SCLC Paradigm Advances With Immunotherapy, Integration of Rapid Research Autopsies

Partner | Cancer Centers | <b>The Ohio State University</b>

Hui-Zi Chen, MD, PhD, discusses the use of immunotherapy in ES-SCLC and the work being done to identify mechanisms of resistance to frontline therapy.

Hui-Zi Chen, MD, PhD

The use of immunotherapy has led to a paradigm shift in the treatment of patients with extensive-stage small cell lung cancer (ES-SCLC), but unmet needs remain, according to Hui-Zi Chen, MD, PhD.

For example, in the phase III IMpower133 trial, patients with ES-SCLC experienced a 24% reduction in the risk of progression or death when they received atezolizumab (Tecentriq) in combination with platinum and etoposide versus placebo/chemotherapy as frontline therapy (HR, 0.76; 95% CI, 0.60-0.95; P =.0154). Earlier, interim findings from the trial served as the basis for the March 2019 FDA approval of the PD-L1 inhibitor for use in combination with chemotherapy in the frontline setting.

However, data from the trial also showed that only 34% of patients in the atezolizumab arm were alive at 18 months, suggesting the need for a more granular understanding of resistance—something that could be made possible with rapid research autopsy, explained Chen.

“We have been studying these tumor samples, their genomes, their RNA, and their protein in the laboratory through different molecular assays, including next-generation sequencing (NGS) to try to understand what makes these tumors so resistant to treatment after first-line platinum,” said Chen. “By identifying genetic changes that drive the resistance phenotype and relapse, we may be able to develop effective therapies against these drivers.”

In an interview during the 2020 OncLive® State of the Science Summit on Lung Cancer, Chen, an assistant professor in the Department of Internal Medicine, Division of Medical Oncology, The Ohio State University Comprehensive Cancer Center—James, discussed the use of immunotherapy in ES-SCLC and the work being done to identify mechanisms of resistance to frontline therapy.

OncLive: Could you shed light on the progress that has been made in SCLC in recent years?

Chen: [In my presentation], I discussed the results of an important and practice-changing phase III study. We have updated results from that trial, specifically overall survival (OS) data. I also discussed [the CASPIAN trial], which is another study that evaluated frontline therapy for patients with metastatic disease. The results were published a few months ago in The Lancet.

Then, there are couple of studies in the relapsed/refractory setting, in which there is certainly a great deal of unmet need at this point. We don’t have very good second-line therapies available. One of the studies I presented could potentially lead to a new therapeutic regimen for these patients, so that’s very exciting; we have not seen that over the past 20 to 30 years.

SCLC accounts for about 10% to 15% of all new lung cancers that are diagnosed worldwide each year. Our knowledge of SCLC is very limited compared with non—small cell lung cancer (NSCLC), where we understand the molecular drivers of the cancer. As a result of that understanding, a wide array of therapeutics has become available for these patients; that isn't the case for SCLC. This is an important area of research and needs further funding to help us develop more effective treatments for these patients.

Could you elaborate on the key trials that have helped propel the field forward?

[The IMpower133 trial] was a landmark phase III clinical trial; it was a randomized study that was published in the New England Journal of Medicine in November 2018. The results of that study changed the way we treat our patients with metastatic SCLC; 2 cohorts [were evaluated] in that study. One cohort of patients received the standard of care, which is a platinum-based combination composed of either cisplatin or carboplatin with etoposide. Patients in the experimental arm received standard-of-care chemotherapy plus the PD-L1 inhibitor atezolizumab. The results of the trial showed a statistically significant improvement in OS with atezolizumab. The median OS was approximately 12.3 months [in the atezolizumab arm] versus approximately 10.3 months in the control arm. Although we only saw a 2-month improvement, it was statistically significant. The results of the trial led to the approval of [atezolizumab and chemotherapy] for the frontline treatment of patients with metastatic SCLC.

Are all patients eligible to receive the combination?

This is a new treatment. At the moment, the decision to use the combination is not based on the presence or absence of any particular biomarkers, such as PD-L1 or tumor mutational burden (TMB). Basically, all patients who have a new diagnosis of ES-SCLC would receive this treatment. In a sense, it’s easy because we don't have to stratify our patients based on [those biomarkers]. That’s certainly [easier] than NSCLC, where we do have to look at PD-L1 expression to determine which therapy to give.

