Lurbinectedin Exhibits Encouraging Efficacy, Signaling Forward Momentum in SCLC Management

The field of relapsed/refractory small cell lung cancer (SCLC) is expanding to include novel options for disease management, most notably, the chemotherapy lurbinectedin (Zepzelca), according to Sanjay Popat, MBBS, FRCP, PhD.

In a phase 2 basket trial (NCT02454972), lurbinectedin elicited an overall response rate of 35.2% and a disease control rate of 68.6%. Furthermore, investigators found the agent had a safety profile that was acceptable and manageable in patients with SCLC.¹ Results from this trial propelled the June 15, 2020, FDA approval of lurbinectedin in this population. The ongoing phase 3 LAGOON trial (NCT05153239) is investigating lurbinectedin monotherapy vs lurbinectedin plus irinotecan vs irinotecan or topotecan in patients with relapsed SCLC. 

“We are looking for additional effective treatments, and we’re looking forward to using different and novel compounds in this arena,” Popat said.

In an interview with OncLive®, Popat, a consultant medical oncologist at The Royal Marsden NHS Foundation Trust and a professor of thoracic oncology at the Institute of Cancer Research, discussed the status of second-line SCLC therapies, the unique qualities of lurbinectedin, and how the LAGOON trial may pave the way for more effective therapies for patients with relapsed disease.

OncLive^®: Could you describe the current treatment landscape for relapsed/refractory SCLC? What therapies are used in the second line?

Popat: The management of relapsed SCLC continues to be challenging. We have few good treatments for this extremely aggressive disease. Up front, we generally use platinum chemotherapy plus the PD-L1 inhibitors atezolizumab [Tecentriq] or durvalumab [Imfinzi]. But after relapse in this setting, we are looking for effective treatment options.

Patients who have disease that seems to be platinum-sensitive by virtue of a reasonable platinum-free interval of 3 months or 6 months are often rechallenged with platinum [and] etoposide. The only licensed drug that exists [for these patients] is oral topotecan. However, the efficacy of topotecan needs much improvement. In some centers, topotecan is not preferred because of its myelosuppressive nature, and combination chemotherapy with anthracycline-based regimens such as CAV [cyclophosphamide, doxorubicin, and vincristine] is favored. However, the efficacy of CAV is probably similar to that of topotecan, as has been demonstrated in previous studies.

What unmet medical needs remain in the second line, and why might current therapeutic options be suboptimal?

In the second-line treatment of SCLC, we need more effective treatments. We’ve had thousands of patients volunteering their services for clinical trials over the years. These [trial regimens] include different combinations of systemic chemotherapy with immunotherapy [in the form of] either PD-1 inhibitors or PD-L1 inhibitors, or a combination of the aforementioned with CTLA-4 inhibitors.

Nevertheless, despite many patients enrolling into clinical trials, we are no further forward. The only approved regulatory standard for relapsed SCLC continues to be topotecan [in the United Kingdom], with no other regimen demonstrating any superiority over topotecan. We need better therapeutics.

We had great hope for immune checkpoint inhibitor therapy. Indeed, the FDA gave accelerated approval for this. Unfortunately, in a head-to-head study of nivolumab [Opdivo] plus ipilimumab [Yervoy] vs topotecan, we saw no improvement in overall survival [OS], a real blow to all of us working in this field.

We need a better understanding of the biology of SCLC. We’re starting to understand the different subgroups driven by different transcription factors, which may cause sensitivity to different types of therapeutics.

What is the mechanism of action of lurbinectedin, and what makes this agent unique compared with other treatment options?

Lurbinectedin is an interesting agent. It’s given intravenously on day 1 every 3 weeks and is a biologically occurring compound from marine life. It seems to function as a transcriptional regressor, which changes the biology of SCLC.

Functionally, it does not seem as myelosuppressive as other compounds that we have seen. Because of its relatively unique nature, it may have certain advantages over cytotoxic compounds that we’ve used. It does have a novel mechanism of action. Compounds related to lurbinectedin have proven efficacious in soft tissue sarcoma, for example, so it does represent a novel strategy moving forward.

A phase 2 basket study revealed lurbinectedin’s efficacy in patients who received this agent. Could you expand on the data that was seen?

The first signal of lurbinectedin’s activity in SCLC came from the basket trial that was presented in 2020, where, in the SCLC cohort, lurbinectedin monotherapy was efficacious, with a 32.5% response rate. Responses were increased in patients with platinum-refractory disease, which is remarkable because the expected response rate in that setting was around 5%. The progression-free survival was also meaningful.

Being a single-arm study, it’s difficult to make any comparisons with it, particularly because there may have been an element of patient selection [bias], as is inevitable in trials of relapsed SCLC. However, that was the first signal that this drug may be something special in the setting of relapsed SCLC.

What did lurbinectedin’s accelerated approval in the US mean for patients with SCLC? Who are the ideal candidates for this agent?

The data from the basket study led to the accelerated approval [of lurbinectedin] in the US. In the US, lurbinectedin has been used as a traditional second-line agent, and has often been the preferred second-line agent over topotecan. This is because the efficacy we saw in the basket study was superior to what would be expected from topotecan, and, although the toxicity profile demonstrates myelosuppression, it’s not the extent of myelosuppression that we would see with traditional cytotoxic chemotherapy. Moreover, we’re seeing efficacy in a platinum-refractory cohort, which we’ve not seen before.

This is an exciting step forward, and lurbinectedin is a novel treatment option for patients in the US. However, at the end of the day, we are looking forward to more data from larger randomized trials.

What is the rationale for the LAGOON trial? How might this trial affect the SCLC population if positive?

The LAGOON trial is evaluating the efficacy of lurbinectedin in a randomized manner. This is the benchmark for whether this drug will reach the regulatory standard required for approval [in the relapsed setting]. It is looking at OS as the primary end point. Patients will be randomized to lurbinectedin, lurbinectedin-irinotecan combination or investigator choice of topotecan or irinotecan.

All of us who follow this field have great hope and anticipation that this trial will meet the primary end point because we need a highly effective treatment for this group of patients. We’ve previously seen lurbinectedin combined at a lower dose with doxorubicin in the [phase 3] ATLANTIS study [NCT02566993], where it did not meet the primary end point of OS when compared with active chemotherapy. [This may not have been] the best trial design, [as it used] a lower efficacy dose of lurbinectedin. Hence, the ongoing LAGOON trial will be critically important in evaluating the efficacy of lurbinectedin, balanced against its safety profile.

What main message would you like to leave with colleagues?

Lurbinectedin has encouraging efficacy and a [manageable] safety profile, [and is] appropriate for this setting in relapsed SCLC. It has accelerated approval by the FDA for use in the US. Despite the negative ATLANTIS trial, which may have used an inappropriate combination and dosing of lurbinectedin, we are looking forward to more data from the ongoing randomized LAGOON trial. We hope [it] will demonstrate that lurbinectedin should be a standard in this setting, a new standard and the first in many years.

Reference

1. Trigo J, Subbiah V, Besse B, et al. Lurbinectedin as second-line treatment for patients with small-cell lung cancer: a single-arm, open-label, phase 2 basket trial. Lancet Oncol. 2020;21(5):645-654. doi:10.1016/S1470-2045(20)30068-1