Small Cell Lung Cancer Spotlight - Episode 14

Clinical Trial Criteria Should Be “Relevant” to the SCLC Population

Martin J. Edelman, MD, chair and professor, Department of Hematology/Oncology, and Deputy Cancer Center Director for Clinical Research, Fox Chase Cancer Center, Philadelphia, discusses barriers to clinical trial enrollment for patients with small cell lung cancer.

Martin J. Edelman, MD, chair and professor, Department of Hematology/Oncology, and Deputy Cancer Center Director for Clinical Research, Fox Chase Cancer Center, in Philadelphia, explains the need to expand the pool of patients with small cell lung cancer who eligible for a clinical trial. Edelman told The American Journal of Managed Care® (AJMC®) that restrictive criteria prevent trials from being “relevant” to the patient population that will need new therapies.

AJMC®: In your experience, what have been some of the greatest challenges in researching and treating small-cell lung cancer, particularly given its poor prognosis?

Edelman: Small-cell lung cancer requires immediate institution of treatment, while many of the clinical trials require variety of steps that before you can place somebody on a study. One thing that I've advocated for is the ability to enroll patients after [the first treatment], particularly those with extensive metastatic disease, after they've had an initial treatment course. This is a disease that is very paradoxical.

Some background may be helpful: small cell lung cancer is the less common [form] of lung cancer. About 10% of patients with lung cancer diagnosed each year in the United States have small cell, and its incidence has decreased since the 1970s. Despite that, 10% of 225,000 is still a lot of patients, so about 25,000 patients per year each year in the United States have small cell lung cancer.

Small cell lung cancer breaks into two major stages in terms of treatment. There's a limited stage, where curative or curative-intent treatment is available, although only between 25% to 30% of patients will actually be cured. And there is extensive stage, which occurs in patients who present with distant metastatic disease—generally, this stage is not felt to be curable. As with everything, there is always some fuzziness at the edges of these 2 areas and some changes in the distribution within those different large categories.

For limited-stage small cell lung cancer, the typical treatment is to combine chemotherapy and radiation. This is a tough treatment, but people do get through it. The questions now involve the role of immunotherapy, which has been established in extensive disease. There are other questions around whether to treat the brain to prevent recurrence. The brain is a very common site of recurrence, and this is a very controversial area right now. It’s the subject of a large, randomized trial.

The problem is that this [treatment]—prophylactic cranial irradiation (PCI)—has been an accepted part of medical practice for 3 to 4 decades now, but it’s really not supported by contemporary clinical evidence. What do I mean by that? The trials that were done that demonstrate an advantage with prophylactic cranial irradiation were done before advent of the MRI or the PET scan, and, therefore, imaging of the brain. The true staging of the patient by modern techniques was simply not available. There's a good reason to believe that this will probably change the potential role of PCI. Again, there's a large, randomized study currently in progress in this area.

With extensive disease—actually, to some extent limited also, but particularly in extensive—there’s a paradoxical response of disease to treatment. As I said previously, many of these patients present with very extensive disease; they're quite symptomatic. These are patients who show up in respiratory distress or with severe life-threatening metabolic problems. They respond dramatically in most cases, 70% to 80%, to initial chemotherapy. That's always been the quandary—these patients respond very rapidly, and then frequently within a period of several months, [the cancer] will recur just as rapidly, only now with resistant disease. I will treat a lung cancer patient who shows up on a ventilator if they've never been treated before, because this individual may very well walk out of the hospital a few days later. They may not be cured, but they can certainly get an excellent quality of life for at least some period of time afterwards.

The frustrating aspect of small cell is that we've known about these rapid responses for many years, and it always felt like, well, the next drug, the next approach would obviously push this into the curative group. That's been the saying now for literally decades with relatively few advances. Over the last 30 years, there have been maybe 3 or 4 drugs that have shown advantages for the treatment of relapsed disease. There are 2 there, topotecan and lurbinectedin, [with] lurbi being the last one to be approved. Though its most recent study was negative, a lot of that was trial design.

AJMC®: Can you discuss the role of immunotherapy?

