On April 16, 2018, data from multiple pivotal trials in first-line (1L) non-small-cell lung cancer (NSCLC) were presented at the American Association for Cancer Research (AACR) Annual Meeting 2018. Clearly, the need to publish data in an expediated fashion is more important than ever for companies developing cancer immunotherapies. Below are Prescient Healthcare Group’s key takeaways from the data and discussant presentations.
Merck continues to generate positive data to support Keytruda uptake in NSCLC
In the short term, KEYNOTE-189 suggests that Keytruda (pembrolizumab; anti-PD-1) is likely to be reinforced as the SoC in NSCLC regardless of patients’ PD-L1 status. Nevertheless, samples will likely still be tested for PD-L1 status to help inform treatment decisions in patients with staining on 50% or more of their tumor cells. When Keytruda + chemotherapy (KEYNOTE-189) was compared with Keytruda alone (KEYNOTE-024) in a PD-L1 high-expressing population, the combination resulted in higher response rates (61% vs. 45%) and a more impressive overall survival (OS) hazard ratio (HR) (0.42 vs. 0.63). The one-year survival rate, however, was not significantly different between the two options (73% vs. 70%); this may result in a more conservative approach for certain patient populations. Specifically, chemotherapy may be reserved for later lines of therapy for physicians wishing to sequence therapies or trying a chemotherapy-free regimen for patients who may be at risk of emerging renal toxicities with the Keytruda-chemotherapy combination.
Opdivo + Yervoy data suggest benefit in patients with a high TMB who were selected with the approved FoundationOne CDx assay, but regulatory timelines remain unclear
There was also a first-time data presentation from BMS’ CheckMate-227 study, which investigated Opdivo (nivolumab; anti-PD-1) + Yervoy (ipilimumab; anti-CTLA-4) vs. chemotherapy. The study had a complex three-arm design, with patients stratified by PD-L1 status and tumor mutational burden (TMB) (the latter was added after a protocol amendment). The presentation stressed that, in patients with high TMB, one-year progression-free survival (PFS) and duration of response (DOR) were tripled for the combination relative to the chemotherapy comparator. The objective response rate (ORR) was also higher for the combination, and the responses were noted to be deeper in the combination arm than in the comparator arm. In addition, a preliminary, descriptive OS analysis was presented suggesting a trend toward improved survival (HR = 0.79; 95% CI: 0.56-1.10). While the trend is not as impressive as in the KEYNOTE studies, it is worth noting that CheckMate-227 includes squamous NSCLC patients who typically have poorer outcomes than those with non-squamous histology. The presentation also noted that there was a step-wise improvement in one-year PFS rates in PD-L1-positive patients when the chemotherapy comparator was compared to Opdivo (+13%), and when Opdivo was compared to Opdivo + Yervoy (+13%). It is unclear whether BMS will be able to submit these data for regulatory approval, as the TMB-defined endpoint was only prespecified and not prospectively studied, but it is becoming clear that the availability of the FoundationOne panel could help physicians incorporate Opdivo + Yervoy into their practices. If the regimen is approved, the area of initial traction is likely to be in the small subset of patients, approx. 12%, who are TMB-high and PD-L1-low. Additional data are needed to ascertain whether this will be a competitive treatment regimen for all TMB high patients, which represents almost half of the patient population.
The combination of Tecentriq, Avastin and chemotherapy is shown to be efficacious in high-risk subgroups, but OS data are needed to prove the overall benefit of Avastin in the anti-PD-(L)1 plus chemotherapy regimen
Roche/Genentech presented Phase III subgroup data from the IMpower150 study investigating Tecentriq (atezolizumab; anti-PD-L1) + Avastin (bevacizumab; anti-VEGF) + chemotherapy (arm B) vs. Avastin + chemotherapy (arm C). These data supported the use of the former combination in two groups of patients with high-risk disease – those with EGFR actionable mutations (PFS HR = 0.41) and those with baseline liver metastasis (PFS HR = 0.40) — despite the low level of PD-L1 expression in both groups. Interestingly, the PFS curves stratified by PD-L1 status had a similar pattern as seen in the KEYNOTE-189 study, hence OS data will be needed to determine whether adding Avastin to the anti-PD-(L)1 + chemotherapy regimen has any additional benefit. At this stage, Roche/Genentech appears to have made the decision to wait and present these data at ASCO 2018, suggesting that the company could make a bigger splash with data the markets may receive positively.
Data presentations highlight an increasingly complex and rapidly evolving NSCLC space
Keytruda regimens are likely to continue to gain traction with NSCLC prescribers and will largely remain unchallenged in the short term, although this could change significantly over the coming months. The Tecentriq + Avastin + chemotherapy regimen could see future use in patients in which data are lacking for Keytruda (e.g., those with EGFR actionable mutations or baseline liver metastasis). When IMpower150 OS data are available, possibly at ASCO 2018, there could be another paradigm shift, but this is yet to be confirmed. Opdivo + Yervoy is another interesting regimen that could have an impact for a small subset of 1L NSCLC patients who are TMB-high, PD-L1-low, if BMS can overcome regulatory challenges. For all studies, there will also likely be intense discussion over the pros and cons of each dataset in complicated cross-trial comparisons, but it does appear that the 1L NSCLC treatment algorithm will become increasingly fragmented.
Overall, the NSCLC commercial and development landscape will continue to evolve rapidly over the next 12 months. Companies will need constant, in-depth and accurate monitoring of this space if they are to make important clinical and commercial decisions with confidence.
- AACR. “Immunotherapy Combinations: The New Frontier in Lung Cancer.” AACR Live. http://aacrlive.capitalreach.com/ (accessed April 16, 2018).
- Gandhi L. et al. “Pembrolizumab plus Chemotherapy in Metastatic Non–Small-Cell Lung Cancer.” New England Journal of Medicine (2018). http://www.nejm.org/doi/full/10.1056/NEJMoa1801005 (accessed April 17, 2018).
- Hellmann M. et al. “Nivolumab plus Ipilimumab in Lung Cancer with a High Tumor Mutational Burden.” New England Journal of Medicine (2018). http://www.nejm.org/doi/full/10.1056/NEJMoa1801946 (accessed April 17, 2018).