Immunotherapy Spearheads Progress in Small Cell Lung Cancer

W. Victoria Lai, MD

The addition of immunotherapy to standard chemotherapy has resulted in an overall survival (OS) advantage in patients with newly diagnosed, extensive-stage small cell lung cancer (ES-SCLC), shifting not only the frontline standard but potentially second-line treatment as well, said W. Victoria Lai, MD.

In the phase III IMpower133 trial, patients with ES-SCLC had a median OS of 12.3 months with the addition of atezolizumab (Tecentriq) to platinum and etoposide versus 10.3 months with placebo and chemotherapy (HR, 0.70; 95% CI, 0.54-0.91; P = .0069).¹ Data from the interim analysis led to the March 2019 FDA approval of the PD-L1 inhibitor in combination with chemotherapy in the frontline setting. After nearly 2 years of follow-up, the atezolizumab regimen continued to showcase an OS advantage of 12.3 months versus 10.3 months with placebo and chemotherapy (HR, 0.76; 95% CI, 0.60-0.95; P = .0154).²

Furthermore, data from the phase III CASPIAN trial presented at the 2019 World Conference on Lung Cancer showed a similar OS benefit with the addition of the PD-L1 inhibitor durvalumab (Imfinzi) to standard chemotherapy. According to the analysis, patients with newly diagnosed disease experienced a median OS of 13.0 months with the durvalumab regimen versus 10.3 months with chemotherapy alone (HR, 0.73; 95% CI, 0.591-0.909; P = .0047).³

“For the last 30 years, SCLC has been a field in which there has been little progress. However, we are currently at a very exciting time in terms of drug development, particularly with regard to immunotherapy,” said Lai. “The IMpower133 and CASPIAN trials have revolutionized our initial systemic treatment for patients with metastatic SCLC.”

However, how these data will impact prior second-line staples, such as consolidative chest radiation and combination immunotherapy, remains less clear, Lai added.

In an interview during the 2019 OncLive^® State of the Science Summit™ on Non—Small Cell Lung Cancer, Lai, a medical oncologist at Memorial Sloan Kettering Cancer, discussed the impact immunotherapy has had in the management of patients with ES-SCLC.

OncLive: Is SCLC an immunogenic cancer?

Lai: Relative to non—small cell lung cancer (NSCLC), SCLC has many more mutations in the tumor itself. On average, it also has a much higher tumor mutational burden (TMB). Based on what we understand about the available biomarkers in NSCLC, including PD-L1 and TMB, we would have thought that immunotherapy would have worked even better in SCLC. However, that’s not really the case. Immunotherapy doesn't have the effect we would expect, which speaks to the fact that we still need to understand much more about the underlying biology of SCLC in order to find novel ways of combining modalities to maximize the efficacy of treatment.

Could you discuss the data from the CASPIAN trial?

CASPIAN is a global, randomized phase III open-label study. Patients were randomized in a 1:1:1 fashion to standard-of-care chemotherapy with platinum and etoposide, platinum plus etoposide plus the PD-L1 antibody durvalumab followed by maintenance durvalumab, or chemotherapy plus durvalumab plus the CTLA-4 inhibitor tremelimumab. The data from the third arm haven’t been presented yet, so we look forward to seeing those results.

We do know that chemotherapy plus durvalumab did improve median OS and progression-free survival (PFS). However, the initial analysis was not powered for a formal PFS comparison. The median OS was 10.3 months with chemotherapy versus 13.0 months with the addition of durvalumab. These data help reinforce that the combinational approach is the proper one. The improvement in median OS is a great starting point, but we would like to see even more improvement. That’s why we’re looking forward to seeing the results from the third arm.

If the combination of durvalumab and chemotherapy is approved in the frontline setting, how might you decide between that regimen and the combination of atezolizumab and chemotherapy?

Biologically, we expect the 2 regimens to be pretty similar. Atezolizumab is also a PD-L1 inhibitor. The results from the [CASPIAN and IMpower133 trials] are fairly similar. However, durvalumab does improve the median OS a little bit more than atezolizumab. When the efficacy is the same in terms of prolonging OS and response rates, the next thing we look at is tolerability.

