Immunotherapy Efforts Forge Ahead in Stage III NSCLC

Gregory M. M. Videtic, MD, CM, FRCPC

The shift in standard of care, based on results from the phase III PACIFIC trial, continue to underscore the role of immunotherapy for patients with stage III unresectable non—small cell lung cancer (NSCLC), said Gregory M. M. Videtic, MD, CM, FRCPC.

"The PACIFIC trial was proof of the benefits of immunotherapy for these patients," said Videtic. "It was remarkable because it was the first innovation in a long time, suggesting that the addition of a new drug could improve overall survival.”

In February 2018, the FDA approved durvalumab (Imfinzi) for patients with locally advanced, unresectable disease who have not progressed following concurrent chemoradiation, based on an overall survival (OS) benefit demonstrated with the PD-L1 inhibitor versus placebo in the PACIFIC trial.¹

Durvalumab’s label was updated following 3-year results of PACIFIC, which showed that the OS remained consistent with the previously reported findings. In this analysis, the median OS was not reached with durvalumab compared with 29.1 months with placebo (HR, 0.69; 95% CI, 0.55-0.86).²

Despite this advancement, questions still remain regarding immunotherapy in this space, explains Videtic.

"Timing of immunotherapy with respect to concurrent chemoradiotherapy remains a question," said Videtic. "Also, there is the question of whether immunotherapy itself could replace conventional chemotherapy. For all the benefits standard chemotherapy has, the associated toxicities still impact how we make decisions with patients. Immunotherapy has a different toxicity profile, so the idea of perhaps replacing chemotherapy with immunotherapy is interesting."

In an interview during the 2019 OncLive^® State of the Science Summit™ on Non—Small Cell Lung Cancer, Videtic, a professor of medicine at Case Western Learner College of Medicine, and a radiation oncologist in the Department of Radiation Oncology at Taussig Cancer Center, Cleveland Clinic, discussed ongoing developments with immunotherapy in stage III NSCLC.

OncLive: Prior to the PACIFIC trial, what developments occurred in this space?

Videtic: Previous research looked at the role of concurrent chemoradiotherapy in terms of managing locally advanced lung cancer and the idea that, sometimes, more is not better. A number of randomized trials have shown that adding more chemotherapy, other than concurrent chemotherapy to radiotherapy, did not improve outcomes.

Also, the development of the definitive dose of radiotherapy in stage III lung cancer was important. A recent trial showed that, again, unfortunately, more radiation did not result in improved outcomes compared with standard radiotherapy.

Until very recently, the backbone for care was based on findings that there is a certain dose of radiation that seemed to be effective. Also, there was a limited amount of chemotherapy that could be given with radiotherapy that produced a certain outcome and a reasonable median survival. The point was to use that as a springboard to discuss how immunotherapy was introduced into the management of stage III lung cancer.

Could you expand on the introduction of immunotherapy to this setting?

Essentially, that came out of the experience in advanced stage IV lung cancer, where immunotherapy was shown to have an impressive impact on survival. Because the feeling was that stage III lung cancer is impacted by its risk of distant failure, the concept of introducing immunotherapy into management was a rational approach—based on its benefits in stage IV lung cancer.

A lot of observations have been made: radiotherapy enhances the efficacy of immunotherapy. In stage III lung cancer, we [thought that] immunotherapy that might improve distant effects and control, and radiotherapy that would be given upfront might enhance the immunotherapy itself.

What were the findings of the PACIFIC trial and the impact they have had on this space?

The results of the PACIFIC trial first came out as a PFS improvement, but in the community, everybody was waiting for the OS benefits, which came out in 2018. They showed a dramatic improvement in OS at each time point that it has been reported at. My recommendation is, as we have done at Cleveland Clinic, we have adopted that as a standard of care for appropriate patients who come in with a diagnosis of locally advanced stage III NSCLC.

The patient cohort that was used in the trial was not stratified by PD-L1 status. It appeared that all patients, regardless of PD-L1 status, had benefit. That is important in real life as to whether or not a physician should start treatment.

Also, there was a suggestion that starting immunotherapy earlier rather than later, after the completion of concurrent chemoradiotherapy, might result in improved outcomes. Although that wasn't a planned analysis, it is still provocative enough that anyone considering durvalumab after completing concurrent chemoradiation should look into starting it earlier rather than later. As far as we are concerned, that is our standard of care now.

There may be patients who have stage III lung cancer who, for other medical reasons, are not appropriate for that therapy. It is still valid to offer them standard of care, but using that treatment as a springboard for making those decisions. That, in essence, is what the core message is.

Did the PACIFIC trial leave any unanswered questions?

Besides the PACIFIC trial, I mentioned other smaller, phase II trials, one of which basically corroborated the findings using pembrolizumab (Keytruda). Although it wasn't a phase III trial, it provides a supportive piece of evidence that it is probably not drug-specific, it may be immunotherapy in general.

The other two trials I mentioned looked at incorporating immunotherapy earlier in disease. The point was that as it stands right now, there is no evidence to support giving durvalumab, for example, before or during concurrent chemoradiotherapy. We don't understand the toxicity impact that these particular combinations have.

One of the trials, which used different drugs, suggests that toxicity is greatly increased when you add immunotherapy with concurrent chemoradiotherapy. That doesn't mean it shouldn't be explored more, but we have to be cautious about looking for improvements where there might be competing toxicity risk.

Historically, we tested chemotherapy and radiation in different combinations. Now it is entirely reasonable to do that in the setting of immunotherapy. There is obviously a large number of ongoing trials that are looking at those questions.

It is very appropriate for treating physicians to use the model of the PACIFIC trial and not to tinker with it in terms of the administration of immunotherapy.

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 J, Villegas AE, Daniel DB, et al. Three-year overall survival update from the PACIFIC trial. J Clin Oncol. 2019;37(15 suppl; abstr 8526). doi: 10.1200/JCO.2019.37.15_suppl.8526.