Edelman: Immunotherapy is now established. There have been 2 studies: 1 using atezolizumab, the other with durvalumab. Both of those showed almost exactly the same degree of benefit; again, this was somewhat modest. There were real improvements in response rates and improvements in median and overall survival, but [there were] relatively few long-term survivors. Having said that, the use of immunotherapy either upfront or sometimes in the salvage third-line setting is the one time when one may occasionally see a long-term responder in this disease, where death otherwise was inevitable in a fairly short period of time. There have been publications now that demonstrate that there may be molecular phenotypes that can predict for who will or will not respond to immunotherapy and other agents. The problem is right now, we do not have prospective trials that validate them as selective measures but hopefully, that will be of utility in the future. It's always better for all concerned to have a drug, that if it works, works 100% in 20% of the population, [instead of] a drug that is 20% effective in 100% of the population. We've certainly seen success in this approach of selective targeted treatments in other diseases, and so we look forward to real evidence for that.

AJMC®: We’refinding more genetic and molecular biomarker targets in a variety of cancers. Where do you see the potential for research findings in small cell lung cancer to apply to other cancers? What targets that are being researched that might help us treat cancer in a different part of the body?

Edelman: Number 1, there are aspects of small cell lung cancer which are probably directly translatable. Small cell lung cancer, which is almost entirely a smoking-related disease, is de novo in this country; it’s what we call a neuroendocrine cancer. It actually has a very particular molecular phenotype in that if you inactivate P53 and RB (retinoblastoma) genes in a mouse, you end up with a small cell cancer. Similarly, we see that other malignancies within the body—most frequently prostate esophagus endometrium, as well as non-small cell lung cancer—as they mutate when they get those P53 and RB commutations, develop a small cell phenotype and behave and respond like small cell cancer. This is called extrapulmonary small cell lung cancer, or small cell that develops as a method of resistance or a mechanism of resistance in predominantly EGFR-mutated lung cancer. Any developments in small cell or sort of run in the mill small cell lung would be directly applicable.

AJMC®: Are there any areas where you see the potential for research findings in SCLC to apply to other cancer types?

Edelman: Approaches developed for one disease potentially can validate at least a mechanism in another disease. For example, there are drugs that are being designed to target both antigens that are specific to small cell and engage the immune system. If that's validated in small cell, as I suspect it will be, then you could use a similar concept but with different antigens in other malignancies. Something that gets validated in one disease works in another. So far, the approaches in small cell have really been to extend the things that we found in other diseases, such as immunotherapy. Small cell by its nature is not likely to be the leader disease [because] number 1, it's less common than non-small cell, and number 2, for the reasons I stated—these patients may be crashing on a Friday afternoon and that doesn't give you the time and leisure to do that careful analysis.

Additionally, there are other certain particularities of small cell. The specimens that are obtained prior to therapy tend to be small; they're frequently bronchoscopic biopsies. We've gotten better at training [pathologists] at getting larger specimens, but small cell by its nature frequently has a large necrotic area so you don't have the viable tissue as opposed to a disease like melanoma, where you can excise a large chunk of viable tumor or breast cancer or colon cancer, where patients typically come in and get large operations. They give you a lot of tissue to work with and do exploratory evaluations. Despite that, progress is being made.

AJMC®: Clinical trial enrollment is a challenge in many cancers. In your experience, what are the barriers to SCLC clinical trial enrollment?

Edelman: Clinical trial enrollment is a challenge, as in many cancers. Number 1, there’s the tendency of these patients to show up in extremis (in very critical condition). What's the answer? [We should] allow upfront therapy, develop trial designs that explore the use of treatments more in a consolidative setting or maintenance setting, rather than necessarily with the initial treatment. The other area which is a big problem in small cell, but also an issue in non-small cell, in breast cancer and a few other diseases, is whether to allow patients with brain metastases on trial. This has been one of my pet peeves for a very long time. The history of this is kind of intriguing. If you go back to when I was a medical student—this spring will mark 40 years since graduation—there were no CT scanners. There were no MRI scanners. There was no good way to image the brain. There was something called pneumoencephalogram at the time. Nobody's ever heard of it—which is fortunate, because it was something that should be banned by the Geneva Convention. In other words, you couldn't really assess whether somebody had brain metastases until they had a large burden of disease in the brain. This led to an exclusion of patients, because they were generally of poor performance status or had severe comorbidity as a result of these paralysis seizures, and usually they would die very quickly. In fact, I remember boilerplate from some of the older trials that because of their severe poor prognosis, no patient with brain metastasis can be on a study.

