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Associate Professor of Medicine
Department of Medical Oncology
Lombardi Comprehensive Cancer Center
Stephen V. Liu, MD, has disclosed that he has received funds for research support from Alkermes, AstraZeneca, Bayer, Blueprint, Bristol-Myers Squibb, Corvus, Genentech/Roche, Lilly, Lycera, Merck/MSD, Merus, Molecular Partners, Pfizer, Rain Therapeutics, RAPT, Spectrum, and Turning Point; consulting fees from AstraZeneca, Bristol-Myers Squibb, Catalyst, Celgene, G1 Therapeutics, Genentech/Roche, Guardant, Inivata, Janssen, Lilly, Merck/MSD, Pfizer, PharmaMar, Regeneron, and Takeda; and other financial or material support from Boehringer Ingelheim.
Dual checkpoint inhibition is now an FDA-approved option for the treatment of advanced non‑small-cell lung cancer (NSCLC). Specifically, the chemotherapy-free combination regimen of the PD-1 antibody nivolumab plus the CTLA-4 antibody ipilimumab was approved by the FDA on May 15, 2020, as a first-line treatment for patients with metastatic NSCLC and PD-L1 expression ≥ 1% who have no EGFR or ALK aberrations, followed quickly by approval of the same combination plus platinum chemotherapy for the same population on May 26, 2020. These represent new immunotherapy options in an area where several effective immunotherapy regimens already exist, with the clinical challenge now being to choose the right regimen for the right patient with NSCLC from among the available options. In this commentary, I discuss the clinical data leading to these approvals, along with how I plan to integrate these regimens into my practice.
Nivolumab Plus Ipilimumab
Nivolumab With or Without Ipilimumab vs Chemotherapy in Advanced NSCLC
The combination of nivolumab plus ipilimumab for newly diagnosed advanced NSCLC was explored in the phase III CheckMate 227 study (N = 1739), which overall compared nivolumab with or without ipilimumab vs histology-based chemotherapy in patients with both PD-L1–positive and PD-L1–negative disease. Nivolumab 3 mg/kg was given every 2 weeks and ipilimumab 1 mg/kg was given every 6 weeks until disease progression, unacceptable toxicity, or up to 2 years. It is important to note that this regimen was not compared with our current first-line standard of care (ie, immune checkpoint inhibitor monotherapy or chemoimmunotherapy); instead, it was compared with the historic standard of chemotherapy, which complicates determining its place in our current treatment algorithm.
In the primary analysis of patients with PD-L1–positive NSCLC (CheckMate 227 Part 1a), nivolumab plus ipilimumab achieved superior OS to chemotherapy. In a recent update reported at ASCO 2020, the median OS at 3 years of follow-up was 17.1 months with the combination therapy vs 14.9 months with chemotherapy (HR: 0.79; P = .0066). This led to the approval of nivolumab plus ipilimumab in this setting, and certainly this is a reasonable option for these patients.
I am particularly impressed with the duration of response (DoR) with dual checkpoint inhibition in the PD-L1–positive subset, which was nearly 2 years (median DoR: 23.2 vs 6.7 months with chemotherapy). With chemoimmunotherapy it can be difficult to determine if a response is an immune‑mediated, durable response, which is what you hope for, or if it is the typical transient response seen with chemotherapy alone. Because both nivolumab and ipilimumab are immunotherapies, we can be confident that all responses are immune mediated, which is also why these response duration data are so remarkable.
Nivolumab Plus Ipilimumab in Patients With PD-L1–Negative NSCLC
Personally, I think the more compelling data from CheckMate 227 were from the PD-L1–negative subset (CheckMate 227 Part 1b), although this group was not part of the primary analysis and therefore is not included in the FDA label. In patients with advanced NSCLC and < 1% PD-L1 expression, the median OS at 3 years of follow-up was 17.2 months with dual checkpoint inhibition vs 12.2 months with chemotherapy, with an HR for death of 0.64.
Although this HR of 0.64 is better than the HR of 0.79 seen for patients with PD-L1–positive disease, this is not because nivolumab plus ipilimumab necessarily performed better in patients with PD-L1–negative disease; rather, it is because the chemotherapy control arm performed worse. Usually patients with PD-L1–negative NSCLC have worse outcomes, but in this study the curves were depressed only in the chemotherapy arm. Otherwise, the survival data with nivolumab plus ipilimumab overlaps between the PD-L1–positive and PD-L1–negative subsets, with similarly shaped survival curves, median OS (17.1 months vs 17.2 months, respectively), and 3-year OS rates (33% vs 34%, respectively). Clearly, nivolumab plus ipilimumab consistently provides benefit regardless of PD-L1 status. In clinical practice, although off‑label, I think the combination of nivolumab and ipilimumab is an interesting option for PD-L1–negative patients.
Toxicity With Dual Checkpoint Inhibition
A primary concern with dual checkpoint inhibitor therapy has been toxicity, but I have been impressed by how well tolerated this regimen is. Despite a high rate of treatment‑related adverse events, fewer than 20% patients discontinued the combination due to toxicity, and treatment‑related deaths were very uncommon. It is important to point out that it took us awhile to find a better-tolerated dose of ipilimumab than what was used in the past: ipilimumab delivered at a dose of 1 mg/kg every 6 weeks is much better tolerated than the higher ipilimumab dosing in some of the historic regimens, at least in this NSCLC population. Furthermore, practitioners who treat multiple tumor types where ipilimumab is appropriate will need to be cognizant that the ipilimumab dosing may be different for different indications and understand how the dose used may affect toxicity.
