Leal Reviews State of Second-Line Therapy Options for ES-SCLC

Ticiana Leal, MD

Director, Thoracic Medical Oncology

Program Associate Professor, Department of Oncology and Medical Oncology

Emory University School of Medicine

Atlanta, GA

CASE SUMMARY

• A 58-year-old moderately active man presented with worsening shortness of breath, persistent dry cough, and fatigue. He is a smoker with a 30 pack-year history.
• ECOG performance status: 1
• Chest x-ray showed opacity in left lung.
• Chest CT showed hilar mass, with invasion of left pulmonary artery and 3 contralateral lung nodules present.
• Brain MRI: negative
• Bronchoscopy with transbronchial biopsy/pathology: small cell lung cancer (SCLC)
• Diagnosis: extensive-stage (ES) SCLC
• He received 4 cycles of carboplatin plus etoposide plus atezolizumab (Tecentriq).
• Initially achieved partial response
• Seven months after his last cycle of platinum chemotherapy, his shortness of breath returned with right upper quadrant pain and midback pain. He is receiving maintenance atezolizumab.
• CT scan of the chest, abdomen, and pelvis showed recurrence of the left upper lobe mass with hematogenous metastases in the liver and adrenal glands.
• MRI: negative for brain metastases
• Laboratory results: within normal limits
• ECOG performance status: 1

TARGETED ONCOLOGY: Can you discuss the latest National Comprehensive Cancer Network (NCCN) guidelines for subsequent systemic therapy in SCLC?

LEAL: The NCCN recommendations for patients with SCLC for subsequent systemic therapy include patients with an [ECOG] performance status of 0 to 2.¹ The preferred regimens include platinum-based doublet, [as well as] clinical trials. A rechallenge with the original regimen, or a similar regimen, by the NCCN guidelines is preferred in patients with a disease-free interval of greater than 6 months and may be considered for a disease-free interval of at least 3 to 6 months.

Other recommended regimens [include] 2 FDA-approved regimens. Topotecan was approved in 1996 for patients with platinum-sensitive disease who have progression of their disease at least 60 days after first-line chemotherapy. Lurbinectedin [Zepzelca] was approved in June 2020 and received accelerated approval for adult patients with SCLC with progression on or after platinum-based chemotherapy. Their threshold for platinumsensitive [disease] is 90 days or greater. Th ere is a lot of variability in what we’re calling sensitive vs not. The NCCN guidelines favor calling sensitive 6 months or greater.¹ There are multiple other potential options—all with phase 2 data, single-arm studies—and we certainly use other agents, such as irinotecan [Camptosar] and paclitaxel, temozolomide [Temodar], and so on.

Q:What did the phase 2 basket trial (NCT02454972) of lurbinectedin show in patients with SCLC?

This is the study that led to accelerated approval of lurbinectedin for SCLC.2 This is a basket trial, focusing on the cohort of patients with SCLC. These were patients with extensive-stage disease who had at least 1 prior chemotherapy line. Prior immunotherapy was allowed. Patients had to have adequate organ function and an [ECOG] performance status of 0 to 2. They excluded patients with CNS [central nervous system] metastasis. [A total of] 105 patients were enrolled in this cohort and received lurbinectedin at 3.2 mg/m² every 3 weeks.

The primary end point was overall response rate [ORR].² The secondary end points included duration of response [DOR], disease control rate [DCR], progression-free survival [PFS], overall survival [OS], pharmacokinetics, and safety. Of note, they did not allow growth factor in cycle 1.

[Most] patients were [men], and the median age was 60 [years]. [Most] patients had a good [ECOG] performance status, although they had 8% of patients with an ECOG performance status of 2. As expected, [most] patients were smokers and had extensive-stage disease at study entry. The median number of tumor sites was 3, and the most common nonlung sites—lymph node, liver, and adrenal—were 82%, 41%, and 26%, [respectively]. Thirty-two percent of the patients had bulky disease, 4% of the patients had CNS involvement, and 9% had paraneoplastic syndromes.

In terms of additional patient characteristics, 58% of patients had prior [prophylactic cranial irradiation].² The median prior lines of therapy was 1; 93% [of patients] had 1 prior line of therapy [and] 7% had 2 prior lines of therapies. The prior therapies [that were] included were platinum in 100%, etoposide in 99%, immunotherapy in 8%, and PARP inhibitors in 2%.

