.[6] 

And how best to pick a specific therapy for a patient depends as much on the patient's condition as it does on any molecular biomarkers. So, I think we'll learn to understand which IO doublets make the most sense for a given patient and in which scenarios chemotherapy plus IO makes sense, in particular for a patient in extremis or with aggressive disease. 


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