Evolving Strategies in Managing and Treating Small Cell Lung Cancer

Ariel Lopez-Chavez, MD

Ongoing research for the treatment of small cell lung cancer (SCLC) is focusing on evaluating PD-L1 therapy in the frontline setting, as well as combining agents to enhance efficacy. Currently, carboplatin or cisplatin with etoposide combined with atezolizumab (Tecentriq) or durvalumab (Imfinzi) followed by maintenance therapy are FDA-approved options in the frontline setting, and lurbinectedin (Zepzelca) and topotecan are options for second-line treatment.

Notably, serplulimab (HLX10) and lurbinectedin combinations with atezolizumab are being evaluated, with a specific focus on assessing their efficacy and toxicity when given for SCLC treatment. Developments on the horizon also include tarlatamab (AMG 757), an antibody-drug conjugate, which has shown impressive results in patients with refractory SCLC. This agent is currently being investigated as a frontline option.

Additional trials are studying other novel agents, aiming to address the high unmet needs in SCLC.

In an interview with Targeted Oncology^TM, Ariel Lopez-Chavez, MD, medical oncologist, director of precision medicine and developmental therapeutics at Allegheny Health Network Cancer Institute, provided insights into the current landscape of SCLC treatment, highlighting approved options and ongoing research.

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Targeted Oncology: Can you discuss some of the currently approved options for patients with small cell lung cancer?

Lopez-Chavez: In the frontline setting, we have carboplatin or cisplatin and etoposide plus either atezolizumab or durvalumab for 4 to 6 cycles, followed by atezolizumab or durvalumab as a maintenance therapy until disease progression. So that's what we have as FDA-approved agents in the first-line setting. In the second-line setting, we essentially have lurbinectedin and topotecan as FDA-approved agents.

Can you highlight some of the latest National Comprehensive Cancer Network guidelines for subsequent systemic therapy and small cell lung cancer?

Talking in particular about lurbinectedin, the safety and efficacy of this agent was very good. In a basket trial, it was observed to have an overall response rate of 35%, a median progression-free survival [PFS] [of] 3.5 months, and a median overall survival [of] 9.3 months, and essentially, based on this efficacy, it has gained its approval by the FDA in the second-line setting for small cell lung cancer.

Now, the particular part that is important to highlight is the safety profile. We have myelosuppression as 1 of the main [adverse] effects of these therapies. We have a grade 3 and 4 neutropenia rate of about 41% and a febrile neutropenia rate of 7%. This is significant; however, the only other option that is FDA-approved is topotecan, and topotecan has double the rate of myelosuppression in this case or more. Then we're talking in regards to safety, we have [about] half the myelosuppression that we have with topotecan, so in this regard, it's a very attractive option for the second-line setting. Now, we're not there yet. This is significant. Myelosuppression, 41% grade 3/4 neutropenia, and 7% of febrile neutropenia still is not great, but at least this is an improvement compared with what we had before, which was only topotecan as the only other FDA-approved agent in the second-line setting.

Can you discuss some of the research on evaluating PD-L1 therapy in this space?

The evolution of PD-L1 therapy has mostly been in the frontline setting. After the approval of atezolizumab and durvalumab in the frontline setting, most of the research has been gravitating around the first line. Essentially, [we are trying] to get all the PD-1/PD-L1 inhibitors into that line of therapy. The latest is serplulimab, which is a PD-1 inhibitor that recently showed positive results in a phase 3 trial.

The other is the combination of other agents in the frontline setting to [see if] the use of PD-1/PD-L1 inhibitors are more effective. The trial is a phase 3 study [NCT05091567] where lurbinectedin is added to atezolizumab in the maintenance setting for extensive-stage small cell lung cancer. Once these patients fail induction therapy, the carboplatin, etoposide, and atezolizumab, they get randomized to either continue to receive what atezolizumab as a single-agent maintenance therapy vs atezolizumab and lurbinectedin.

This will be an interesting study to see because lurbinectedin is now approved in the second-line setting. It will be interesting to see what the efficacy is bringing it to the maintenance setting. In particular, to see at what cost in regards to the toxicity in the maintenance setting. Then, there are other agents being combined in the frontline setting.

What other agents and combinations are being evaluated in the frontline setting?

I am excited about tarlatamab, which is an antibody-drug conjugate. The specific molecule that is targeting the delta-like ligand 3 and CD3, which is highly expressed in small cell lung cancer. That makes it an attractive target in small cell lung cancer. We already have data for our phase 1 study with tarlatamab for refractory small cell lung cancer. Here, we saw impressive results. We have an overall response rate of 23%, a median PFS of 3.7 months, that's not that impressive, but then the thing that was really impressive was the median overall survival of 13.2 months.

To put that into context, the median overall survival in the frontline setting for atezolizumab and durvalumab was between 12 and 13 months. Here, we are seeing that tarlatamab in the second-line setting is 13.2 months. The [adverse] effects [and] the safety profile [are] manageable. We do not have as much myelosuppression as we see with topotecan or lurbinectedin. This is an attractive agent. Now it is being brought to the frontline setting and being studied during the frontline setting. I am excited about that combination.

What ongoing research in this space has caught your eye?

There are ones that are currently going towards registration, and we have another GM1 anibody by [Bristol Myers Squibb] that looked interesting in their initial results in the refractory setting. In particular, when they combined that with nivolumab [Opdivo] in the second-line setting, they got a median overall survival of around 18 months, which was encouraging. They are bringing it into the frontline setting as well. They are also studying it in combination with carboplatin, etoposide, and nivolumab. The results were not as impressive as with the latter, but it is something to follow-up on.

We also have radionuclide therapy also coming into the frontline setting. One more space that I am interested in is the use of cellular therapies. A lot of companies are going in the space of cellular therapies, in particular in solid tumors, non-small cell lung cancer, and there are some studies now going into small cell lung cancer.

What unmet needs still exist in this space?

The entire space of small cell lung cancer is a high unmet need because even though we have these new agents, compared with other tumor types, there is still a high unmet need. In the second-line setting in particular, we have high myelosuppressive agents. We are going to bring more compounds with better safety profiles, and it will be important in small cell lung cancer, in particular in the second line. Small cell lung cancer is a hard disease to treat, and most patients will not see more than 2 lines of therapy. It is important to bring, in particular in the second-line setting, drugs that have a better safety profile. I think that is 1 of the biggest unmet needs now for this patient population.

For a community oncologist, what would you recommend to take away from this talk?

Supporting the clinical trials and the development of these drugs that are coming is extremely important. Without the participation of people in the community, we would not have [everything we have]. Supporting the new trials that are coming and supporting the development of new drugs in small cell lung cancer is great. One thing that is important is that many of these trials are being designed so that you can treat your first cycle of chemotherapy without the investigational agent.

A lot of companies are allowing patients to have had already 1 cycle of carboplatin, etoposide, atezolizumab, or durvalumab, and then initiate the investigational agent on the second cycle so that investigators have time to do all the work necessary to enroll in the clinical trials. Many times, 1 of the major barriers for enrollment in small cell lung cancer trials is that it may take too much time. We need to treat these patients fast. A lot of the sponsors grab on to this, and they are now designing the trials to allow investigators to take their time to enroll patients into these trials. The main thing is to support the clinical development of all these new agents coming for small cell lung cancer.