Moffitt’s Dr Michael Shafique Discusses Growing Importance of Subtypes in SCLC

Michael Shafique, MD, is an assistant professor of thoracic oncology at Moffitt Cancer Center. He devotes most of his clinical time treating patients with lung cancer but also cares for patients with other diseases as during early phase clinical trials. Shafique spoke with The American Journal of Managed Care® (AJMC®) about efforts to characterize small cell lung cancer (SCLC) into subtypes as well as the process for treatment selection in this disease. This interview has been lightly edited for clarity.

AJMC®: Let’s discuss recent efforts to characterize small cell lung cancer. It's a very heterogeneous disease, and there has been research characterizing 4 different subtypes of small cell lung cancer: the A, N, P and I subtypes. Can you tell us a little more about these subtypes? What defines them, and how are patients evaluated for these subtypes in practice?

Shafique: This has been a work in progress over the last several decades. It used to be that we could break SCLC down into neuroendocrine- and non-neuroendocrine-behaving tumors. And in the last couple of years, teams from MD Anderson and other centers across the globe have been able to further define these [subtypes] based upon RNA sequencing and protein expression. And so, the subtypes that you're describing here are the 4 major subtypes that teams across the world are settling on, which helped define the spectrum of small cell tumors that we see.

The A and P, and then the I subtypes are looking to define subtypes of small cell based upon protein expression and transcription factors. The A subtype is referring to ASCL1; [while] the NeuroD1 subtype is the N subtype. And these 2 subtypes are classically what we would call neuroendocrine-like tumors. And then the other 2, the POU2F3, and then the I subtypes have historically been the non-neuroendocrine types.

As for the I subtype….a few years ago, we were trying to investigate YAP1….YAP1 as a potential transcription factor to define that cohort. But really, it now looks like the I subtype is really an inflamed subtype. So, these are markers that are really making it as if the tumor is really an inflamed subtype, with lots of immune system cells that are infiltrating the tumor. So, I think those are the aspects that the group; [especially as] MD Anderson was able to home in [and] break these tumors into these 4 groups.1

In clinical practice, it's very hard to elucidate which tumor subtype a patient's cancer will fall into. If you read their papers, they really used extensive RNA sequencing, next generation genome sequencing to arrive at these subtypes. So, it's hard in everyday clinical practice to really find where these patients will fall in.

AJMC®: With that in mind, this provides a starting point to better characterize this disease and improve the way we treat it in the near future. In what ways do you think that will become possible? Do you think we will see clinical trials that are focused on these subtypes and use those advanced testing tools to find new therapies—and perhaps push small cell lung cancer treatment forward?

Shafique: Yes, I think so. This is going to be a starting point, a springboard to redefine how we do clinical trials in small cell lung cancer. Just a few years ago, we were enrolling all comers—an unselected population of patients—into small cell lung cancer studies. If you look at the IMpower133 trial, that was the clinical trial with platinum etoposide and immunotherapy. It was really an unselected population, and the data from MD Anderson was really based on looking at a large group of patients from that study. And they were able to tease out some of these subtypes and home in on the inflamed subtype that benefited the most from immunotherapy. Even recent trials that have been, I don't want to say disappointing, but didn’t quite move the bar like we wanted them to, were really looking at an unselected population of patients. But what we know about these subtypes is they really seem to be driven by transcription factors that may respond to specific inhibitors of these pathways. So, the A subtype may be more sensitive to BCL2 inhibitors and the NeuroD1 subtype may be more sensitive to Aurora kinase inhibitors. And then PARP inhibitors seem to be a little bit more beneficial in the P subtype. And then the inflamed subtype—the I subtype—these patients may be better suited to receive immunotherapy, maybe upfront or maybe after they progress on standard chemotherapy-containing treatments. But this is all the starting point, to begin to look at patients and their tumors and begin to say, can we enrich a clinical trial with patients more likely to respond to any of these therapies like BCL2 inhibitors, PARP inhibitors, or other novel therapies that will target the actual mechanics of the tumor.?

AJMC®: What other progress has been made in terms of attempting to identify actionable biomarkers or mutations in the setting of small cell lung cancer?

Shafique: It’s an emerging area, where small cell lung cancer has been behind the non-small cell lung cancer space for quite some time. There was always the idea that chemotherapy would be and always has been the defining treatment, that really has [offered] the biggest gains in small cell. But I think I'm beginning to see a lot more interest in these drugs [such as] PARP inhibitors, BCL2 inhibitors, Aurora kinase inhibitors. And there's ongoing research, [including] here at Moffitt, that’s looking at treatment within these specific subtypes and trying to home in on the molecular pathways that really impact the growth of the tumor, and then areas that are actionable and targetable with pill therapies. That being said, in the last couple of years, the treatment for small cell lung cancer does revolve around platinum-based chemotherapy. We recently have had 2 immunotherapies that were approved, in combination with chemotherapy in the upfront setting. And then another chemotherapeutic agent, lurbinectedin, was approved in a second-line setting, not that long ago. So, I think the majority of the advances in day-to-day clinical practice in the upfront setting and in the second-line setting still seem to be agnostic of the underlying subtype. But as we further define these subtypes, we're going to go back and see in some of these studies, such as the chemoimmunotherapy trials, or the trial with lurbinectedin, where we may find and tease out patients that respond better or derive more benefit from some of the standard of care treatments that we've been giving for years.

