Will Immunotherapy Move Into All Lung Cancer Patient Populations?

Experts in the field predict that one day, all patient populations of patients with non-small cell lung cancer (NSCLC) will be eligible for immunotherapy — even those who are not PD-L1-positive.

The efficacy of single-agent immunotherapy in NSCLC has been showcased, most recently with the five-year follow-up results of the CA209-003 trial at the 2017 AACR Annual Meeting. Here, it was demonstrated that treatment with the PD-1 inhibitor Opdivo (nivolumab) was associated with a five-year overall survival (OS) rate of 16 percent versus the historically seen 4 percent OS with standard chemotherapy. Opdivo was approved by the FDA in March 2015, followed by Keytruda (pembrolizumab) in October 2015, its frontline indication in October 2016, and the PD-L1 inhibitor Tecentriq (atezolizumab), also in October 2016.

Immunotherapy combinations have been moving through the pipeline, as well. The first combination regimen to potentially be approved, however, is the PD-1 inhibitor Keytruda with carboplatin/pemetrexed as a treatment for patients with metastatic or advanced non-squamous NSCLC without EGFR or ALK mutations and regardless of PD-L1 expression. The supplemental biologics license application for the regimen was granted a priority review designation by the FDA in January 2017.

“Immune checkpoint inhibitors are here to stay,” said Daniel Morgensztern, M.D. “There is a potential for a very prolonged benefit. Everybody is afraid of saying the word ‘cure’, but perhaps a few patients will be cured. Having PD-L1—negative disease is not a contraindication for this treatment, as patients who are PD-L1 negative may still benefit from it. We will give it to everybody and, if some people are lucky enough, they will have a wonderful prolonged benefit. Without a good biomarker, everybody should get a try.”

Where are we with immunotherapy in NSCLC?

In an interview with CURE, Morgensztern, associate professor, Department of Medicine, Oncology Division, Medical Oncology, Washington University School of Medicine in St. Louis, discussed both the single-agent and combination immunotherapy data in NSCLC and what researchers are poised to do next in the field.We gave an overview of the immune system, the initial data with single-agent immune checkpoint inhibitors, and then we moved on to first-line immune checkpoint inhibitors for specific patient populations. We concluded with biomarker predictors for response and the new updates from the CA209-003 trial, which looked at the five-year survival for Opdivo alone.

We have seen an explosion of immunotherapy in lung cancer for more than five years. Did you ever predict that we would get to a place where these checkpoint inhibitors make such a huge impact—and are even considered to be a first-line treatment?

We hear about Keytruda and Opdivo often, but what is new with Tecentriq?

No. I bet you nobody could even dream of having such an interesting treatment. We started to really think about this in 2012, when the first study was published. By then, we didn’t know how long the effect would last. We had seen some interesting responses and not much toxicity. By 2015, when we had the update for patients with NSCLC with the three-year survival at 27 percent with the 3 mg/kg of Opdivo, then we started to think, “Maybe we found something that will be really good; it just needs some improvements.”Tecentriq was the third immunotherapy drug to be approved in lung cancer; it was approved earlier for bladder cancer. We are seeing interesting data, and the efficacy is not much different than from Keytruda or Opdivo.

Are there combination studies of Tecentriq being conducted?

But, this is an interesting thing about Tecentriq on the studies: it also uses tumor-infiltrating lymphocytes (TILs) and PD-L1 staining, while the other studies have not considered that. All of these agents are fair game. There is a possibility that there will be less toxicity and less pneumonitis. Moreover, there is a chance that someone who progresses on anti—PD-1 therapy may still benefit from anti–PD-L1 therapy. This is something that will have to see.There are many combinations with all sorts of other PD-1/PD-L1 antibodies with anti—CTLA-4 agents, IDO inhibitors, and vaccines. There are so many studies. I am sure that some of them will be very important.

Can you highlight one or two exciting ongoing trials being done in this space?

We know what single-agent immunotherapy can do. The question is, “How can we improve that? Which will be the best combination to improve the survival without causing too much toxicity?”There has been a lot of studies with Opdivo and Yervoy (ipilimumab), the anti—CTLA-4 inhibitor, which are both from the same company. The results, at least the response rates and survival, show that the combination seems to be better than single-agent Opdivo. However, they have increased toxicity.

What we are doing is looking at the combination of Opdivo and the HS-110 vaccine, and the name of the study is DURGA—which is the name of an ancient goddess with multiple arms. That tells you that we are increasing the number of arms in the trial.

What are your thoughts on the combinations of immunotherapy plus chemotherapy?

The initial results are very encouraging. One of the aspects is that just having PD-L1 expression in the tumor may not mean much. It has to be taken in the context, and we need to have TILs to kill the cancer cells. For some patients, single-agent anti—PD-1/PD-L1 may be enough; however, for the majority of patients, we need to increase the number of TILs. You can possibly do it with anti–CTLA-four therapy, but the toxicities may not allow you to give them [a high dose], for example. Whereas, if you give a vaccine, that will increase the number of TILs without adding too much toxicity to the existing checkpoint inhibitors. Perhaps, you can give them three therapies. We [could] cure with more than one or two drugs.I think it is a good idea. There is the KEYNOTE-021 study where patients receive chemotherapy with or without Keytruda. The results, in terms of response rate and PFS, favored the combination therapy. Yet, there was no difference of OS. The difference there I see is that, for the patients who are eligible for this study, they probably have a second chance. Meaning, if they got the chemotherapy (and progressed) they may have a chance of receiving Keytruda later.

If you were to jump ahead a few years in this field, what does immunotherapy in NSCLC look like?

However, there are some patients that we see who will not be eligible for this study. We just want to decrease the tumor, and this arrangement gives you almost a 50 percent response rate— regardless of PD-L1 test results. It is a valuable asset for the treatment of these patients who are not previously eligible, for example.In the near future, everybody will receive some form of immunotherapy. It will include checkpoint inhibitors, vaccines, combinations of chemotherapy plus checkpoint inhibitors—there are many possible combinations. I find it hard to believe that any patient should be precluded from receiving those treatments. The only patient population that will be left behind are the ones with comorbidities or complications.

However, there are studies even looking to that. At some point, we have to take a risk. When we started, patients with parotitis or hypothyroidism were not eligible, and patients with hepatitis C were considered to be dangerous (to treat with immunotherapy). Now, we are increasing the number of patients who can be treated. Hopefully, we will have a better idea of which patients are a prohibitive risk and which patients can be tried. Now, we have a very good treatment. We don’t want anyone to be left behind unless it is really dangerous. And, if it is dangerous, can we revert that? Can we give it at least a try?