The chief of medical oncology and hematology at Bryn Mawr Hospital and associate principal investigator for Main Line Health's NCI Community Oncology Research Program discusses therapeutic advances along with ongoing challenges in enrolling patients with small cell lung cancer (SCLC) in clinical trials.
About 15% of patients with lung cancer have small cell lung cancer (SCLC), which for years has been characterized by rapid progression, poor prognosis, and limited treatment choices. Most patients with SCLC are current or former smokers; they frequently have other health problems, which can create barriers for those who want to qualify for clinical trials. But in the past few years, SCLC has seen new hope with the rise of immunotherapy and, just last year, the approval of lurbinectedin (Zepzelca) for certain patients in the relapsed and refractory setting.
For a discussion of changing times in SCLC, The American Journal of Managed Care® (AJMC®) spoke with John G. Devlin Jr, MD, the chief of medical oncology and hematology at Bryn Mawr Hospital and associate principal investigator for Main Line Health NCI Community Oncology Research Program (NCORP) in southeastern Pennsylvania.
The following has been edited lightly for clarity.
AJMC®: Historically, small cell lung cancer has had poor survival rates, especially once a patient has a relapse. But in recent years there have been new treatment approaches that have been more encouraging. Can you describe the changes that your clinical trial program has seen in the past 5 years?
Devlin: We're seeing more studies and more study participants in general, because of the explosion of new drugs, targets, and progress in small cell lung cancer, after a relatively quiet stretch in small cell for many years prior. That being said, these are still challenging patients to enroll [in trials] primarily because SCLC is a less common lung cancer compared to non–small cell lung cancer, and also because of the nature of the disease and the nature of the patients who get it, vis-à-vis tobacco comorbidities.…We're also seeing more studies with combinations [of therapy], particularly with immunotherapy. That's obviously been a big step forward with cancer in general, and it's also true in small cell.
We also have a trial open with hippocampal avoidance to try to minimize cognitive impacts of radiotherapy for brain metastasis. That's another interesting, non-medical oncology [approach], but still an interesting study. And I think overall, my sense is that patients are just doing better and living longer than they were before when all we had to use were cytotoxic chemotherapy drugs.
AJMC®: The rapidly changing developments and evidence have caused 2 indications for checkpoint inhibitors [nivolumab and pembrolizumab] to be withdrawn in the second-line setting. But despite that, the most recent National Comprehensive Cancer Network guidelines—released just in the last month—retain and even bolster the recommendations for these therapies. Can you offer your thoughts on this?
Devlin: There's some data in small cell that you alluded to it was initially phase 2 data with pembrolizumab in 1 study, and nivolumab in another study, suggesting that they had pretty vigorous clinical activity with a reasonable response rate, [with] symptom improvement, disease improvement, and as usual, they received conditional approval pending the outcome of phase 3 studies that bolstered overall survival or [disease-free survival] or [progression-free survival] improvements. And they didn't meet their overall survival goals. So, the companies pulled the indications and decided not to pursue them, in conversation with the FDA.
However, atezolizumab [Tecentriq], another immunotherapy, looks pretty good in a recent study, IMPower133, where it actually did improve overall survival when combined with chemotherapy versus chemotherapy alone. So, we're sort of getting this mixed picture with immunotherapy. Not so much on which particular drug—but I think more with whether or not it's combined with chemotherapy. That's my reading of the data. It seems like these drugs in some tumors work better when we combine them with chemotherapy drugs, or sometimes with radiation, which perhaps we'll get to later. I think that's probably the way forward is to evaluate these immunotherapy drugs in combination with other drugs. And as time goes on, I think we'll learn more about biomarkers and how to better select patients that will get the maximum bang for their buck with these drugs.
AJMC®: Lurbinectedin has been approved for second-line treatment of SCLC. What’s been your program’s experience with this therapy thus far?
Devlin: I think overall it's been positive. Certainly, the study that led to it being approved and used as a standard second-line therapy for advanced disease looks pretty good. And patients seem to tolerate it well. There are some cytopenias, infection risk and things that we have to watch. That's been an issue occasionally, with my patients, leading to some dose reductions. But overall, it's been pretty efficacious. It seems to add something meaningful to the armamentarium that we have for these patients. And certainly, the more options, the better. Again, I think that's part of the reason why people are living longer and doing better—because we have more options and more active options than we used to have.
AJMC®: We hear that too few patients enroll in clinical trials. In your experience, what are the chief barriers to clinical trial enrollment, particularly for patients with lung cancer?
Devlin: As I said earlier, something like 90% of all lung cancer patients are tobacco smokers or former tobacco smokers. Tobacco-related comorbidity or other medical problems often accompany these patients with their new lung cancer diagnosis. So, when it comes to clinical trial enrollment, there are some patients whose comorbidities are too much for them to be eligible for a clinical trial. You might think that you'd include those patients in lung cancer studies because of how common those problems are in these patients. But, there are still comorbidity issues that arise with who's eligible for what study. There are issues with small cell lung cancer in particular, because of the timing of how fast this tumor can grow. Often, these patients are presenting to a hospital symptomatic in need of urgent therapy. I think the best small cell lung cancer study allows for one cycle of treatment before [patients] get randomized or are considered ineligible; you have to have to treat them quickly as a matter of life and death. And we can't enroll them to a study that says they have to be treatment naive if they've presented to the hospital in bad shape. So that’s sometimes an issue with small cell.
