Chemoimmunotherapy Prolongs Time to Disease Recurrence, But Work Remains to Deliver Durable Benefit in ES-SCLC

Melina Elpi Marmarelis, MD

The combination of atezolizumab (Tecentriq), carboplatin, and etoposide, as well as durvalumab (Imfinzi), etoposide, and platinum chemotherapy, each have shown survival improvements vs chemotherapy alone as frontline therapy in patients with extensive-stage small cell lung cancer (ES-SCLC), explained Melina Elpi Marmarelis, MD, who added that immunotherapy could also play a role in the second-line setting pending data from the phase 1/2 LUPER trial (NCT04358237).

“ES-SCLC is entering an era, hopefully, of new and exciting treatments, both in the first-line and the second-line setting. We currently have good options in the first-line setting with combinations of standard chemotherapy and immunotherapy that are providing durable benefit in some patients,” said Marmarelis. “We’re starting to explore new options in the second-line setting, such as combinations with the recently approved lurbinectedin [Zepzelca] and look forward to additional data on those combinations and other novel combinations.”

In the multicenter, open-label LUPER trial, patients with relapsed SCLC will receive lurbinectedin plus pembrolizumab (Keytruda). During the phase 1 portion, patients will receive pembrolizumab at a fixed dose of 200 mg in 30-minute intravenous (IV) infusions followed by lurbinectedin at a starting dose of 2.4 mg/m2 in 1-hour IV infusions on day 1 of every third week.

During the phase 2 portion, patients will receive pembrolizumab at a fixed dose of 200 mg in 30-minute IV infusions followed by lurbinectedin in 1-hour IV infusions on day 1 of every third week at the recommended dose determined during the phase I stage.

In an interview with OncLive® during an Institutional Perspectives in Cancer webinar on lung cancer, Marmarelis, an assistant professor of medicine at the Hospital of the University of Pennsylvania, discussed the significance of using immunotherapy in ES-SCLC and ongoing research that could further help prolong the time to disease recurrence in patients with aggressive disease.

OncLive®: Atezolizumab was the first checkpoint inhibitor to be approved in ES-SCLC. How has that approval affected the patients you see with ES-SCLC?

Marmarelis: [IMpower133], the trial looking at carboplatin, etoposide, and atezolizumab, was really a landmark trial in ES-SCLC and was one of the first times we’ve seen overall survival [OS] benefit by adding something to the backbone of chemotherapy in a long time, which was very exciting and has really opened up the field to combination chemoimmunotherapies and combination immunotherapies and has made it part of our standard of care. It was a huge advance even though the absolute gain in OS was small at about 2 months, it still opened the door for a new way of thinking about ES-SCLC.

How would you characterize the durability of responses we’re seeing with the 2 approved chemoimmunotherapy combinations?

For patients who do have a durable response to presumably the immunotherapy portion of the regimen, their responses are durable in the framework that we have for SCLC, which is that inevitably patients do have disease recurrence. It’s delaying the time for the most part, until there is disease recurrence. There may be a very small percentage of patients that have durable responses that lead to potentially no evidence of disease for a period of time. However, the vast majority of patients, unfortunately, are seeing relapsed disease, despite there being a longer time between first- and second-line treatment.

How do you decide between atezolizumab and durvalumab for patients with ES-SCLC?

The 2 chemoimmunotherapy options are really equivalent, and either one could be used. There are no data to suggest that one is better than the other.

Do patients tend to prefer 1 combination vs the other?

No, I think it’s a coin toss. The differences to patients are not perceptible, which is appropriate because I don’t think there are differences in efficacy. They really are truly equivalent regimens.

In terms of toxicity, what data suggest a dose reduction with the immunotherapy agent could be beneficial apart from chemotherapy alone?

The chemotherapy can be dose reduced, and that would be our standard practice if patients were experiencing toxicity. Dose reduction of immunotherapy is more controversial since the toxicity is not dose dependent, so I would not necessarily dose reduce immunotherapy for toxicity. We have other ways of managing toxicity with immunotherapy.

In terms of management strategies, the main tool we have is steroids. We can use steroids to mitigate some of the adverse effects that come with immunotherapy in addition to holding the medication or discontinuing the medication in patients that have more severe toxicity.

What are your thoughts on the analysis that was presented from the IMpower133 trial that demonstrated the importance of continuing immunotherapy into the maintenance setting at the International Association for the Study of Lung Cancer 2020 World Conference on Lung Cancer?

There was an analysis of carboplatin, etoposide, and atezolizumab, looking at the importance of the maintenance phase. Instead of starting the analysis at the time of randomization, they started at the time of initiating maintenance immunotherapy. They found that there was still a benefit to receiving immunotherapy compared with placebo even if you start the clock at the start of maintenance, which had not been previously seen. In fact, when studies looked at chemotherapy followed by maintenance immunotherapy, they did not find a benefit for switch maintenance to immunotherapy in SCLC, so this was a new finding.

What ongoing trials in the frontline setting could potentially move the bar even further?

Several trials are looking at chemoimmunotherapy combinations, as well as chemotherapy and combination immunotherapy combinations. We’re going to see additional benefit, hopefully from some of those trials. In SCLC, it’s really important to have the best treatment in the first-line setting, because a lot of patients unfortunately do not make it to receive second-line treatment. Having a very effective first-line treatment is helpful.

That being said, chemotherapy is still the backbone of [treatment in] SCLC, and relapse is a very difficult problem in this disease.

Moving on to the relapsed setting, what are your thoughts on lurbinectedin, which is now approved for patients with disease progression following platinum-based chemotherapy?

Especially with chemoimmunotherapy in the frontline setting as the clear standard of care, we are stuck with chemotherapy in the second-line setting. Lurbinectedin is a fairly non-toxic and somewhat effective treatment in that setting. It unfortunately does not have an indication in patients with brain metastases, and a lot of patients with ES-SCLC do develop disease progression in the brain. However, it’s an important tool; it can be an effective tool, and it does not add a lot of toxicity. It is going to be an important chemotherapy drug going forward in this setting.

Could lurbinectedin be an effective agent for patients with brain metastases?

It could be effective. Patients that have SCLC and brain metastases potentially have more aggressive disease. It may be that it is less effective in that setting. However, there’s no reason to think that it should be ineffective in controlling systemic disease and extracranial disease. It’s certainly possible. Unfortunately, we don’t have those data in the single-agent setting.

What investigational combinations have piqued your interest in the relapsed setting?

There was lurbinectedin and doxorubicin. Unfortunately, that combination did not meet its primary end point [in the ATLANTIS trial], but we don’t have the data yet to look and see if there are potentially patients that could benefit from that combination. Earlier phases of that trial showed a very impressive overall response rate for the combination. We’ll have to take a closer look [at the data]. Investigators presented data on lurbinectedin and irinotecan in combination in a non-randomized, earlier-phase trial; data showed a nice response rate. Those are the combinations I would look out for. There are additional combinations, including the LUPER trial looking at lurbinectedin and immunotherapy.

There has been some talk about PARP inhibitors. Are they still an area of active investigation?

PARP inhibitors are an interesting area in SCLC, and there certainly are small trials in ES-SCLC that seem to show activity with PARP inhibitors in patients. It doesn’t seem to be related to any mutational characteristics of the tumor as we’ve seen in breast cancer, such as having a BRCA mutation for instance. There is a future for PARP inhibitors in SCLC. I don’t think it will be as a single agent; it will likely be in combination with other agents that are hopefully synergistic with PARP inhibitors.