Expert Says Paradigm Shift Imminent in SCLC

Anne Chiang, MD, PhD

Immunotherapy has the potential to change the treatment paradigm of small cell lung cancer (SCLC), said Anne Chiang, MD, PhD. Moreover, recent results with immunotherapy agents in the second-line setting have already influenced guidelines.

In April 2018, the FDA granted a priority review designation to a supplemental biologics license application for nivolumab (Opdivo) based on findings from the phase I/II CheckMate-032 trial in patients with SCLC with disease progression following 2 or more lines of therapy.

The combination of nivolumab and ipilimumab (Yervoy) has shown impressive results in SCLC with a high tumor mutational burden (TMB), said Chiang. In an exploratory analysis from CheckMate-032, this combination induced an objective response rate (ORR) of 46% in patients with recurrent SCLC with high TMB. This was compared with an ORR of 21% with nivolumab monotherapy.

Additionally, data with pembrolizumab (Keytruda), atezolizumab (Tecentriq), and durvalumab (Imfinzi) are expected to read out within the next few years.

Aside from immunotherapy, Chiang says that PARP inhibitors and lurbinectedin all may have a place in this landscape in the future, either as monotherapy or in combination.

OncLive: Can you provide some insight on the current treatment landscape of SCLC?

In an interview with OncLive, Chiang, a professor and thoracic oncologist at Yale Cancer Center, discussed recent developments with immunotherapy and the overall outlook for the treatment landscape of SCLC.Chiang: The landscape has changed, and that is something that is very new for SCLC because it hasn't changed that much in the past 30 years. Right now, the standard of care is giving a platinum doublet upfront for extensive-stage disease, and cisplatin and etoposide for limited-stage disease concurrent with radiation.

Nivolumab was recently granted a priority review designation by the FDA. What is the outlook for that agent, both as a single agent and in combination?

The results with immunotherapy in the second-line metastatic setting has now changed the recommendations. The NCCN guidelines have now included nivolumab alone or nivolumab plus ipilimumab for second-line treatment. That is a major change.This is an interesting situation, really. While it has not been formally approved by the FDA, it has been included in the NCCN guidelines. On the ground, many folks are starting to use it in practice. [The priority review] is based on the CheckMate-032 data, which initially showed an ORR of around 11% for patients treated with nivolumab alone and 13% for nivolumab plus ipilimumab. The exciting aspect of that is not only the response rate in the second-line setting, but also the median duration of response, which was between 14 and 18 months. Some patients had ongoing responses at 2 years. That really changed the landscape.

Are there any other immunotherapy agents coming down the pike that look promising?

At the 2017 IASLC World Conference on Lung Cancer, studies looked at incorporating the biomarker of TMB. It was reported that folks with high TMB that were treated with nivolumab alone had a response rate of around 21% versus nivolumab/ipilimumab, which was 42%. That underscores that the combination of nivolumab plus ipilimumab seems to perform better than nivolumab alone, although it is more toxic. There may be the opportunity to use a biomarker such as TMB to understand which patients are going to respond much better versus not as much. It is still a little early to say with pembrolizumab. There was a maintenance trial of about 45 patients with a disease control rate of 13%, although the response rate was much lower. We are still waiting to hear about the first-line studies from KEYNOTE-604 looking at pembrolizumab plus chemotherapy. In the original KEYNOTE-028 trial of 24 patients with SCLC, there was 1 patient with a complete response, 7 with partial responses, and an ORR of about 30%. It looks promising, but it did not perform that well in the maintenance trial.

For atezolizumab, the phase I trial showed an ORR of around 6%. However, there were a couple of patients who had a prolonged response beyond 12 months. Atezolizumab is certainly an option. The IMpower133 trial will report out relatively soon. That will be very interesting. It did recently report out that atezolizumab in combination with carboplatin and nab-paclitaxel (Abraxane) did better than chemotherapy alone. That is something that we are looking out for.

There is also the CASPIAN trial, which is with durvalumab and tremelimumab, which is a PD-1 plus CTLA-4 inhibitor combination. The trial has just finished accrual. CheckMate-451 is looking at ipilimumab plus nivolumab in the maintenance setting. That study is closed and will be reporting out in 2019.

The landscape is very exciting; there is a lot of stuff that will report out in the next year. We may have the opportunity to change the treatment paradigm for SCLC. With non—small cell lung cancer and melanoma, there are patients who do respond and patients who don't. By being able to look at the biomarkers that can predict that response—and if you can find that out early on—you can really tailor the therapy accordingly.

Are there any biomarker developments with immunotherapy in this space?

Could PARP inhibitors have an impact in SCLC?

Is there anything else happening in SCLC that we should be paying attention to?

The question for frontline trials is whether immunotherapy will be able to improve chemotherapy alone, as chemotherapy alone is already very effective for SCLC.I have a trial now looking at patients in the second- and third-line settings treated with nivolumab plus ipilimumab with a biological endpoint. We are looking at the ratio of effector cells to suppressor cells to see if that could help. Folks are looking at circulating tumor cells; there is some interesting data there. Certainly, the TMB data are really interesting. It is currently not part of standard practice; it is only available through some of the tests that are commercially available. PARP inhibitors have always been interesting for SCLC. They are involved in DNA repair, and SCLC has very actively growing cells and a high TMB. There is a lot of DNA repair going on. Olaparib (Lynparza), veliparib, and talazoparib are very exciting PARP inhibitors. There is a phase II study with temozolomide plus veliparib versus placebo that looks very promising, with a response rate of 40% or so versus 15% for temozolomide alone. It will be important to find a biomarker for that group of agents, as well as to help predict which patients will respond. PARP inhibitors in combination with immunotherapy might be a great.There was a lot of interest in rovalpituzumab tesirine as a first-in-class antibody-drug conjugate. The initial data showed about a 40% response rate in high-DLL—expressing patients. Recently, the trial with heavily pretreated patients reported out and it did not look positive. However, that drug is still interesting—perhaps in combination or for a very select population.

Lurbinectedin is another agent that has a number of different mechanisms, including DNA double-strand breaks, which effects the tumor microenvironment. That in combination with doxorubicin had a very nice response rate in the second-line setting. The single-agent trial is ongoing. That is something to look out for.

There will also be a lot of interesting combinations. Some investigators are looking at demethylation agents.

At Yale Cancer Center, we are interested in trying to understand the signature and what is happening in patients with SCLC. SCLC tumors don’t typically overexpress PD-L1, so we need to understand how to activate those tumors. Do you use immunotherapy in combination with some sort of interleukin? We are exploring those combinations now.