Searching for Novel Agents to Augment Atezolizumab Approval in Small Cell Lung Cancer

Stephen Liu, MD

Despite the integration of frontline immunotherapy into routine practice for patients with extensive-stage small cell lung cancer (SCLC), researchers are still searching for agents with a high clinical impact that do more than fill a space of unmet need, explained Stephen V. Liu, MD.

“The only study we have that has shown a survival benefit is the IMpower133 trial, which tested the addition of atezolizumab (Tecentriq) to standard carboplatin and etoposide followed by atezolizumab maintenance,” said Liu. “For now, our standard of care is the addition of atezolizumab to carboplatin and etoposide.”

On March 19, 2019, the FDA approved atezolizumab for use in combination with carboplatin and etoposide for patients with treatment-naïve, extensive-stage SCLC based on a 2-month extension in overall survival (OS) versus chemotherapy alone (HR, 0.70; 95% CI, 0.54-0.91; P = .007).

Another immunotherapy agent, pembrolizumab (Keytruda), was granted an approval in June 2019 for use as third-line therapy. However, the agent has had a limited impact in the paradigm, as few patients are able to make it to the third-line setting, explained Liu.

Despite these challenges, several drugs and targets are showing promise in the paradigm. One such agent is lurbinectedin, a marine-derived compound, which was granted an orphan drug designation from the FDA in August 2018.

In an interview during the 2019 OncLive^® State of the Science Summit™ on Advanced Non—Small Cell Lung Cancer, Liu, an associate professor of medicine at Medstar Georgetown University Medical Center, discussed the impact of immunotherapy in the first-, second-, and third-line settings of SCLC, as well as novel agents and targets on the horizon.

OncLive: Could you discuss the rationale to explore immunotherapy in SCLC?

Liu: We had high expectations for immunotherapy in SCLC; this is a carcinogen-related cancer characterized by high mutational burden. We had seen early signs of activity, but in the past few years, we've seen modest outcomes. Nivolumab (Opdivo) was granted an accelerated approval in the third-line setting based on a response rate of 11.9% and durable responses lasting about 1.5 years.

Pembrolizumab was also approved in June 2019 in the third-line setting. The approval was also based on a relatively modest response rate of about 19% in a pretty small sample size of only 16 responders. Responses were durable, but the approval speaks more to the unmet need as we didn’t have anything else in the third-line setting. These drugs do have activity, but there is a very limited impact.

Most of our patients don't survive long enough to receive third-line treatment. If these are potentially transformative drugs, drugs that can lead to extended survival, we want to be sure to deliver them earlier. However, strategies that have been tested in second-line trials, such as CheckMate-331, and maintenance trials, such as CheckMate-451, failed to improve survival over standard of care. Other trials will read out over the next calendar year, including KEYNOTE-604 and CASPIAN, which are looking at the contributions of pembrolizumab and durvalumab (Imfinzi) with or without tremelimumab.

How would you define the impact of the FDA approvals for atezolizumab and pembrolizumab?

Pembrolizumab was approved in the third-line setting, but it's had a pretty limited impact. Very few of our patients make it to the third-line setting. There's a very high attrition rate with SCLC. In ideal circumstances, maybe about 20% of patients will get to the third-line setting. If these are drugs that provide a benefit, we want to ensure that they are given drug earlier on.

While the pembrolizumab approval is a welcome addition to the arsenal, it's overshadowed by the frontline approval of atezolizumab. For patients with newly diagnosed extensive-stage SCLC, we should be delivering atezolizumab with chemotherapy as it has shown a survival benefit. Saving treatment for later lines of therapy is an inappropriate strategy because patients won't survive long enough to receive those drugs.

Could you highlight potential biomarkers for SCLC treatment?

Our expectations for immunotherapy in SCLC were high because it has a high mutational rate, it's a carcinogen-related cancer, and it has a high link to smoking. The outcomes have been somewhat modest. We've come to learn that there's much more than mutational burden. Mutations are a poor surrogate for the actual neoantigen load. Unlike other tumors, some of the powerful immunosuppressive mechanisms located within the microenvironment are present in SCLC, which really prevents an immune response. Until we can factor in the host's immunosuppressive factors, we really won't be able to develop a proper predictive biomarker for SCLC.

What agents are showing promise in this space?

At the 2019 ASCO Annual Meeting, Luis Paz-Ares, MD, of the Hospital Universitario 12 de Octubre, presented data on lurbinectedin. The single-arm, phase II study looked at single-agent lurbinectedin. This is a very exciting drug that is similar to trabectedin (Yondelis), which is a marine-derived compound that affects transcription. The agent also affects tumor-associated macrophages which may play some role in immunogenic response. We saw great responses greater than 30%. What was most impressive is that we saw responses in chemotherapy-sensitive patients, as well as responses of about 20% to 22% in those who were refractory to chemotherapy.

Historically, the drugs we have, such as topotecan, have a response rate that is much closer to 0% in that setting. For chemotherapy-refractory SCLC—in which the chemotherapy-free interval is less than 3 months—having a drug with a response rate greater than 20% is very exciting. We will wait for the randomized phase III data looking at the combination of lurbinectedin with doxorubicin versus topotecan. The primary endpoint in that study is OS. If that is a positive trial, the drug should be made available to all of our patients.

Should investigation continue with rovalpituzumab tesirine (Rova-T) or do the data suggest that it should be retired?

Rova-t was an exciting drug in terms of fulfilling an unmet need. DLL3 is a very clear target; it has all the right properties of a therapeutic target. DLL3 is expressed on the tumor, but not as highly expressed on normal tissue. Rova-T is an antibody-drug conjugate targeting DLL3. While there were signs of activity, the toxicity is probably too great to overcome. This doesn't negate the validity of the target, but I'm not sure the drug has a place in the current environment. Other drugs that are targeting DLL3 look much more exciting at this point.

What role will chemotherapy have in the future of SCLC treatment?

Right now, chemotherapy plays a major role in the management of SCLC; this is an unrelenting and unforgiving disease. While there certainly is a move toward chemotherapy-sparing treatments in non—small cell lung cancer, the same would be quite scary in SCLC. If you're giving a drug without a response, the natural history of the disease is such that patients won't survive very long at all. Chemotherapy still plays a very strong role in the frontline setting. To remove chemotherapy from the frontline setting, we would need a pretty powerful predictive biomarker. My hope is that we will get there eventually. Right now, chemotherapy is still a central part of frontline therapy, even though the addition of immunotherapy has improved outcomes.

Horn L, Mansfield AS, Szczęsna A, et al. First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer. N Eng J Med. 2018;379(23):2220-2229. doi:10.1056/NEJMoa1809064.