Anne Chiang, MD, PhD, Studies Biomarkers for Immunotherapy Response in SCLC

Anne Chiang, MD, PhD
Associate Professor of Medicine
Yale School of Medicine
Chief Integration Officer
Deputy Chief Medical Officer
Smilow Cancer Network
New Haven, CT

A pilot study¹ (NCT03670056) of paired biopsies following treatment with ipilimumab (Yervoy) and nivolumab (Opdivo) in recurrent extensive-stage small cell lung cancer (ES-SCLC) suggested potential predictors of treatment efficacy, according to initial results presented at the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting.

In an interview with CancerNetwork^®, Anne Chiang, MD, PhD, associate professor of medicine at the Yale School of Medicine, deputy chief medical officer and chief integration officer for Smilow Cancer Hospital, and lead investigator of this study, spoke about the potential importance of biomarker analysis in the treatment of ES-SCLC and the implications for this research in understanding responses to immunotherapy in this setting.

In 15 patients with ES-SCLC whose disease was recurrent after 1 platinum-containing chemotherapy regimen and who had responses evaluable per RECIST, the overall response rate (ORR) was 13%, comprised of 2 partial responses. The disease control rate (DCR) was 40%, with 4 instances of stable disease (27%). Moreover, multiplexed quantitative immunofluorescence analysis of paired biopsies obtained from patients revealed changes to both CD8-positive effector T cells and CD4-positive regulator T cells which were associated with clinical activity. Investigators therefore concluded that these results supported further exploration of biomarker analysis as predictive of immunotherapy efficacy in patients with SCLC.

CancerNetwork^®: What was the rationale for assessing ipilimumab and nivolumab in ES-SCLC?

Chiang: [Effective treatment for] ES-SCLC is such an unmet need. New drug approvals [in this space] have been very exciting over the past few years, but we still have a long way to go. Currently, a major issue is that patients on maintenance with immunotherapy may develop resistance [to that treatment]. This combination of ipilimumab and nivolumab originally showed activity in a phase 1 trial [NCT01928394],² so we were very interested in understanding this combination’s mechanisms of response in ES-SCLC.

It’s a huge issue for all lung cancer that [only a subset] of patients may respond to therapy. In fact, out of 22 patients in this trial, there was 1 patient who showed a very good response to treatment and is still doing well almost 2.5 years since starting this therapy.

The rationale for this trial was to acquire biopsies both before and during treatment in week 4, by which time patients had taken 2 doses of the combination. This allowed us to examine differences in the tumor microenvironment and to better understand which patients were responsive and which were not. One of the ‘Holy Grails’ for SCLC research is to find biomarkers that can help us determine which patients will respond to treatments. Of course, [our other objective was] to develop an effective combination therapy for patients with ES-SCLC who progress on immunotherapy.

Did a biomarker analysis occur in this study or is it planned for a future study?

This study involved biomarker analysis as a primary end point. Our main objective was to look for changes in the tumor microenvironment from the pretreatment biopsies to the week 4 biopsies. In SCLC, obtaining tissue to study changes at the cellular level has [historically] been very difficult. This was identified by the National Cancer Institute [NCI] as an area of unmet need. As such, we were very happy to acquire 14 paired biopsies which is almost unheard of in our field. This allowed us to examine those changes in the biomarkers and the tumor microenvironment from pretreatment to after 2 cycles of treatment.

Did any other findings stand out to you?

More analysis will be necessary, but some patients did respond to ipilimumab with nivolumab, including some patients who had already been on maintenance immunotherapy or had been exposed to immunotherapy in the past. That’s the most important result. Regarding biomarkers, our study also showed that these paired biopsies are feasible in SCLC. Additionally, when we examined the CD8-positive effector T cells, CD4-positive regulatory T cells, and the Foxp3-expressing regulatory T cells in the pretreatment biopsies, we found low levels of T-cell infiltration, which reinforced what we already knew about these tumors. However, in the week 4 biopsies, we found marked T-cell infiltration, especially CD8 T-cells, and it seemed to correlate with clinical activity, either a response to treatment or stable disease. We’re very excited about these results because understanding what’s happening in the tumor microenvironment will help us better determine which patients with ES-SCLC will respond to therapy.

Where do you see future research going from here?

We still have a lot of work to do examining these changes in the tumor microenvironment. In the current literature, there are many papers in which researchers are starting to examine tumor microenvironments in lung cancer, including SCLC. [With the help of] my collaborator, immunopathologist Kurt Schalper, MD, PhD, we used quantitative immunofluorescence to examine a whole host of molecules and biomarkers on the outsides of cancer cells and immune cells in the tumor microenvironment. Pairing that with information around sequencing will allow us to examine the mechanisms of resistance to immunotherapy and determinants of response in SCLC directly.

What are some of the multidisciplinary implications of this research?

Multidisciplinary care is at the heart of our work. [We collaborate with] radiation oncologists in limited-stage SCLC and with surgeons in early-stage SCLC to obtain tissue. Beyond that, we also collaborate with our pathologists, radiologists, and interventional pulmonologists to obtain biopsies. We’ve developed great working relationships with many researchers at Yale and that has allowed us to obtain these kinds of biopsies for this translational work.

What you hope that your colleagues take away from our conversation?

The bottom line is that ipilimumab with nivolumab shows activity in SCLC. [We’ve also shown that] it’s both feasible and important to obtain paired biopsies to learn more about the tumor microenvironment. The story so far is that we observed increased T-cell infiltration, particularly CD8-positive T-cell infiltration, in patients who showed some clinical activity.

References

1. Chiang AC, Austin M, Stewart TF, et al. A pilot study of ipilimumab and nivolumab in recurrent extensive-stage small cell lung cancer after platinum-based chemotherapy. J Clin Oncol. 2022;40(16):8583. doi:10.1200/JCO.2022.40.16_suppl.8583
2. Antonia SJ, López-Martin JA, Bendell J, et al. Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (CheckMate 032): a multicentre, open-label, phase 1/2 trial. Lancet Oncol. 2016;17(7):883-895. doi:10.1016/S1470-2045(16)30098-5