Boosting Impact of Immunotherapy in Earlier NSCLC Settings

Jamie E. Chaft, MD

The improvement in progression-free survival (PFS) and overall survival (OS) with durvalumab (Imfinzi) after concurrent chemoradiotherapy in patients with stage III unresectable non—small cell lung cancer (NSCLC), and the preliminary signals of activity reported with checkpoint inhibitors in the neoadjuvant setting have shown the tremendous impact immunotherapy can have in earlier NSCLC stages, explained Jamie E. Chaft, MD.

Data from the phase III PACIFIC trial changed the standard of care for patients with unresectable stage III NSCLC with an 11.2-month improvement in median PFS with the addition of durvalumab in those who had not progressed on chemoradiation (16.8 vs 5.6 months; HR, 0.52; 95% CI, 0.42-0.65; P <.001).¹ These data led to the 2018 approval of the PD-L1 inhibitor in this indication. Updated results showed that, at a median follow-up of 33.3 months, the median OS had yet to be reached in the durvalumab arm (95% CI, 38.4 months—not reached) versus 29.1 months in the placebo arm (95% CI, 22.1-35.1).²

Despite these survival gains, the regimen is not suitable for every patient, said Chaft, who cited autoimmune conditions, pneumonitis, and interstitial lung disease as primary contraindications.

“A lot of education is needed to better understand who may benefit and who may be harmed by these interventions, as well as what the actual advantages are, so that there is more uptake across the community,” explained Chaft.

In the neoadjuvant setting, checkpoint inhibition could prove to be an equally effective strategy. Currently, nivolumab (Opdivo) is under investigation both as a single agent and in combination with ipilimumab (Yervoy; NCT02259621) in patients with resectable NSCLC. Checkpoint inhibitors are also being evaluated in combination with chemotherapy in the neoadjuvant setting, which, in the absence of a predictive biomarker, may be the most rationale route forward, according to Chaft.

“At this point, there is tremendous commitment from industry around the world to study pre- and postoperative immunotherapy,” said Chaft. “There are real opportunities to improve upon the outcomes of all of our patients.”

In an interview during the 2019 OncLive^® State of the Science Summit™ on Non—Small Cell Lung Cancer, Chaft, a medical oncologist at Memorial Sloan Kettering Cancer Center, explained how the PACIFIC trial has impacted the treatment of patients with stage III unresectable NSCLC and the research being done to move immunotherapy into the neoadjuvant setting.

OncLive: Could you discuss the most recent data that have been reported from the PACIFIC trial in stage III NSCLC?

Chaft: The data presented on the PACIFIC trial at the 2019 ASCO Annual Meeting were really reaffirming. The data showed that OS continues to trend as we would have hoped. It truly looks like some patients are being cured by this intervention. Of course, we always like to see longer-term follow-up, but the use of durvalumab after concurrent chemoradiotherapy has shown an improvement in PFS and OS in a very real-world patient population. This regimen is a standard of care in all patients [with unresectable stage III disease], particularly in those with PD-L1 expression.

Are you giving durvalumab within 14 days of completing chemoradiation in eligible patients in accordance with the subgroup analysis?

No. Unfortunately, that subset is heavily biased in that these were fitter patients who were well enough to start [durvalumab] within 2 weeks [of completing concurrent chemoradiotherapy]. I don't find that cut-off to be that clinically relevant.

What are the contraindications to receiving durvalumab after chemoradiotherapy?

One is pneumonitis from the chemoradiotherapy. Unfortunately, we do not always know that at the time of initiating [durvalumab]. The main contraindications are autoimmune diseases or interstitial lung disease. A strong family history of autoimmune disease may be another reason to [forego durvalumab]. There is less clarity on what to do in patients with oncogene-driven disease.

Could you discuss the research that is being done to move immunotherapy into the neoadjuvant setting?

We published data in The New England Journal of Medicine in conjunction with investigators at Johns Hopkins Medicine. We showed that a small subset of patients who received just 2 doses of nivolumab had a very unexpected response rate. That was replicated at The University of Texas at MD Anderson Cancer Center where Tina Cascone, MD, PhD, and colleagues reported an impressive major pathologic [response] rate with nivolumab. The data were even more impressive [with nivolumab] in combination with ipilimumab, particularly in terms of the number of pathologic complete responses (pCRs).

The data we have with atezolizumab (Tecentriq) does not look as overwhelming, but that is what happens when you have more patients [enrolled on the trial]. It is also more reflective of the real-world [population] and more along the lines of what we would expect in terms of the pCR rate being comparable with chemotherapy. This tells us that we need better biomarkers in this patient population. The way of the future in this patient population lies in the combination of chemotherapy and immunotherapy, [based on prior data] demonstrated by Catherine Ann Shu, MD, of Columbia University Irving Medical Center, et al, and also Mariano Provencio, MD, of Hospital Puerta de Hierro. We are seeing truly amazing pCR rates with the combination of chemotherapy and immunotherapy in the preoperative setting.

My goal in the next few years is to have a clinical trial for all patients with early-stage lung cancer, whether it is an observational study to try to improve on available biomarkers, or an interventional study to try to improve patient outcomes. In doing this, we can make medicine more personalized.

References

1. Antonia SJ, Villegas A, Daniel D, et al. Durvalumab after chemoradiotherapy in stage III non—small-cell lung cancer. N Engl J Med. 2017;377(20):1919-1929. doi: 10.1056/NEJMoa1709937.
2. Gray JE, Villegas AE, Daniel DB, et al. Three-year overall survival update from the PACIFIC trial. J Clin Oncol. 2019;37(suppl 15; abstr 8526). doi: 10.1200/JCO.2019.37.15_suppl.8526.