Small Cell Lung Cancer Spotlight - Episode 6

After PD-1 Inhibitor Indications Are Withdrawn in SCLC, What Now?

Mary Caffrey

Martin J. Edelman, MD, chair of the Department of Hematology/Oncology and associate director for Translational Research at the Fox Chase Cancer Center in Philadelphia, Pennsylvania, discusses the the nuances of rescinded indications in small-cell lung cancer.

One of the big stories in oncology in 2021 has been the tale of “dangling approvals.” These are accelerated approvals that landed in limbo, after follow-up trials failed to confirm the results that caused FDA to allow these cancer drugs to reach the market for certain patients.

FDA held 3 days of hearings in late April to weigh whether some therapies in this category should stay on the market.1,2 But in some cases, manufacturers voluntarily withdrew indications after talks with FDA. During the hearings, some manufacturers cited that fact that therapies were already incorporated in National Comprehensive Cancer Network (NCCN) Clinical Guidelines, and thus in use.

Two such cases involved the programmed cell death-1 (PD-1) inhibitors nivolumab (Opdivo), from Bristol Myers Squibb, and pembrolizumab (Keytruda), from Merck; indications were withdrawn for some patients with metastatic small-cell lung cancer (SCLC),3,4 a type where there has been some progress of late, but there is still great unmet need.

The question is, what now? For a discussion on how leading clinicians are responding to these announcements, along with other developments in SCLC, The American Journal of Managed Care® (AJMC®) spoke with Martin J. Edelman, MD, chair of the Department of Hematology/Oncology and associate director for Translational Research at the Fox Chase Cancer Center in Philadelphia, Pennsylvania.

This interview has been edited lighted for clarity.

AJMC®: Over the past year, we've seen the voluntary withdrawal of some indications in small cell lung cancer after the FDA moved to address what they call “dangling approvals.” What are your thoughts on how this process played out?

Edelman: The most important thing to understand is, it's not that the drugs were not effective. It was that the trial design, [or] probably the nature of the population had changed. With these immunotherapy drugs, since the initial approvals, there were similar agents that had now been demonstrated to be effective in combination with chemotherapy in the front line. So, the use of them in second and subsequent lines of therapy became more questionable. But it's not that they were not effective.

The FDA processes continue to evolve over time. They're not always as clear as we'd like—what’s the basis for approval? In the past, it had to be based upon a fairly hard point of overall survival; then they moved to other issues in terms of progression-free survival and sometimes response rate. So, it's not always obvious as to why something is approved.

But I think in this situation, it's important to recognize that pembrolizumab and nivolumab in second line for small cell are, in fact, drugs that do potentially have utility in populations that have not received immunotherapy alone or in combination previously.

I think part of the basis for removing the approval was that, in the future, [the FDA] didn't want patients who had gotten immunotherapy as part of their initial treatment with one drug to get essentially another anti-PD-1 or PD-L1 in second- or third-line therapy. That’s reasonable, but there still will be a number of patients who will not have received immunotherapy as part of their initial treatment for whom an immunotherapy agent is still reasonable down the road.

AJMC®: How do the recent FDA proceedings affect the NCCN guideline process, specifically in SCLC?

Edelman: So, I'm actually I'm on that committee, I don't know to what extent I can discuss deliberations. But there still will be an NCCN guideline that lists these as potential agents, in second- or third-line use. so I think that, as I said, there's no question that these are active agents. [As for] the NCCN process…certainly the FDA approvals and disapprovals can influence that. But again, it doesn't take away from the potential the guideline, which moves down from heavily based on evidence in randomized phase 3 studies, to more expert opinion, but there's certainly a fair amount of published evidence prospective studies indicating activity in these drugs.

AJMC®: What kinds of questions do physicians and even patients have about immunotherapy and SCLC relative to other types of treatment?

Edelman: Immunotherapy certainly gets a lot of buzz. You know, I can't think of other things that have TV commercials. In lung cancer, I kind of knew we had hit the big time when suddenly, there were TV commercials for immuno-therapeutics. I was watching one of these, and I said to my wife, I said, “You know, it's no day at the beach.” And the next thing is they show this guy walking on the beach.

They are drugs that have a role in the treatment of cancer—they are not the only drugs. And I think that patients should understand that these can be potentially valuable agents—in some instances, indispensable agents—but they are part of a larger strategy, which may include chemotherapy, radiation, sometimes even surgery. They are drugs that certainly have potential significant and even lethal side effects. For the most part, [they] lack of acute side effects that we are used to seeing with chemotherapy—and even those [effects] to a large extent are ameliorated with modern antinausea therapies, etc.

You don't have that potential for nausea, the hair loss, etc, that you still see with chemotherapy, but the side effects of immunotherapy can be quite profound. They are less predictable. I spend a lot of time educating patients about side effects of all therapies: chemotherapy, immunotherapy, radiotherapy, etc, and their combinations. But immunotherapy is no day at the beach. Many patients feel very well until they don't. Some go through their course of treatment and have remarkably few side effects. Other people can get life-threatening effects. Sometimes, interestingly, those may presage really dramatic and long-term benefit. But people can get life-altering therapy [and have] problems, [such as] diabetes, which requires lifelong insulin. I mean, it's a very unpredictable set of side effects. They are drugs that require a great deal of respect.

