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Expert Says Paradigm Shift Imminent in SCLC

Angelica Welch
Published: Thursday, Jun 07, 2018

Anne Chiang, MD, PhD
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.

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.

OncLive: Can you provide some insight on the current 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.

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.

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?

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.

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. 

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

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.




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