Dr Alberto Chiappori on the Difficulties and Recent Progress in SCLC Research

As it stands, patients diagnosed with small-cell lung cancer (SCLC) typically face a poor prognosis. While non-small cell lung cancer (NSCLC) has a 5-year survival rate of roughly 24%, the 5-year survival rate in SCLC is just 6%.¹ Progress in the research and treatment of SCLC, which makes up about 13% of overall lung cancer diagnoses and is often diagnosed in later stages, was largely stagnant until recent years compared with NSCLC.² 

Given the slower progress in identifying disease subtypes and effective therapies for SCLC, there are still fewer treatment options than there are in the NSCLC armamentarium, where an array of therapeutics have been approved in recent years.

The American Journal of Managed Care® (AJMC®) spoke with Alberto Chiappori, MD, a senior member of oncology and medicine in the department of thoracic oncology at the H. Lee Moffitt Cancer Center and Research Institute, to discuss some of the challenges associated with researching and treating SCLC, as well as recent progress in the management of the disease.

The following has been edited lightly for clarity.

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

Chiappori: Well, I guess [part of it is] the poor prognosis. To be more specific, one of the things with small-cell lung cancer is that typically it’s a disease that is diagnosed in an advanced stage. I would probably say that 80% to 85% of all the patients with small-cell lung cancer are diagnosed with stage IV disease. And many of those patients have quite massive, bulky disease. Even in those patients where the disease is localized to the chest, usually, it's localized with lymph nodes, to a point where surgery is not frequently done. I think that you probably don't operate in more than a few percentage points of patients with small-cell lung cancer. And in many of those, you probably operate because you think that they have non-small cell lung cancer or you don't know what they have, they just have a resectable lesion. So the clear minority of patients with small-cell lung cancer are patients who present with early-stage disease.

Because of that, you are, as a physician, presented with 2 things. First, the rush that you need to treat this person quickly, because they have really lethal, advanced disease. As a result, you don't spend a lot of time thinking about how many different biopsies or places you're going to biopsy to get tissue. You just get a biopsy, you get an FNA [fine needle aspiration] with a few cells, it shows small-cell lung cancer, you move forward with treatment.

And second, because you rarely operate on patients, you actually do not have much tissue to do much of any study of the disease. Those are probably the main 2 obstacles that we have had with studying small-cell lung cancer. And then, of course, the poor prognosis, regardless of the treatment, you could argue is directly associated to the fact that you can’t study it. If you cannot study it, you cannot find new treatments. If you cannot find new treatments, how can you improve the prognosis? And you get this vicious cycle that we've been in.

AJMC®: Earlier this year, you published an update on the management and treatment of SCLC. What have been some of the biggest recent developments in SCLC treatment, and are there any novel therapies or combinations you see potential in?

Chiappori: Well, from a therapeutic point of view, probably the number 1 advancement has been the incorporation of immunotherapy to chemotherapy. In small-cell lung cancer, there have been 2 studies that have led to FDA approvals. IMpower 133,³ which combined chemotherapy—the traditional etoposide and carboplatin—with atezolizumab, which is an anti–PD-L1 inhibitor. And so that study showed to be a positive study and led to the approval of atezolizumab in combination with chemotherapy for small-cell lung cancer in March 2019.⁴ There was another positive study, the CASPIAN study,⁵ which showed that the addition of durvalumab—another anti–PD-L1 checkpoint. inhibitor—to chemotherapy was superior to chemotherapy alone. So that led to the approval of durvalumab, as well.⁶ So as of the last year and a half or so, we have 2 new anti–PD-L1 checkpoint inhibitors to combine with chemotherapy. Those are the 2 most important advances. They are small advances, but they're advances after all.

Another approval recently in relapsed small-cell lung cancer was lurbinectedin, which is a different type of chemotherapy. That is an accelerated approval based on a phase 2 study.⁷ And just this month, the FDA also approved another drug called trilaciclib.⁸ Now, trilaciclib has been approved not based on improving survival, but based on diminishing myelosuppression in patients with small-cell lung cancer. So it is also another approval in the small-cell environment, but it's not based on efficacy. It's more based on safety, or toxicity.

AJMC®: In light of the accelerated approval of lurbinectedin and the approval of durvalumab for SCLC, both within the past year, can you discuss the importance of frequent regulatory and payer coverage updates as the treatment landscape changes?

Chiappori: It is important in that you need to update the portfolio so that third-party payers have that in their rules to cover these medications and they can be readily available [to patients]. Imagine if we did not update those things. You could say, well, if I want to use trilaciclib tomorrow, or late next week, giving some time for every regulatory step and process—and it always takes time. You could say, well, no company would ever approve that or pay for that, because they haven't updated their approval processes. So yeah, absolutely, from that point of view, that should be a continuous process. That is responsibility of the insurance companies or any third-party payers, because they're the ones who make the decisions in the end, and they should make the decisions based on the most current available scientific data.