AJMC®: That’s a great jumping off point to the next question here, which is what is your preferred treatment approach in the primary setting for someone with extensive-stage small cell lung cancer? What sort of platinum-based chemotherapy are you choosing? Are you going for immunotherapies? Is there a particular product or a patient profile that you prefer when you're making treatment decisions in that setting?

Shafique: For the most part, in extensive stage small cell lung cancer, the standard therapy now is revolving around some sort of platinum doublet. I tend to use carboplatin with etoposide. And then we have 2 immunotherapy agents that have both been approved in combination with platinum and etoposide—those are atezolizumab and durvalumab. They see, to be equivalent in terms of what they've been able to add to chemotherapy in their respective clinical trials. So, it's hard to select one over the other, I've certainly used both. And in the national guidelines, both are recommended with Category 1 evidence. So, I think, unless patients have a clear contraindication to immunotherapy—and that may be preexisting, or active autoimmune conditions, history of transplants, solid organ transplant, something like that—then I think, for the most part, the standard ought to be platinum with etoposide and 1 of the immune checkpoint inhibitors.

AJMC®: Along the same lines, have you experienced barriers in trying to get these treatments to patients? Does your institution use something like a clinical pathway to direct you to a particular agent or another? You mentioned lurbinectedin in the second line, that's a newer agent. Are there particular guidelines or restrictions on using something like that, that you must work through as you're making treatment decisions with a patient?

Shafique: I think the biggest hurdles that we have sometimes relate to just how acute the patients will present. So, oftentimes small cell will present very quickly with rapid onset of symptoms, and then the challenge is managing thosesymptoms and getting treatment started as soon as possible. With a lot of these agents being administered in the outpatient setting, then there is a little bit of lead time, to where when you evaluate the patient, to getting chemotherapy. And then really, it's the immunotherapies really the main thing that needs to be authorized for insurance. And so, I think initially, there were some delays there, but for the most part that's been a lot faster and clinical pathway certainly help. With the understanding of these are the agents that we prefer to use, this is the way we prefer to use, and it really helps streamline the approval process. And likewise, for lurbinectedin, I find that pathways allow providers and provider systems to be upfront with payers, as far as what to expect for certain cases, certain presentations, and certain lines of therapy for patients. I think that, especially for a diagnosis like small cell, it's important that we communicate what the best evidence is. And I think, for the most part, a lot of those hurdles have been overcome, and we've been able to really get authorization and approvals done rapidly for patients. So, it doesn't really hamper delivery of care as much as we had feared when drugs were first approved in the last few years. Oftentimes, patients are also presenting in the hospital setting, and so that makes it a little bit challenging sometimes to get the drugs authorized in the inpatient setting. But we'll treat with the standard chemotherapy and then a patient is well enough and discharged at the hospital we'll use the other drugs, the immune checkpoint inhibitors or lurbinectedin once we're able to get authorization and see the patient in the clinic.

AJMC®: Would you like to offer some closing thoughts on treatment of small cell lung cancer to share with your colleagues?

Shafique: Yes, I'd like to talk a little bit about how I think these molecular subtypes that we talked about earlier—how I think they're really going to change the approach for clinical trial design. At my institution, at the Moffitt Cancer Center, we're working on some protocols that will allow us to evaluate for, not just specific to small cell, but also non-small cell tumors, and look for these kinds of molecular subtypes in advance—at first diagnosis, to take a patient's tissue. And maybe it doesn't affect upfront treatment. Maybe most patients will still move on to the carboplatin, etoposide immune checkpoint inhibitor therapies that have been standard for the last couple of years. But the idea being that [is] we find their subtypes and have them ready and matched to a clinical trial later on, either as an add on maintenance, following their initial treatment, or for a trial in the second-line setting, or subsequent lines of therapy. But the idea really is to find these molecular subtypes and look for them in advance with next generation sequencing, RNA sequencing to really help streamline enrollment and identification on clinical trials for these patients.

Reference

1. Rudin CM, Poirier JT, Byers LA, et al. Molecular subtypes of small cell lung cancer: a synthesis of human and mouse model data. Nat Rev Cancer. 2019;19:289–297 https://doi.org/10.1038/s41568-019-0133-9