Immunotherapy Generates Hope for the Treatment of Small Cell Lung Cancer

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In an interview with Targeted Oncology, Gene G. Finley discussed the many wins and losses experts have seen in the small cell lung cancer space. He also explained his hopes for the future of this space.

The use of immunotherapy in the small cell lung cancer (SCLC) space has sparked interest for researchers over recent years, bringing new improvements and treatment options to the space.

Two influential trials include the phase 3 CASPIAN study (NCT03043872) of durvalumab (Imfinzi) with or without tremelimumab added to platinum etoposide chemotherapy1 and the phase 3 IMpower133 trial (NCT02763579)of carboplatin, etoposide, and atezolizumab (Tecentriq).2

The CASPIAN trial demonstrated an overall survival (OS) improvement compared with chemotherapy alone. Patients in the trial with extensive-stage small cell lung cancer (ES-SCLC) also found durvalumab to have a favorable safety profile.1 For IMpower133, the addition of atezolizumab to standard upfront carboplatin and etoposide significantly prolonged survival for patients with ES-SCLC.2

However, questions remain in this space and options are lacking, especially regarding patients who relapse. According to Gene G. Finley, MD, this is because most of the second-line treatment options are unsatisfactory.

While the FDA approval of lurbinectedin [Zepzelca] for adult patients with metastatic SCLC with disease progression on or following platinum-based chemotherapy in June 2020 was a big advance, research for SCLC has remained fairly quiet since.

“I think the challenge that we're having in extensive-stage disease for the patients that have primary resistance is that they respond initially, they'll stay in remission for a while, and then they'll relapse. In the second-line setting, we haven't been very successful,” stated Finley, medical oncologist at Allegheny Clinic Medical Oncology of Allegheny Health Network, in an interview with Targeted OncologyTM.

In the interview, Finley discussed the many wins and losses experts have seen in the small cell lung cancer space. He also explained his hopes for the future of this space.

Targeted Oncology: Can you discuss some of the advances in small cell lung cancer over the past few years?

Finley: There has been a lot of interest in the use of immunotherapy in lung cancer and specifically in the small cell space, there have been several immuno-oncology drugs that have had significant activity in improving the outcomes of extensive stage small cell lung cancer. The CASPIAN trial with durvalumab and IMpower133 with atezolizumab really added something to the advanced disease setting and most of these patients we see are advanced and not candidates for local therapy. I think that's a positive. CASPIAN gave us about a 3-month increase in median survival and in IMpower133, about 2 months. We've gone over that 12-month barrier now, which has been a barrier for some time.

One of the things that's challenging in small cell lung cancer that doesn't seem to be in play in non–small cell lung cancer is, what is the magnitude of benefit of immunotherapy in the setting? It's very modest in small cell lung cancer and that's kind of unexpected for me because if you look at graphs of tumor mutation burden vs response, small cells are always on the right side of the graph where there are high mutational and genomic changes in the cancer. That usually correlates with robust immunotherapy response, and that's where the melanoma is and where lung cancers in smokers and bladder cancers are. Those diseases have had tremendous changes in their response rates and in survival end points in a non–small cell space. We're not seeing that so much in small cells, so I find that a little puzzling, and I'm not sure if we know a good mechanism for that. So in terms of immunotherapy, there's a lot more opportunity.

In terms of conventional chemotherapy, the big news was the registration of lurbinectedin which was a couple of years ago now. We're using that in the second-line setting. These drugs are better than the older drugs like topotecan, but the myelosuppression is a little bit worse, but we've learned to handle that. I think that's been a significant benefit. Then, if the patient has been off first-line therapy for a long time, it can reintroduce platinum chemotherapy and can even reintroduce immunotherapy if they've been several months off treatment. I think the challenge that we're having in extensive-stage disease for the patients that have primary resistance, is that they usually respond initially, they'll stay in remission for a while, and then they'll relapse. In the second-line setting, we haven't been very successful.

Can you talk about some of the pitfalls with treatment in this space?

One is, what do you do with the extensive-stage patient, which most of them are, who relapses, because the treatments in the second-line setting are unsatisfactory. Lurbinectedin was a bit of an improvement and there's other single-agent chemotherapy, but we haven't had much mileage out of reintroducing immunotherapy. if it's been given in the first-line setting.

In terms of limited disease, I think we're doing quite well and are looking forward to the time where we will have other drugs to give after chemoradiation. The way it is now, you incorporate the radiation in first-line therapy with platinum-based doublets for topotecan for example. Then after that, it's mainly an observational strategy. Most patients will stay in remission and many end up relapsing. Then, we're looking again at IO or chemotherapy with IO depending on the duration and the length of their admission. I think there's room to introduce immunotherapy or other drugs and in the post-chemotherapy radiation setting. I know that's of interest and people are designing trials in that space.

There are some new drugs that are getting the FDA attention in terms of fast track designations and breakthrough therapy designations. What can you tell me about some of these drugs?

Irinotecan is pretty interesting. In the early 2000, there was a study comparing irinotecan and platinum with the etoposide and platinum, and that looked like a positive study. There were improvements in the overall survival in the patients receiving the irinotecan and platinum vs etoposide and platinum. Unfortunately, when we took it here, there was no difference. We sort of got stuck in this paradigm of giving etoposide and platinum in the first-line setting. But Irinotecan has activity in this disease, so the idea of using it has been promising.