The best response to prior platinum included a complete response in 9%, a partial response in 67%, 18% had stable disease, and 4% had progression. Importantly, they define a chemotherapy-free interval [CTFI] for [platinum]-sensitive vs resistant as 90 days. The median CTFI was 3.5 months, 43% of the patients [experienced a CTFI of] less than 90 days, and 57% of the patients had [a CTFI of] 90 days or greater.

Could you discuss the efficacy of lurbinectedin in this patient population in more detail?

The results of the study showed an ORR of 35% [95% CI, 26.2%-45.2%], with a DCR of 68.6% [95% CI, 58.8%-77.3%].^2,3 The patients with a CTFI of less than 90 days—[who are] considered the platinum-resistant population—had an ORR of 22% [95% CI, 11.2%-37.1%] and a DCR of 51.1% [95% CI, 35.8%-66.3%]. This compares very favorably with the topotecan data, in which the responses were less than 10%.

The patients with a CTFI of 90 days or more had an ORR of 45% [95% CI, 32.1%-58.4%] and a DCR of 81.7% [95% CI, 69.0%-90.5%]. The median DOR in the overall population was 5.3 months [95% CI, 4.1-6.4], 4.7 months in the population with CTFI of less than 90 days [95% CI, 2.6-5.6], and
6.2 months in the population with a CTFI of 90 days or more [95% CI, 3.5-7.3]. Patients responding at 6 months in this refractory population were 43% [95% CI, 25.6%-60.5%], 11.7% in the group with CTFI of less than 90 days [95% CI, 0.0%-33.1%], and 55% in the group with CTFI of 90 days or more [95% CI, 34.5%-76.0%]. This is with a median follow-up of 17.1 months.

The median PFS was 3.5 months overall [95% CI, 2.6-4.3], 2.6 months in the group with CTFI of less than 90 days [95% CI, 1.3-3.9], and 4.6 months in the group with CTFI of 90 days or more [95% CI, 2.8-6.5]. The median OS was 9.3 months [95% CI, 6.3-11.8]. It was 5 months in the group with CTFI of less than 90 days [95% CI, 4.1-6.3] and 11.9 months in the patients [who] had CTFI of 90 days or more [95% CI, 9.7-16.2]. Highlighting the median OS for the patients [in the] group with CTFI of 90 days or more, the median OS was 11.9 months, and—strikingly here—the median OS for the CTFI of 180 days or more was 16.2 months [95% CI, 9.6–not reached].³ So the OS at
12 months is 48.3% for the group with CTFI of 90 days or more [95% CI, 32.5-64.1] and 60.9% [95% CI, 35.7-86.2] for the group with CTFI of 180 days or more

Historically, you have to think about how these patients did before lurbinectedin, and this is a cross-trial comparison. But for a platinum-refractory population with topotecan, the OS is a lot lower than what we’re seeing here. Granted, this is a single-arm phase 2 study. We do have an ongoing confirmatory study—[the phase 3 LAGOON trial; NCT05153239]—that is randomly assigning patients to lurbinectedin or lurbinectedin plus irinotecan vs standard of care.

How was lurbinectedin tolerated in this study?

In terms of doing the next line of therapy, tolerability of a regimen in patients with relapsed/refractory SCLC is quite important. Here, the regimen is well tolerated overall, but the major adverse events [AEs] are hematologic in nature.² [Most] of them are grade 1 or 2, but we are seeing 21% of patients with grade 3 neutropenia, 19% with grade 3 leukopenia, and 3% with grade 3 thrombocytopenia, although the rates of febrile neutropenia are quite low.

Another thing that is important—that I’ve experienced in my own practice—is a 7% rate of grade 3 fatigue, [which] is independent of anemia. At least in my practice, that’s how it’s been. Other things to keep an eye on include [aspartate aminotransferase] and [alanine aminotransferase] abnormalities. Here, it is 2%, [which is a] low rate of grade 3 hepatotoxicity, but it is certainly something to monitor. The rate of discontinuation due to treatment-related [AEs] was also low, at 2%.

Can you review the evidence for topotecan as a second-line therapy for SCLC?