In the CASPIAN study, you do see fewer adverse events overall with durvalumab. [You do need to] keep in mind that the CASPIAN study was not blinded and it didn't involve a placebo control. I believe the 2 regimens would be interchangeable [if the durvalumab combination is approved]. We've been using atezolizumab because it’s approved, but we're excited to start using durvalumab to see if we get different results in the real-world setting.

How has immunotherapy in the frontline setting impacted the use of radiotherapy?

Before the addition of immunotherapy to first-line chemotherapy, consolidative chest radiation after initial chemotherapy was a standard of care. However, this approach was not necessarily practiced at every institution. If patients have a great response everywhere else in the body, but they have residual thoracic disease, their OS can be prolonged with chest radiation.

However, chest radiation was not allowed in [the IMpower133 and CASPIAN] studies. One of the open questions is how we sequence and integrate that modality now. We know that prophylactic cranial radiation was allowed [in those trials], and some providers did opt for that approach. The optimal way we sequence these treatment modalities is a question that we'll need to examine further.

What is the role of immunotherapy in the second-line setting? How might the potential approval of lurbinectedin in that space impact treatment?

With the addition of immunotherapy, we are seeing a shift in what the optimal second-line treatment should be. Before the addition of immunotherapy to chemotherapy in the first-line setting, our preference was to use the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) in the second-line setting, based on the data from the phase I/II CheckMate-032 trial. Having immunotherapy in the first-line setting has opened up our options in the second-line setting. We have more room for other treatments from other drug classes. If someone progressed on anti—PD-L1 therapy, we might think twice about putting them on another PD-1 inhibitor, even if we are adding a CTLA-4 inhibitor.

Do any other targets of interest exist in SCLC?

Unfortunately, we haven't found oncogenic drivers like the ones that have been well described in NSCLC. However, certain key alterations that are characteristic of the disease, including p53 and RB1. Gradually, we're beginning to understand that much of what’s driving the disease may happen later on at the RNA level or protein expression level. Those are the areas we want to examine further in order to identify patients who may respond to certain treatments over others.

Over the past few years, we have also learned much more about different subsets of SCLC based on the presence and absence of certain endocrine transcription drivers. A lot of work is ongoing in those areas to further characterize how those differing expression patterns affect response to treatment.

Could you discuss the importance of clinical trials in furthering progress?

Many patients come to us and have the notion that clinical trials are for when you are at the end of your treatment course; that's certainly not the case. IMpower133 and CASPIAN were both first-line studies. Other first-line studies are being conducted, and new trials are always opening—particularly in SCLC, in which the benefits of our current treatments are not where we like them to be. I really do encourage providers and patients to consider clinical trials at every line of treatment. The standard treatment options will always be there, but patients might miss out on a potential spot in a clinical trial that could make a difference for them.

What is your take-home message regarding the current management of SCLC?

It’s a very exciting time for drug development in SCLC. [We’re in a much better place than we were] 10 or 20 years ago. However, we still have a long way to go in terms of improving OS and long-term outcomes for our patients.

References

1. Horn L, Mansfield AS, Szcęsna A, et al; IMpower133 Study Group. First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer. N Engl J Med. 2018;379(23):2220-2229. doi: 10.1056/NEJMoa1809064.
2. Reck M, Liu SV, Mansfield AS, et al. IMpower133: updated overall survival (OS) analysis of first-line (1L) atezolizumab (atezo) + carboplatin + etoposide in extensive-stage SCLC (ES-SCLC). Ann Oncol. 2019;30(5 suppl; abstr 1736O). doi: 10.1093/annonc.mdz264.
3. Paz-Ares L, Chen Y, Reinmuth N, et al. Overall survival with durvalumab plus etoposide-platinum in first-line extensive-stage SCLC: results from the CASPIAN study. Presented at: IASLC 20th World Conference on Lung Cancer; September 7-10, 2019; Barcelona, Spain. Abstract PL02.11. doi: 10.1016/j.jtho.2019.08.061.