AJMC®: Genomic testing has been practice-changing in several cancer types, including NSCLC. What has been its role in identifying potential therapy options in SCLC?

Chiappori: That is probably the other area where recently—and by recently, I mean a few years—there have been some advances in small-cell lung cancer. That's why I specified therapeutic advancement or improvements earlier. These [genomic testing] advances are not therapeutic in the sense that they have not yet led to any specific drug. But they are advances in the sense that we are beginning to better understand the biology of small-cell lung cancer. We are beginning to understand that, in fact, there are subtypes or subgroups of small-cell lung cancer, and that potentially those subtypes or subgroups of small-cell lung cancer may be more or less sensitive to particular drugs that are in our armamentarium already. It may also lead to development or investigation in a more targeted fashion of newer drugs for that specific subgroup or subtype of small-cell lung cancer, just like we have been doing now in non-small cell lung cancer, particularly in adenocarcinomas for, the last 20 years.

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

Chiappori: Yes, of course. Small-cell lung cancer is what we call a neuroendocrine tumor, or a high-grade, neuroendocrine tumor. Neuroendocrine tumors can occur in the lung, but they can occur in many other places in your body—the pancreas, the gastrointestinal tract, the thymus, you name it, the bladder, the prostate. Now, even within the neuroendocrine tumors of the lung, there is small-cell lung cancer and large-cell neuroendocrine carcinoma on one extreme, the high-grade tumors; and you have the carcinoids, or the atypical carcinoids, more low-grade tumors on the opposite extreme. And to the extent that there are some similarities among all these neuroendocrine tumors—they are not identical, they're not genetically or transcriptionally exactly the same—but to the extent that they may have some similarities, you can extrapolate, or you can extend findings in small-cell lung cancer to those other types of tumors, and vice versa, the opposite applies as well.

AJMC®: Is there anything that you would like to add regarding the current state of research or treatment of small-cell lung cancer?

Chiappori: Well, I think that we are beginning to study small-cell lung cancer a little bit more in the, I guess you can call it traditional, fashion that we've been studying non-small cell lung cancer, so that's a positive thing. But in order to do that, we require tissue, and tissue has always been the most limited resource that we’ve had in small-cell lung cancer. So as a research community, we have to figure out a way by which we can obtain more of that resource, either before the patient is treated or during the period that the patient is being treated or progressing. Only in that way can we really learn how the tumor is behaving and what the evolution of the of the tumor is. We can do some of that probably with blood or circulating tumor DNA or other things like that, but I think that tissue remains crucial component. Whether we need to make a commitment to do better biopsies on patients, or whether we should consider operating in more patients—within a reasonable ethical frame of course—I've always been in favor of all those things.

References

1. Lung cancer - non-small cell: statistics. Cancer.Net. May 2020. Accessed February 26, 2021. https://www.cancer.net/cancer-types/lung-cancer-non-small-cell/statistics

2. Koinis F, Kotsakis A, Georgoulias V. Small cell lung cancer (SCLC): no treatment advances in recent years. Transl Lung Cancer Res. 2016;5(1):39-50. doi:10.3978/j.issn.2218-6751.2016.01.03

3. A study of carboplatin plus etoposide with or without atezolizumab in participants with untreated extensive-stage (ES) small cell lung cancer (SCLC) (IMpower133). ClinicalTrials.gov. Updated January 27, 2021. Accessed February 26, 2021. https://clinicaltrials.gov/ct2/show/NCT02763579

4. FDA approves atezolizumab for extensive-stage small cell lung cancer. FDA. March 19, 2019. Accessed February 26, 2021. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-atezolizumab-extensive-stage-small-cell-lung-cancer

5. Durvalumab ± tremelimumab in combination with platinum based chemotherapy in untreated extensive-stage small cell lung cancer (CASPIAN). ClinicalTrials.gov. Updated January 11, 2021. Accessed February 26, 2021. https://clinicaltrials.gov/ct2/show/NCT03043872

6. FDA approves durvalumab for extensive-stage small cell lung cancer. FDA. March 30, 2020. Accessed February 26, 2021. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-durvalumab-extensive-stage-small-cell-lung-cancer

7. FDA grants accelerated approval to lurbinectedin for metastatic small cell lung cancer. FDA. June 6, 2020. Accessed February 26, 2021. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-grants-accelerated-approval-lurbinectedin-metastatic-small-cell-lung-cancer

8. FDA approves drug to reduce bone marrow suppression caused by chemotherapy. News release. FDA; February 12, 2021. Accessed February 26, 2021. https://www.fda.gov/news-events/press-announcements/fda-approves-drug-reduce-bone-marrow-suppression-caused-chemotherapy