Levy Lends Insight on Promise of Checkpoint Inhibitors in SCLC

Benjamin P. Levy, MD

The reach of immunotherapy has extended into small cell lung cancer (SCLC), waking up a treatment landscape that had become somewhat dormant. Despite these advances, however, investigators are still struggling with this patient population, said Benjamin P. Levy, MD.

In the pivotal IMpower133 study, the addition of atezolizumab (Tecentriq) to the combination of carboplatin and etoposide led to a 30% reduction in the risk of death compared with carboplatin/etoposide alone (HR, 0.70; 95% CI, 0.54-0.91; P = .069). At a median follow-up of 13.9 months, median overall survival (OS) in the atezolizumab arm was 12.3 months compared with 10.3 months in the control arm. In addition, median progression-free survival (PFS) was 5.2 months versus 4.3 months in favor of the atezolizumab arm (HR, 0.77; 95% CI, 0.62-0.96; P = .017).

These data led to the March 2019 FDA approval of the PD-L1 inhibitor in combination with carboplatin and etoposide for the frontline treatment of patients with extensive-stage SCLC.

Pembrolizumab (Keytruda) is also showing promise in this space. Based on positive data from the phase II KEYNOTE-158 and phase Ib KEYNOTE-028 trials, the PD-1 inhibitor was granted a priority review designation from the FDA in February 2019 for the treatment of patients with SCLC who progressed on 2 or more prior lines of therapy. However, Levy stressed that new data will need to be “astounding” in order for pembrolizumab to replace the use of atezolizumab.

“If the data turn out to be the same, it would be hard for physicians to change their practice of adding atezolizumab to chemotherapy,” said Levy. “Nevertheless, I look forward to the data and I look forward to seeing if a PD-1 inhibitor confers the same benefit that we have seen with atezolizumab.”

OncLive: What is your perspective on the FDA approval of atezolizumab plus carboplatin and etoposide in SCLC?

In an interview with OncLive, Levy, an assistant professor of oncology and the clinical director of Medical Oncology at Sidney Kimmel Cancer Center and Johns Hopkins Medicine, discussed the rise of checkpoint inhibitors in SCLC, an emerging targeted agent in non—small cell lung cancer (NSCLC), and the road that lies ahead in the overall landscape.Levy: For many years, we have been looking for novel therapies to improve outcomes for patients with SCLC, an unforgiving disease. Time after time, we have seen that the drugs we tried have just failed to work. Things have changed, of course, with IMpower133. This was a trial looking at the combination of atezolizumab with carboplatin and etoposide versus carboplatin and etoposide alone in patients with extensive-stage SCLC. There were more than 400 patients enrolled in this study and they were randomized 1:1. The bottom line is that when atezolizumab was added to carboplatin/etoposide and continued as maintenance, there was a benefit not only in PFS, but also in OS. There was roughly a 2-month improvement in OS, with a hazard ratio of 0.7. These are numbers that have really been unheard of in SCLC.

Again, we have tried multiple times to improve outcomes but have failed. The authors for this trial and the efforts made here should be commended. The uptake [of this combination] will be brisk, given how long we've waited for a new therapy and the enthusiasm with immunotherapy in other diseases. Now, for any patient with extensive-stage SCLC that I have, and I have several, I have begun to use the regimen with the addition of atezolizumab. Just a footnote, [we still need to be cognizant of] toxicity, because there is always concern when adding immunotherapy to chemotherapy.

Pembrolizumab has also received a priority review designation by the FDA. What are some ongoing trials that are evaluating this agent in SCLC?

However, what we have found in this trial, as we have found in NSCLC, is that the toxicity is not prohibitive. Generally, the 3-drug regimen is well tolerated. This is a welcome change for doctors and oncologists, but more importantly, for patients.We are on waiting on these data. It The [ongoing KEYNOTE-604] trial has a very similar design [to IMpower133]: adding pembrolizumab to carboplatin and etoposide versus carboplatin and etoposide alone in extensive-stage disease. We will have to see how these data shake out.

Are there any other trials to look out for in the SCLC space?

Of course, pembrolizumab has an approval for use in combination with chemotherapy in the treatment of both adenocarcinoma and squamous cell NSCLC in patients without a genetic alteration. In trying to forecast, the data would have to be much better than what we saw with IMpower133 for there to be anything practice-changing, in my mind.We are still struggling with how to optimize outcomes with novel therapies in SCLC. There have been novel chemotherapy approaches that are being looked at. An antibody-drug conjugate called rovalpituzumab tesirine (Rova-T) is another drug that has traction in some lines of therapy for SCLC.

In terms of NSCLC, what data are we seeing with entrectinib in ROS1-positive and NTRK fusion—positive disease?

However, we are still at the very beginning of the story on how to optimize outcomes for these patients. Unfortunately, SCLC has not shared the same advances that have been made in NSCLC. We don't have genetic alterations in SCLC that we can use to target with targeted therapies, so we really have to be nimble in our approaches to treatment. IMpower133 changed the standard, and the next steps will be to look at the refractory setting post-atezolizumab to see if the science fits in there as well.Entrectinib is yet another targeted therapy that is making its way into the NSCLC space. The current evaluation of this drug is in ROS1 and NTRK fusions in patients with advanced-stage cancers. We've seen a composite endpoint from multiple trials evaluating entrectinib in both ROS1 and NTRK fusions. In NTRK fusions, entrectinib elicits a response rate close to 55% and a PFS of anywhere between 10 to 12 months. I would say that's important.

Of course, we already have a drug called larotrectinib (Vitrakvi) that is FDA approved, and where this fits into the space is something that we will have to sort out in the future. With ROS1—remember, entrectinib not only hits NTRK but also ROS1—we have some really good data coming out from the STARTRK trials, which have shown that the agent elicits a response rate ranging form 70% to 75%. This drug is really not active in crizotinib (Xalkori)-refractory patients; it is mostly for genotype-directed, therapy-naïve patients. Therefore, we will have to see what the FDA does with these data in order to determine if entrectinib will be another available option for NTRK fusions.

Horn L, Mansfield AS, Szczęsna A, et al. First-Line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer. N Eng J Med. 2018;379(23):2220-2229. doi: 10.1056/NEJMoa1809064.