Nivolumab Plus Ipilimumab With 2 Cycles of Platinum-Doublet Chemotherapy
CheckMate 9LA: Nivolumab Plus Ipilimumab Plus Chemotherapy vs Chemotherapy in Advanced NSCLC
Nivolumab plus ipilimumab with 2 cycles of platinum-doublet chemotherapy was explored for newly diagnosed, advanced NSCLC without EGFR or ALK alterations in the phase III CheckMate 9LA trial (N = 719). CheckMate 9LA was a straightforward trial with a simple 1:1 randomization to nivolumab (360 mg every 3 weeks) plus ipilimumab (1 mg/kg every 6 weeks) with histology‑appropriate chemotherapy (two 3-week cycles) vs standard chemotherapy (four 3-week cycles). Pemetrexed maintenance was allowed in the control arm for patients with nonsquamous NSCLC.
The rationale for this trial was built on our collective clinical experience with dual checkpoint inhibition, which has shown that, although this regimen can induce durable, immune‑mediated responses vs chemotherapy, in the first few months the survival curves for the combination do not look as impressive, and the curves even cross. To help avoid this depression in the initial part of the survival curve, the rationale of 9LA was to administer chemotherapy upfront with nivolumab and ipilimumab to preserve its survival superiority, potentially by inducing initial transient chemotherapy‑mediated responses to allow patients to survive long enough for the immune responses to take hold, or alternatively, by countering the risk of the poorly understood phenomenon of immune-mediated hyperprogression. Furthermore, limiting chemotherapy to 2 cycles should reduce the overall cumulative toxicity.
The primary endpoint of OS was met for CheckMate 9LA, with an HR of 0.69 at the interim analysis and 0.66 at the updated analysis. The updated survival curves are as we would want—they do not cross, they widen over time, and we see a clear tail of the curve. There was a significant improvement in landmark survival at 1 year, from 47% with chemotherapy to 63% with chemoimmunotherapy, with a corresponding median OS of 15.6 vs 10.9 months, respectively. These data are fairly immature, but appear to be on par with other treatment strategies.
These data led to the approval by the FDA of nivolumab plus ipilimumab with 2 cycles of chemotherapy for advanced NSCLC, even before the data were presented at ASCO 2020, which is the first time I have heard of that happening.
Toxicity With Dual Checkpoint Inhibition Plus Chemotherapy
However, giving chemotherapy and dual immunotherapy together resulted in a fairly high toxicity rate: Most (92%) patients suffered a treatment‑related adverse event, with nearly one half and one quarter experiencing a grade 3/4 or a serious grade 3/4 treatment-related adverse event, respectively. Adverse events led to discontinuation of at least part of the combination regimen in 19% of patients compared with 7% with chemotherapy alone.
Impact of This Approach on Subsequent Therapy
What impact does this approach have on subsequent therapy? I think it depends on timing of relapse. If a patient with NSCLC progressed fairly quickly after the 2 cycles of chemotherapy at the beginning of the CheckMate 9LA regimen, our standard approach would probably be to treat with docetaxel‑based chemotherapy. On the other hand, a patient who progressed later might benefit from revisiting platinum-doublet chemotherapy. Not giving chemotherapy continuously may permit additional therapeutic options in subsequent lines.
Clinical Implications of New Dual Immunotherapy Approvals
As discussed above, for me the most compelling use of nivolumab plus ipilimumab will be off-label for PD-L1–negative disease, primarily because it is driven by need and because it performed quite well in that setting.
I can also imagine that using nivolumab plus ipilimumab in the first-line setting could serve to save other treatments for later use. By starting with dual checkpoint inhibition, my second‑line regimen now becomes platinum-doublet chemotherapy, and my third‑line regimen becomes docetaxel plus ramucirumab. If I start with chemoimmunotherapy, I lose platinum-doublet chemotherapy as my second‑line regimen and move directly to docetaxel plus ramucirumab. This is said with the caveat that outcomes with nivolumab plus ipilimumab would need to be roughly comparable with that of chemoimmunotherapy, as we always want to use our best strategy first when treating our patients with NSCLC.
Furthermore, in the midst of the COVID-19 pandemic, I certainly find the chemotherapy‑free regimen of nivolumab plus ipilimumab to be appealing because it has the advantage of not including myelosuppressive chemotherapy.
Finally, I have not yet integrated dual checkpoint inhibition plus chemotherapy into my practice but am encouraged to have yet another option in the armamentarium to consider for our patients.
Conclusions: Learning As We Go
The true test for all of these NSCLC regimens—whether nivolumab plus ipilimumab in CheckMate 227, dual immunotherapy plus chemotherapy in CheckMate 9LA, or any other immunotherapy approach—will be long‑term survival. When we are able to look back with 10 years of follow-up, how many long-term survivors will we have with each regimen? Although there are many complexities with cross-trial comparison (eg, heterogeneous patient pools), if we end up seeing a clear difference between any of these regimens in terms of long-term survival, or even cure, then I think that could sway us to favor 1 regimen over another. This remains an area of constant debate because we do not have validated surrogates for long‑term survival, so we need to wait for these differences to emerge. While there is certainly rationale for using any of the approaches discussed here, at the end of the day, without the benefit of time we won’t know which is the true winner. It is also likely the optimal approach will vary from patient to patient, and eventually, predictive biomarkers will serve to guide the field in a more rational manner. For now, I think these are all reasonable approaches and the chosen approach should be tailored to a patient’s specific clinical situation, values, and characteristics, and informed by our own clinical experience.
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