Could you shed light on the SCLC study you’re currently working on?

The study I'm working on is being done in collaboration with the faculty in the Thoracic Oncology Center at The Ohio State University Comprehensive Cancer Center—James, led by David Carbone, MD, PhD, as well as with our colleagues in the Department of Pathology. The study involves rapid research autopsy for patients who die from their advanced cancer. The barrier to studying SCLC in the past few decades has been the inability to acquire tumor tissue for functional studies in the laboratory as well as in NGS studies to be able to examine the genomes of these cancers, especially in the relapsed/refractory setting.

In order to overcome that barrier regarding tissue acquisition, we thought that an approach through rapid research autopsy—which are focused autopsies that are performed shortly after a patient has passed in order to obtain tumor tissue that has viable DNA, RNA, and protein— would be a good way to obtain as much tumor tissue as possible to study back in the laboratory.

To date, we have acquired numerous tumor tissues from 5 patients who have died from SCLC. We have been studying these tumor samples, their genomes, their RNA, and their protein in the laboratory through different molecular assays, including NGS, to understand what makes these tumors so resistant to treatment after first-line platinum [chemotherapy]. We are slowly making progress. We’re starting to collaborate with another institution to get [access to] the samples they have acquired from a similar autopsy study in patients with lung cancer. We’re hoping to combine these data in a big publication from which we can draw conclusions [regarding] genomic drivers of resistance. If we can identify these molecular drivers, we can potentially study them in a controlled setting in the laboratory and validate them. The goal would then be to see whether we are able to translate these findings into something that's clinically meaningful for our patients.

Why is it important to research these drivers?

Mutations or changes in the genome could drive the resistance phenotype. SCLC is a disease that is sort of typified by initial sensitivity to chemotherapy. The majority of patients who are treated with first-line chemotherapy demonstrate a response; that response is very short lived, and the disease will inevitably relapse. We get into trouble when the cancer comes back; that’s where chemotherapies like topotecan and others don't work. We need more effective therapies in the second-line setting.

Do you discuss potential donation with your patients?

As a clinician, I bring this up to my patients. It's always a difficult conversation when you're nearing the end and running out of options. I’ve had patients bring it up without me having to ask them. I have been surprised by the number of patients who have said they want to help even though they wouldn’t be the beneficiary. It has been a very gratifying experience. We continue to have relationships with their families after they pass. I’ve been told that it gives the families a sense of satisfaction that their loved one did not die in vain. I appreciate the opportunity to do this. It's a great opportunity that is not available at many other institutions. It's a unique opportunity and I find it very humbling.

You conducted a similar study in a different cancer type. Could you highlight the results of that study?

That study was published in the Journal of Oncotarget. Through rapid research autopsy, we were able to procure multiple metastatic tumor samples from a patient with a very rare kind of cancer. In addition to the rare histology, the patient had an ultra-high mutated phenotype and a very high TMB. He didn't really have the classic drivers leading to this ultra-hyper mutation. We hypothesized that this hyper-mutation may have occurred through changes or mutations in this family of proteins called APOBEC. Different mechanisms lead to ultra-hypermutation. In our paper, we showed how this cancer evolved in response to the therapies the patient had received. This study serves as an example of the kind of studies we're able to do with the autopsies protocol.

What is your key takeaway regarding the treatment of patients with SCLC?

It’s a very exciting time to be an oncologist. We’re in an era of precision oncology and immunotherapy and it's changing so quickly. Our goal is to be able to cure cancer someday. We’re not quite there yet, but we’re certainly making big strides. The translational research needs to continue so that we can enable the next generation of new therapies. The take-home message is that we need to keep trying. We have to keep looking [for solutions]. SCLC is an evolving landscape. We should never give up in our efforts to look for more effective therapies for our patients.

Reck M, Liu SV, Mansfield AS, et al. IMpower133: updated overall survival (OS) analysis of first-line (1L) atezolizumab (atezo) + carboplatin + etoposide in extensive-stage SCLC (ES-SCLC). Ann Oncol. 2019;30(suppl 5; abstr 1736O). doi: 10.1093/annonc.mdz264