Molecular profiling also matters, too, because a lot of studies these days—not so much small cell necessarily, but cancer in general. The studies have to do with what particular target the cancer does or doesn't have. And obviously, that does restrict the pool of patients that they're looking for. As long as we have enough studies open with enough different targets, it works out well. But for a given patient, they may not be eligible if their cancer doesn't have a certain target. Finally, clinician interest and time to enroll patients on study is frankly an issue, especially in private practice. It's really difficult sometimes to find the time to deal with the various forms and regulations [or] to find extensive time in your schedule to sit down and have a proper informed consent. It's a balancing act for everybody. It always seems like there's never enough time and never enough staffing to do that. I might also add, there are just some patient populations or individual patients that, for whatever reason, don't want to enroll in a clinical study—they’re nervous about medical science; they don't trust the system. They've had a bad experience previously, it's the sort of thing we're also seeing with the COVID-19 vaccine discussion these days. And that's also present when it comes to cancer clinical trials. Some of these barriers are easy to overcome; some are more difficult to overcome. But I do think, at least in our practice, in our program, we've made some headway in enrolling more patients and more often.
AJMC®: Do patients with lung cancer discuss with their clinicians or others on the on the care team any issues they have in dealing with their insurance company? And does this impact the ability to deliver the right therapy at the right time in small cell lung cancer?
Devlin: The short answer is yes to all the above. Insurance coverage is obviously a major issue considering the cost of all of these drugs, particularly the new drugs, the immunotherapies, and whatnot. We don't let it get in the way of initiation of patient care, using proper therapy for patients, etc. There's usually copay assistance programs; there's usually some foundational support. There are ways to get patients what they need, even if there are barriers. I'd be lying if I said we never have the need for a peer-to-peer review or a delay because of a precertification issue on the insurance company side or something like that. They certainly do get in the way occasionally, and they are things that we have to address in advance. But I think if we're all proactive about it, the practice is aware of the need for [pre-certifications], and things get done quickly and efficiently, then usually patients get what they need. And as long as the out-of-pocket cost is not ridiculous for a patient and there's adequate assistance, we can usually, get through the morass pretty well.
AJMC®: This spring the US Preventive Services Task Force (USPSTF) expanded lung cancer screening guidelines to cover more patients. Historically, uptake of these screenings has been subpar. Do you think the change of criteria will catch more cancers early?
Devlin: Considering the lung cancer is the second most common cancer in men and women—and the most commonly fatal cancer in men and women—one would think we'd want to catch all patients we could for screening and cast a very wide net. But the original guidelines really had a pretty restrictive criteria for who we should screen with [computed tomography] CT scans. And that was a reflection of who they put in the study to establish there was a benefit in doing so in the original CT study.
So recently, [the USPSTF] had lowered the age from 55 years to 50 years. Hopefully now younger patients can be screened. There's even a push on the part of some to lower [the age range even further]. And also, they've dropped the number of pack years that people had to have from 30 pack years as a minimum to 20 pack years. Hopefully, they'll drop it lower, to something like 10. Again, I think casting a wider net will obviously make more people eligible. And as long as they're interested, and people can get the work done to get them screened, I think we'll end up saving more lives against lung cancer. The estimates I've seen were something between 30,000 and 60,000 lives saved every year, considering how many people are diagnosed with lung cancer, if we do cast a wider net and screen more people. So, it's a pretty significant thing. And I think we should all make an effort to go in that direction.
AJMC®: What are the most promising developments you see on the horizon for patients with SCLC, whether it's in screening, therapy, or overall treatment?
Devlin: Well, certainly screening as just mentioned, is a major one. If we can convince a former smoker who was at risk for lung cancer to undergo CT screening, we've really helped them. We finally have a way to screen for a very common and commonly fatal cancer; we should all take advantage of it to whatever extent we can.
Certainly, there are treatment options that are better. Radiation targeting is better and more precise than it's ever been before. We have new immunotherapies that seem to be helpful and other new drugs as well. There are more and more targets and research being directed towards small cell. And even though it's relatively more uncommon, compared to non-small cell lung cancer, I think that will drive progress. And oncology as a whole is going towards more niche treatment, where it might be a smaller patient population with a given disease, but there are more options within that space. We saw that with [chronic myeloid leukemia], we saw that with various other cancers, I think the same thing is happening with small cell lung cancer as well.
Finally, if we can improve supportive care for patients overall, whether it's quitting smoking, or adding Cosela [trilaciclib], which is another recent FDA-approved drug to protect their marrow while they go through therapy for small cell, anything like that, I think is a valuable thing. It's not just all about efficacy and response rates. It's about also making it a reasonably good quality of life and minimizing toxicity for these patients, since a lot of them unfortunately have extensive disease.