AJMC®: After a stretch of comparatively less progress than advances in treating non–small cell lung cancer, SCLC has seen the recent designation of subtypes.5 How do you expect this advance to affect patient care?

Edelman: A number of subtypes have been described, based upon primarily cell lines and archive tissues. We do not yet have any prospective clinical data on the utility of these types. So, that remains to be seen. If I sound a little cynical about that, it's because after 30 years or so of work in the field, a lot of stuff that comes from biology doesn't always translate. On the other hand, if you don't have the biology, you'll never get there. So, some of these subtypes, I think, may help to better identify who will respond to immunotherapy. Clearly, that's one of the subtypes. And, it would be good if we knew—it’s important to know—in whom things will work as well as in whom things will not work. Because if you give somebody immunotherapy and it doesn't work, then that's both expensive and potentially dangerous. It’s never good to get side effects with no chance of benefit. So that's one aspect, which I think is going to be really important. The other side is to figure out, is who will benefit from chemotherapy and which chemotherapy drugs. There does appear to be some evidence that may be useful. But we need to have well-designed good clinical trials that tell us, “This is better.” And, I look forward to those studies.

AJMC®: How is the rise of advances in the use of biomarkers going to affect treatment of SCLC going forward?

Edelman: Well, the biomarkers are the clinical subtypes—and to extent that some of those are already available, number one, in small-cell lung cancer, you need to have an adequate tissue size. So, I think one of the things that's going to change about this is, there’s going to be demand for more tissue.

You know, we saw this in non–small cell, where many years ago, I ran a prospective study, it was in what was then the Cancer and Leukemia Group B.6 And this was a non–small cell, and we needed tissue and people kind of screamed and yelled and said, “There's just no way we can get tissue and analyze it before we treat people for cancer.” That was unimaginable. And that's not that long ago—that’s about 2006. That delayed that study for a couple of years and may have contributed it failing, because the marker that we had identified was in immunohistochemistry. There are antibodies, they shift, [and] so we never could cross-validate back to the original specimens. But, the fact is, is it will require that we get bigger chunks of tissue, that will be one thing. And hopefully it will turn out like non–small cell where it will just become routine. We’ll be able to say, I've got a higher probability that this will be beneficial.

The issue of small cell is going to be more complex, because in non-small cell where we had biomarkers like EGFR, ALK, ROS1, or RET, the treatments that we have are extremely effective—basically, they're 80% to 90% effective, and they tend to be durable. The issue in small cell has never been getting an initial response. The vast majority of patients respond to drugs that have been around for, you know, 30-40 years. The problem is maintaining the response. And so, it's going to be that durability of response that's far more crucial. And that's where I mean no therapy has been remarkable—and maybe identifying the population that gets durable response.

Everybody always loves anecdotes. You know, we had a patient who had progressed and was treated with definitive treatments, chemo radiation for a limited stage, small cell, he relapsed, he was placed on one of our trials that's going to be reported in a couple of weeks. And then he was on another study, which he was on the control arm, but that was another negative trial. And then he got a few doses of immunotherapy, anti–PD-L1 treatment, and ended up with a rip-roaring colitis after 3 or 4 doses. He got better from that. And I have not treated him in that since then. And that was over 2 years ago. So, here's a disease where the median life expectancy for recurrent refractory disease is measured in weeks. And it's 2 years later. And his big problem is really from his other smoking-related illnesses—his heart disease, his lung disease.

You wave a magic wand over a small-cell lung cancer patient—take away their cancer, and they're still stuck with their terrible heart, lung disease. And, you know, that's really a big rate-limiting step for a lot of this.


  1. Beaver JA, Pazdur R. “Dangling” accelerated approvals in oncology. N Engl J Med. 2021;384:e68. doi: 10.1056/NEJMp2104846
  2. FDA Oncologic Drugs Advisory Committee to review status of six indications granted accelerated approval. News release. FDA in Brief. March 11, 2021. Accessed May 8, 2021.
  3. Bristol Myers Squibb statement on Opdivo (nivolumab) small cell lung cancer US indication. News release. December 29, 2020. Accessed May 26, 2021.
  4. Merck provides update on Keytruda (pembrolizumab) indication in metastatic small cell lung cancer in the US. News release. Accessed May 26, 2021.
  5. Gay CM, Stewart CA, Park EM, et al. Patterns of transcription factor programs and immune pathway activation define four major subtypes of SCLC with distinct therapeutic vulnerabilities. Cancer Cell. 2021;39(3):346-360.e7. doi:10.1016/j.ccell.2020.12.014
  6. Schilsky RL, McIntyre OR, Holland JF, Frei E. A concise history of the Cancer and Leukemia Group B. Clin Cancer Res. 2006;12(11):13553s-3555s. doi:10.1158/1078-0432.CCR-06-9000