[There was a] study that led to the FDA approval of topotecan in patients with SCLC as second-line therapy.^4,5 In this study, 211 patients were randomly assigned 1:1 to topotecan or CAV [cyclophosphamide, doxorubicin, and vincristine], which is a combination we rarely use. In this study, patients were considered to be sensitive to first-line chemotherapy if they were responders who then subsequently progressed 60 days or greater after completion of first-line therapy—a bit of a different definition. Patients received a frontline platinum/etoposide-based regimen.^4,5 In this study, there were no significant differences between topotecan and CAV with regards to ORR, DOR, time to progression, or OS. The median time to response was similar in both arms—topotecan at 6 weeks vs CAV at 6 weeks. The ORRs range from 11% to 31% for the patients who were platinum-sensitive and 2% to 7% for the [patients who were] refractory. Topotecan has been challenging to use in clinical practice because of associated hematologic toxicities. When you look at the median OS of using topotecan, it has ranged from 6 to 8 months and is certainly lower in the patients who are platinum-refractory.

The ORR for topotecan is 24% [95% CI, 16%-32%] vs 18% with CAV [95% CI, 11%-26%], with a DOR of 3.3 months [95% CI, 3.0-4.1] vs 3.5 months [95% CI, 3.0-5.3] and a time to progression of 3.1 months [95% CI, 2.6-4.1] vs 2.8 months [95% CI, 2.5-3.2], respectively.4,5 [Also], the median OS is 5.8 months [95% CI, 4.7-6.8] vs 5.7 months [95% CI, 5.0-7.0], respectively. I think one of the things that led to approval of topotecan was that they saw less deterioration of symptoms, or improvement in symptoms, related to their lung cancer with topotecan vs CAV.^4,5 This was the main push to approve topotecan vs CAV in the late 1990s.

Do the data support platinum rechallenge?

The platinum rechallenge recommendation from the NCCN¹ for patients who relapse 3 to 6 months after therapy is based on a phase 3 study [NCT02738346].⁶ This was a randomized study [in which] patients received carboplatin/etoposide vs topotecan as second-line treatment in the platinum-sensitive setting, defined as 90 days or greater after completion of their first-line therapy. The median PFS was superior in the platinum rechallenge—4.7 months vs 2.7 months—with [an HR] of 0.57 [95% CI, 0.41-0.73; P = .0041]. The ORR was also higher—49% vs 25%—with a positive P value [P = .0024]. However, there was no significant difference in median OS—7.5 months vs 7.4 months—with [an HR] of 1.03 [95% CI, 0.87-1.19; P = .94]. Interestingly, toxicities were not significantly different, either. I think this is an option, but keep in mind that this did not show a difference in median OS.

There are multiple studies [of platinum rechallenge], and, of course, this is hard to compare across trials, but…certainly the platinum-sensitive population is a population that may still derive significant benefit from therapies [in the second line].³ We have to think about which ones are going to be the most beneficial. But certainly, this is a population in which, across the board, there is activity of different agents. A lot of the studies with platinum rechallenge have been retrospective in nature, showing some benefit. In my opinion, we have to select who we’re going to use platinum rechallenge for.

_REFERENCES

_{1. NCCN. Clinical Practice Guidelines in Oncology. Small cell lung cancer, version 3.2023. Accessed March 16, 2023. https://www.nccn.org/professionals/physician_gls/pdf/sclc.pdf}

_{2. 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.}

_{3. Subbiah V, Paz-Ares L, Besse B, et al. Antitumor activity of lurbinectedin in second-line small cell lung cancer patients who are candidates for re-challenge with the first-line treatment. Lung Cancer. 2020;150:90-96. doi:10.1016/j.lungcan.2020.10.003}

_{4. von Pawel J, Schiller JH, Shepherd FA, et al. Topotecan versus cyclophosphamide, doxorubicin, and vincristine for the treatment of recurrent small-cell lung cancer. J Clin Oncol. 1999;17(2):658-667. doi:10.1200/JCO.1999.17.2.658}

_{5. Topotecan injection. Prescribing information. Teva Pharmaceuticals USA; 2014. Accessed March 16, 2023. https://bit.ly/3qz24oz}

_{6. Baize N, Monnet I, Greillier L, et al. Carboplatin plus etoposide versus topotecan as second-line treatment for patients with sensitive relapsed small-cell lung cancer: an open-label, multicentre, randomised, phase 3 trial. Lancet Oncol. 2020;21(9):1224-1233. doi:10.1016/S1470-2045(20)30461-7}