Novel Agents for R/R and the Future of Extensive Stage SCLC


Stephen Liu, MD: Now that we are incorporating PD-L1 [programmed death-ligand 1] antibodies in the first-line setting, atezolizumab or durvalumab with chemotherapy, for those patients who don’t derive that long-term benefit, what are our second-line options? Our approved option, our standard of care here is topotecan, a drug that’s FDA approved but a drug that we’re not too excited about. It’s fairly toxic. It’s not particularly effective. The responses are fairly transient. And so, what are the other options? There certainly is an opportunity and unmet need to develop new drugs in that space.

One of the more promising drugs that is probably closest to regulatory approval is lurbinectedin. Lurbinectedin is a marine-derived molecule that has a direct anti-tumor effect, affecting DNA transcription. It’s shown promising activity, both as a single agent and in combination with doxorubicin. And so, this is a drug that we hope to be able to make available to our patients relatively soon. It is not without toxicity, primarily hematologic in nature. But often, those are paper toxicities that we can manage, that don’t necessarily decrease the quality of life for specific patients. The activity we’ve seen has been promising, but we’re waiting for randomized data to really show us the precise benefit of lurbinectedin.

There are several other drugs in development. Unfortunately, a drug that’s been taken out of development is Rova-T [rovalpituzumab tesirine]. That’s a drug targeting DLL3. It had shown promising activity, initially. Unfortunately, serial trials since then have shown disappointing outcomes, particularly with regard to safety and toxicity. At ESMO 2019 [European Society for Medical Oncology annual meeting], we saw one of the first-line trials with rovalpituzumab tesirine in combination with chemotherapy being studied. Unfortunately, that trial did not meet its primary endpoint. And so, that drug will not be further developed.

It does not negate DLL3 as a possible target. Because this is expressed in small cell lung cancer, and not normally expressed on other healthy tissue in adult patients, it still is a viable target that can be exploited. It still represents this context of vulnerability for small cell lung cancer, but perhaps through a different strategy. There are BiTEs [bispecific T-cell engagers]. There are CAR [chimeric antigen receptor] T-cells targeting DLL3 that are in development now, that hopefully will be able to be added to our armamentarium in the near future.

I think that for extensive stage disease, we’re still looking for novel agents; for better options for salvage therapy. There are 2 main areas of research that I think will have the biggest impact. First is in limited-stage small cell lung cancer. About one-third of our patients will present with limited-stage disease, a potentially curable stage. With a combination of chemotherapy and definitive thoracic radiation, we will cure some patients but not most patients—probably somewhere around a third, at best, of those patients. So how do we increase the rate of cure there?

We’re looking at incorporating immunotherapy in limited-stage in combination with chemotherapy and radiation, building on our experience with immunotherapy in IMpower133 and CASPIAN, and building on our experience in combining immunotherapy with radiation in PACIFIC in non—small cell lung cancer. And so, we have the ADRIATIC study looking at patients who had received chemotherapy with radiation for limited-stage small cell lung cancer who would then receive durvalumab consolidation. We have NRG-LU005, an NCI [National Cancer Institute] Cooperative Group study, looking at chemotherapy with radiation and concurrent atezolizumab. And so, these 2 limited-stage studies will hopefully lead to more cures and prevent relapse for a significant portion of our patients.

And really, the last frontier is biomarker work. What we’re seeing with these immunotherapy studies—with IMpower133, with CASPIAN—is there is a benefit. It’s a real benefit, a survival benefit, but it’s being carried by a subset of patients. If we can identify who those patients are, we can be sure they receive the right therapy. And for patients who aren’t in that subgroup, we can explore novel strategies. We can figure out why they aren’t deriving that response and alter our treatment approach so they can develop that immune response with the addition of things like PARP [poly ADP ribose polymerase] inhibitors, radiation, or other novel checkpoints or drugs targeting the microenvironment. And so, it comes down to appreciating the differences between small cell lung cancer. Some of the newer work being done in terms of transcription expression to identify specific molecular subsets of small cell lung cancer will be very important in taking that next big step forward.

One thing to keep in mind with extensive stage small cell lung cancer: It’s a rapid pace of disease. This is an aggressive cancer that moves quickly and will not tolerate delays. When we look at some of the early placebo-controlled trials in the 1970s, we see the natural history of this disease is really a survival limited to a few months. And so, it is an unforgiving cancer. Delays will really not be tolerated, and may lead to patients losing their opportunity to receive a therapy that extends survival and improves quality of life. And so, if you wait for conditions to be perfect, you might be waiting too long.

A lot of the patients we treat for small cell lung cancer don’t fit that clinical trial population. They have a worse performance status, more symptoms, and perhaps untreated asymptomatic brain metastases. And yet, we need to move forward. Because if we wait for everything to be perfect to meet trial conditions, that patient, again, will lose the opportunity to receive very beneficial therapy.

And that therapy has been chemotherapy, platinum/etoposide, which was first introduced in the 1970s and has been our standard of care since the 1980s and 1990s. What chemotherapy does is it induces responses. They can be fairly quick. They can be deep. You can have complete responses. Patients will feel better, but that benefit is transient and progression-free survival is usually around 4 or 5 months. So patients progress shortly after or during chemotherapy. And when cancer relapses, when small cell lung cancer recurs after platinum/etoposide, it’s highly refractory to the treatments that we have. And so, it’s important to maximize the benefit in the frontline setting.

We’ve looked at different variations of platinum/etoposide. We’ve looked at cisplatin versus carboplatin. We’ve looked at 4 cycles versus 6 cycles. We’ve seen different doses of platinum, of etoposide. We’ve looked at split doses. All of these variations didn’t really make much impact. If there’s any difference, it’s incremental at best. These were the debates we had for years, because we had nothing else to talk about. And now, finally, we’re starting to make some advances.

Transcript Edited for Clarity

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