In terms of other IO drugs, Chinese pharmaceutical companies that are introducing PD-1 drugs in the marketplace and they've shown similar activity to what we've seen with both durvalumab and atezolizumab, and I believe that they've achieved registration status. For example, serplulimab [HLX10] and Toripalimab [Tuoyi] are both on track. Toripalimab has FDA approval in an extensive-stage setting, and the other has an orphan drug status, so they can be used. It looks like the magnitude of benefit is quite similar to what we've seen with other drugs, so I think they'll fit into that marketplace. This is a general trend. Pharmaceutical companies tend to like drugs that are similar in character to the older drugs, so that we get many drugs in a similar class rather than taking the high-risk approach of looking for a completely new therapeutic.

We'll have 5, 6, or 7 drugs all interacting with a PD-1 or PD-L1 access, but they really are not substantially different from one another. If I could wave my magic wand, I would wish for a more ecumenical approach to looking for different targets. Even in the immunotherapy space, there are so many potential targets, and many of those have borne fruit in the melanoma and are moving into the non–small cell lung cancer space. We hope that some of those compounds will impact the small cell space as well.

How do you envision the treatment landscape evolving over the next 5-10 years?

My interest is in biomarkers and there's not many well to find biomarkers that are useful in the small cell space, unfortunately. What I do think has some legs is this idea of using a liquid biopsy as a strategy to predict patients that are destined for relapse and then providing an intervention there. We know in colorectal cancer, for example in patients with early-stage resected disease, you can utilize a liquid biopsy or bespoke assays to detect tumor-related DNA as it reappears in the blood. There are many intervention trials that are underway and many that have been completed showing that that does have benefit and that we would expect most oncologists would have predicted that treating patients in an earlier setting is going to have more benefit than waiting until they have a radiographic relapse.

Applying that to the small cells setting might help and I think trials like that would be in order. We have a large biomarker biobanking project related to that across all cancer patients that we see at the Allegheny Health Network, so we're very excited about that approach in terms of early-relapse detection and then introduction of therapeutics at a much earlier stage before you have radiographic relapse.

In terms of other drugs, when you think about lung cancer generally, non–small cells have become the poster child for targeted therapy. A number of targeted drugs have been attempted in small cell lung cancer and have really fallen flat, as most single-agent chemotherapies have. We also tried using more intensive chemotherapy in the first-line setting and small cell lung cancer, and that was not helpful either. I'm hopeful that some of the newer targeted drugs and some of the antibody drug conjugates that are in development will ultimately be useful. I'm hoping that this irinotecan formulation will be helpful.

What are some of the challenges that community oncologists are facing with small cell lung cancer treatment? Are there any solutions that you can think of for these problems?

One of the biggest challenges in small cell lung cancer is the rapid doubling time. While most human solid tumors have a clinical doubling time of between 2 and 3 months, small cell lung cancer is kind of unique in the solid tumor setting where the growth rate is akin to an aggressive non-Hodgkin lymphoma, where you can see doubling of tumor size in a couple of weeks.

This creates a serious challenge, especially in the lung cancer space, because lung cancer patients tend to be very nihilistic because it may have been caused from smoking, they tend to be older, a more frail population, a smoking population, so they tend to have a lot of medical comorbidities, they tend to present at later stage. It's very important to institute therapy quickly in these patients. Even in patients who have poor functional status, you can have the sort of “Lazarus Effect” that we see in other aggressive malignancies where the growth fraction of the cell population is so high, that they have profound responses up to and including tumor lysis syndrome. That is the key thing with small cells, and with many non–small cells as well, is to institute therapy early.

In SCLC, that's not really a problem generally, but if you have to wait to get the transition between an inpatient and outpatient setting, we have lost many patients in that transition over the years. We've taken to moving up the chemotherapy and trying to administer the first cycle of chemotherapy while the patient is still hospitalized because that's a much more facile way of getting their treatment going. Because of economic reasons and the way treatment is paid for in the United States, we can't really give them immunotherapy as an inpatient, but we can introduce it for the first cycle as an outpatient. I think that's 1 of the challenges that we have in the small cell space, the need to start chemotherapy early because the patients can progress and you can lose them so rapidly, particularly if they start out with a high volume of disease.

What key advice do you have for your peers in community oncology about treating patients with small cell lung cancer?

For the most part, the backbone of etoposide and platinum is one that most community oncologists are familiar with. I think the vast majority of us have medical oncologist are aware that how fast small cell lung cancers can grow, and even that varies quite a bit. I think the most important thing for them is to make the diagnosis prompt and Institute treatment when you find out they have the very high grade neuroendocrine cancers with a very high Ki67. We deliver extremely high-quality care in community cancer centers nationwide. There's so much push technology that brings awareness of newer treatments. That is much better than it ever was before. The information dissemination has really helped not only the doctors and nurses, but the patients themselves who become their own advocates. That's been a welcome change from the ways that it was when I was starting out.

The best thing we could do for lung cancer patients is to encourage smoking cessation. If you look at lung cancer incidence, it's starting to decline, especially in the United States because many people have stopped smoking. In other parts of the world, the prevalence of smoking has not changed much. Certainly, in China, the prevalence of smoking is extraordinarily high, and worldwide it is as well. I think prevention is the most efficient way to do this. Unfortunately, nicotine is extremely addicting and it's very difficult to get people to stop smoking once they've started. Public health dollars spent in prevention are going to pay many dividends. That would be the biggest impact we could make over the next few years if we can get more people to stop smoking cigarettes.

REFERENCES:
Goldman JW, Dvorkin M, Chen Y, et al. Durvalumab, with or without tremelimumab, plus platinum–etoposide versus platinum–etoposide alone in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): updated results from a randomised, controlled, open-label, phase 3 trial. Lancet. 2021;22(1):51-65. doi: 10.1016/S1470-2045(20)30539-8
Horn L, Mansfield AS, Szczęsna A, et al. First-Line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer. New Eng J Med. 2018; 379(23):2220-2229. doi: 10.1056/NEJMoa1809064