Immunotherapy Advances SCLC Paradigm, But More Work to Be Done With Combos

Neal E. Ready, MD, PhD

Neal E. Ready, MD, PhD

The biggest advancement seen in small cell lung cancer (SCLC) in recent years was the data that came from the phase III IMpower133 trial, which showed that the addition of atezolizumab (Tecentriq) to chemotherapy led to a statistically significant improvement in overall survival (OS), said Neal E. Ready, MD, PhD.

“In that trial, there was a clinically meaningful 2-month improvement in OS with the addition of the atezolizumab to chemotherapy, and this had not been seen in any phase III trials trying to improve standard of care in this setting over the last 20 to 30 years,” said Ready.

The combination of atezolizumab with carboplatin and etoposide for the frontline treatment of patients with extensive-stage SCLC was approved by the FDA in March 2019 based on the IMpower133 data, which showed that the combination resulted in a median OS of 12.3 months (95% CI, 10.8-15.9) compared with 10.3 months (95% CI, 9.3-11.3) in those who received the chemotherapy alone at a median follow-up of 13.9 months.¹ This translated to a 30% reduction in the risk of death (HR, 0.70; 95% CI, 0.54-0.91; P = .0069). The regulatory decision marked the first cancer immunotherapy approval for the initial treatment of extensive-stage SCLC.

Immunotherapy combinations have also been an exciting area of research in the space. One combination of particular interest is that of nivolumab (Opdivo) plus the CTLA-4 antibody ipilimumab (Yervoy). Although this combination has shown high response rates, according to Ready, it failed to improve OS when used as a maintenance therapy in patients with extensive-stage disease without progression following platinum-based chemotherapy in the phase III CheckMate-451 trial.²

“I was involved with that trial and we were certainly disappointed by [the results from] that,” said Ready. “One concern was that there was significant toxicity with the combination and the other was in the way the drugs were combined in that particular setting, in a large randomized trial. There is also the concern that we weren't able to give enough treatment to enough patients to see a difference.”

In an interview during the 2019 OncLive^® State of the Science Summit™ on Non—Small Cell Lung Cancer, Ready, a professor of medicine and member of the Duke Cancer Institute, highlighted recent advances that have been made in the treatment of SCLC, the promise of immunotherapy, and opportunities to improve patient care.

OncLive^®: What is the role of immunotherapy in SCLC?

Ready: The major progress in this space is the IMpower133 trial, and that was a large, randomized phase III trial in which patients received standard chemotherapy with or without the PD-L1 checkpoint antibody atezolizumab.

Immunotherapy activates the body's own immune system to fight the cancer, and there have been only anecdotal responses seen in various settings over the last 100 years or so. The basic science that led to two Nobel prizes showed that there are certain checkpoints on the immune cells that allow the tumor to turn the immune system off, and now we have ways to target that “off” switch on the immune system to react against the tumor and potentially attack it.

That’s what atezolizumab does; it's one in that class of antibodies that can activate the immune system to attack the cancer, and in this situation, the addition of atezolizumab to standard chemotherapy added on OS to patients with SCLC; it was particularly important that for some of the patients, even though it was a minority, some of that benefit seemed to extend out to 1 or 2 years.

What other immunotherapy agents or combinations are under investigation?

Immunotherapy as a single therapy, like nivolumab or pembrolizumab (Keytruda), has been shown to have activity in patients who had already received chemotherapy. While it's a minority of patients who have responded [to this approach], what's exciting is that the responses have been durable, with sometimes 1, 2, or even more, years of cancer control with minimal toxicity. Immunotherapy combinations have also shown some promise. For example, the combination of nivolumab plus ipilimumab has shown high response rates, but that has not [translated into] improved OS yet in randomized trials. Regardless, there are early promising results [with this approach].

Could you expand on the ongoing research with pembrolizumab?

Pembrolizumab is being studied in the upfront setting in a trial very similar to the IMpower133 trial: the KEYNOTE-064 trial. In that trial, patients received standard chemotherapy, just like in IMpower133, but in KEYNOTE-064, pembrolizumab was added to chemotherapy rather than atezolizumab. That was a randomized, phase III trial that completed accrual quite a while ago, so now we're waiting for the results. We’re hoping that this will also be a positive trial because it would be nice to have additional options.

