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Frontline IO Combos
What’s New Regarding Frontline Immunotherapy Combinations in Advanced NSCLC

Released: December 30, 2019

Expiration: December 28, 2020

Matthew Gubens
Matthew Gubens, MD, MS
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The introduction of immunotherapy has greatly improved treatment outcomes for patients with advanced NSCLC. The presentation of the phase III KEYNOTE-189 trial data at AACR 2018 marked the first time we saw evidence that adding immunotherapy to standard first-line chemotherapy improves OS in a broad swath of our patient population with advanced NSCLC regardless of PD-L1 expression level. Since then, we have seen additional positive datasets from several other phase III trials evaluating frontline immunotherapy combinations, offering alternative treatment options for patients with advanced NSCLC.

Immunotherapy/Chemotherapy Combinations
In nonsquamous advanced NSCLC, the KEYNOTE-189 regimen of carboplatin, pemetrexed, and pembrolizumab remains the most popular choice as frontline combination therapy. Aside from an OS improvement in the entire study population, the OS benefit held up in each subgroup with various levels of PD-L1 expression, and the tolerability of this regimen was acceptable compared with chemotherapy alone. Besides KEYNOTE-189, there have been other important phase III trials showing an OS benefit with immunotherapy/chemotherapy combinations in the nonsquamous patient population. The IMpower150 study demonstrated an OS benefit with the addition of atezolizumab to first-line carboplatin, paclitaxel and bevacizumab. However, it is hard to dethrone pemetrexed as the platinum partner of choice in the first-line setting given its relatively favorable tolerability and ease of use in the maintenance setting. Therefore, the KEYNOTE-189 regimen remains much more popular at least in the US. Nevertheless, IMpower150 demonstrates the potential synergy between immunotherapy and antiangiogenic agents and offers an option for patients who are not eligible for pemetrexed (eg, those with impaired renal function). It is also important to note that IMpower150, unlike KEYNOTE-189, enrolled patients whose tumors harbored EGFR or ALK alterations after progression on appropriate targeted therapy. Similar to the overall population, adding atezolizumab to bevacizumab/chemotherapy in patients with EGFR- or ALK-positive tumors also produced an OS benefit. For this reason, I strongly consider the IMpower150 regimen in patients with EGFR or ALK alterations after progression on available targeted agents although they are not included in the FDA label yet. Besides Impower150, the phase III IMpower130 trial showed an OS benefit with the addition of atezolizumab to carboplatin plus nab-paclitaxel, providing a more tolerable taxane option, especially in bevacizumab-ineligible patients.

Historically, patients with squamous advanced NSCLC have lacked effective treatment options until recently. In these patients, the most compelling data of frontline immunotherapy/chemotherapy combinations to date are from the phase III KEYNOTE-407 trial that demonstrated clear OS benefit with pembrolizumab added to carboplatin plus paclitaxel or nab-paclitaxel independent of PD-L1 expression level. While the phase III IMpower131 trial showed a PFS benefit with the addition of atezolizumab to carboplatin plus nab-paclitaxel, an OS benefit has not yet been demonstrated with early follow-up.

Immunotherapy/Immunotherapy Combinations
Following the lead of metastatic melanoma, where the anti-PD-1/anti-CTLA-4 combination of nivolumab plus ipilimumab has shown superiority to single-agent immunotherapy, there have been studies to investigate this approach in advanced NSCLC as well. Although frontline durvalumab plus tremelimumab failed to show an OS advantage vs chemotherapy in advanced NSCLC in 2 separate phase III trials, positive results from the phase III CheckMate 227 trial enrolling patients with both nonsquamous and squamous histology were presented at ESMO 2019. In CheckMate 227, frontline nivolumab plus low-dose ipilimumab demonstrated a significant OS benefit vs standard chemotherapy in patients with advanced NSCLC whose tumors have ≥ 1% PD-L1 expression in a formal statistical analysis. In a descriptive analysis, there was also an impressive OS benefit in patients whose tumors have <1% PD-L1 expression. Although the nivolumab/ipilimumab combination is not yet approved by the FDA as frontline treatment for advanced NSCLC, the opportunity to forgo chemotherapy altogether in the first-line setting may be an attractive option for certain patients. Tumor mutational burden (TMB) has been extensively evaluated as a potential predictive biomarker  for immune checkpoint inhibitors. At this point, it remains unclear whether TMB can be used as a biomarker to select appropriate patients for this chemotherapy-free approach using nivolumab plus ipilimumab as frontline treatment of advanced NSCLC.

Your Thoughts?
What are your thoughts on using frontline immunotherapy combination regimens in patients with advanced NSCLC? I encourage you to answer the polling question and post your questions and thoughts in the discussion box below.