As time I went on, we found these things earlier and earlier. Then, the other thing that came up was the blood-brain barrier. That was known even earlier, from the dawn of medical oncology when the first treatments were to treat acute leukemia in kids. The brain was frequently a sanctuary site in leukemia, but it's different, and therefore you had to develop various approaches, radiation, high-dose methotrexate, or intrathecal methotrexate to get around this. The difference is that in solid tumors, usually there's a neovasculature, which is leaky. The literature on the penetration of drugs into the brain is also quite old. I can remember reading about this early on in my fellowship, but that's been sort of studiously ignored despite overwhelming and repetitive evidence of the ability of drugs to treat solid tumors that are in the brain. It's kind of a willful ignorance.

It's also been so established that these patients should be referred to radiation oncology. Then, they would get radiated, but meanwhile, their systemic disease takes off. One of the great barriers to enrollment is with the use of say something like MRI, you image patients doing really well. You image the brain, there's a one-millimeter brain metastasis. The entry criteria state that it's an untreated brain metastasis that has to be treated and then you have to wait 2-4 weeks. Well, that's unethical. A, it doesn't need to be treated, B, it'll respond to anything, whatever you're going to throw at it, and, C you can't wait a month to get these patients on studies because their systemic disease takes over. This has been a big problem.

We’ve dealt with this, and we have an open study right now, with a very promising agent. I actually have seen an incredibly dramatic response in 1 of my patients, but I had a least 3 others that I was unable to put on the same trial who were just as eligible, except that literally on their last day or so before going on, their MRI showed a 1- or 2-millimeter brain metastasis. This issue is now being addressed by the Friends of Cancer Research, by ASCO (American Society of Clinical Oncology) and is leading to changes in the way that trials eligibility criteria are written.

The is a particular issue in small cell because of the very, very high incidence of brain metastases—40% to 50%—but again, not all that different from other malignancies. Non-small cell is kind of just behind it and other diseases. The other big challenge with small cell is the exclusion of a history of other malignancies. Again, this is something that's changing. Small cell hits a population that generally didn't get there because they led a life of good cardiopulmonary health. Many of these, number 1, the median age is about 70; cancer is a disease of aging. There's a lot of these patients who are treated for prostate cancer or they have a low-grade prostate cancer where they had stage 1 melanoma or something like that or had a small head neck cancer, none of which are going to impact their natural history. An untreated extensive small cell has a median life expectancy of about 8 weeks. The thought that it's important, [that] 5 years has gone by or 3 years has gone by since their low-grade prostate cancer was or wasn't treated is really not relevant. Those are big impediments to trial accrual. When they're removed, I think will improve.

AJMC®: What are the most promising developments you see on the horizon for patients with SCLC?

I think further exploration of various ways of modulating immunotherapy are going to be very exciting. Clearly that's been a game-changer in multiple malignancies. I have to say to my astonishment; I would not have predicted how successful this would be. I think like many of those who began our training in the late 80s and had the experience of the interferons and IL-2 and similar things that we did not anticipate the level of activity and the overall reasonably good tolerance of these drugs. When they work, not just in small cell, but in the other diseases it's dramatic, sometimes durable, and really has changed the clinic.

In some ways it's made my life a lot harder—my clinics are now quite crowded because people live much, much longer, and that includes [patients with] small cell. There are now durable responders that I'm seeing, which I never used to. Again, new drugs, new treatments are there, but it remains a very difficult disease to manage. I think what we need are trials that are written, that are relevant to the disease that we are seeing. I think people have to get a little bit more selective in how they use their word processors and take out the eligibility requirements that are irrelevant to the disease because we're just not going to make progress if we have to screen 10 patients to enroll 2 or 3.