Could you discuss some of the negative studies that we’ve seen, such as the CheckMate-451 trial? What did we learn from that research?

That was a trial where patients received standard chemotherapy. The thought was that, if the cancer became controlled and patients were stabilized so that they were in better shape and maybe their immune systems were also in better shape, then perhaps adding immunotherapy after the chemotherapy would be better tolerated. We would be able to give single-agent immunotherapy or the combination of nivolumab and ipilimumab—and have it be better tolerated and more effective. However, SCLC has just been a particularly “tough nut to crack,” and for whatever reason—and there are probably several—it just didn't work in this setting.

What are some of the reasons why this approach did not work?

That's just a tough question. The current combination of nivolumab and ipilimumab that was studied in the trial was determined in a large phase I trial and there was significant toxicity. The Checkmate-451 trial was a large, randomized phase III trial that was done worldwide, and it may have been difficult for people out in the community who didn't have experience using nivolumab and ipilimumab in that combination. They may have just had a hard time giving that treatment and dealing with the immune-related toxicity.

Doctors who are involved with phase I trials, lung cancer experts at big centers who have done a lot of work with combination therapy, or melanoma doctors who are used to giving that combination to younger and fitter patients, probably have the ability to give the therapy and manage the adverse events better.

However, those data are still under analysis, so we'll just have to see. [Regardless), immunotherapy combinations are going to be important. When you look at the combination therapy that was decided upon for a study in non—small cell lung cancer, which was full-dose nivolumab with low-dose ipilimumab given at 1 mg/kg every 6 weeks, that was found to be tolerable in a large phase III trial. Then, there is the CheckMate-227 trial, which looked at tumor mutational burden, [and found that the combination] did improve progression-free survival compared with chemotherapy and it was tolerable. Combination immunotherapy is approved for use in melanoma and in renal cell carcinoma, so I still believe that it does have the opportunity to be effective in lung cancer if we just get the right combination and the right setting.

Beyond immunotherapy, are there any exciting emerging approaches on the horizon?

DLL3 is a potentially important target [in this space]. The DLL3 protein is generally not expressed on the normal cells on our body, but it is expressed in about 70% of SCLC. An antibody-drug conjugate called rovalpituzumab tesirine (Rova-T) showed activity when targeted against DLL3, but due to a combination of modest activity and some significant toxicity, it hasn't yet gotten over the hump to receive an FDA approval. However, it certainly has shown promising activity and it has validated DLL3 as a target.

PARP is also a target; it is an important enzyme in DNA repair, which is important for cancer cell growth and survival; it's also important for presenting potentially developing antigens that the immune system can respond against. Including PARP inhibitors with chemotherapy has shown some promise, but not enough promise by itself to receive an approval. We would have to identify either a biomarker to [determine which] patients are benefiting the most. There is also some research looking at PARP inhibitors with temozolomide (Temodar) that looks promising, as well as preclinical research looking at PARP inhibitors with immunotherapy.

DLL3 is now being looked at with the bispecific T-cell engager antibody approach that is being pursued by some pharmaceutical companies; it is also looking like a good target for CAR T-cell therapy, which has been shown to be active and is standard therapy in some leukemias and lymphomas.

References

1. Liu S, Mansfield A, Szczesna S, et al. IMpower 133: primary PFS, OS and safety in a ph1/3 study of 1L atezolizumab + carboplatin + etoposide in extensive-stage SCLC. Presented at: IASLC 19th World Conference on Lung Cancer; September 23-26, 2018; Toronto, Canada. Abstract PL02.07.
2. Bristol-Myers Squibb Announces CheckMate-451 Trial Study Did Not Meet Primary Endpoint of Overall Survival With Opdivo Plus Yervoy Vs. Placebo as a Maintenance Therapy in Patients with Extensive-Stage Small Cell Lung Cancer After Completion of First-Line. Bristol-Myers Squibb. Published November 26, 2018. http://bit.ly/2MIbwln. Accessed June 11, 2019.