Adding Maintenance Chemotherapy to Maintenance Immunotherapy: Lurbinectedin and Atezolizumab for Extensive-Stage Small Cell Lung Cancer
Authors
- Ming-Hei Tai, PharmD, BCOP, Oncology Pharmacist, Karmanos Cancer Institute at McLaren Flint
- Alexis Chapman, PharmD, BCOP, Clinical Pharmacy Specialist - Oncology, Allegheny Health Network
Background
Lung cancer is the third most diagnosed cancer in the United States and is the leading cause of death of both men and women in the United States. Approximately 15% of lung cancer diagnoses are classified as small cell lung cancer (SCLC).1 Even though the overall incidence of SCLC has declined in the last several decades, likely due to a reduction in smoking rates, the relative overall survival (OS) has not made significant improvements. The 1-year relative survival rate increased from 33.6% in 2000 to 36.7% in 2021, and the 3-year relative survival rate increased from 9% in 2000 to 14.3% in 2019.2
Extensive stage SCLC (ES-SCLC) is SCLC which has spread extensively throughout the body and is considered incurable.1 The U.S. Food & Drug Administration (FDA) has approved the following first-line options for ES-SCLC: carboplatin/etoposide/atezolizumab, carboplatin/etoposide/durvalumab, or cisplatin/etoposide/durvalumab.3 All regimens are given on days 1-3 every 3 weeks for the first four cycles followed by maintenance phases of single agent atezolizumab or durvalumab. Atezolizumab and durvalumab are both monoclonal antibodies that bind to programmed cell death ligand 1 (PD-L1) and block its interaction with both PD-1 and B7.1 receptors which restores the body’s anti-tumor immune response and increases T-cell activation.4,5
The atezolizumab-based regimen was studied in IMpower133, which was a double-blind, placebo-controlled, randomized phase 3 trial evaluating first-line atezolizumab versus placebo plus carboplatin and etoposide for ES-SCLC. This regimen was given for four cycles followed by a maintenance phase of single agent atezolizumab versus placebo. At a median follow-up of 22.9 months, the median OS was 12.3 months in the atezolizumab group versus 10.3 months in the placebo group (HR 0.76, 95% CI 0.60-0.95, p=0.0154). The median progression free survival (PFS) was 5.2 versus 4.3 months, respectively (HR 0.77, 95% CI 0.63-0.95, p=0.02).6
In a phase 3 extension study, IMbrella A, patients were allowed to roll over from Roche/Genentech-sponsored atezolizumab trials including those on IMpower133. The patients were allowed to roll over to atezolizumab if they continued to receive atezolizumab at IMpower133 closure or if they were in survival follow-up after discontinuation. There were 18 patients that rolled over and those patients had a 3-year OS rate of 16% and 5-year OS rate of 12%.7
For patients who experience disease progression after platinum-based chemotherapy, one of the FDA approved agents is lurbinectedin.3 Lurbinectedin is an alkylating agent that binds to guanine residues in the minor groove of DNA which forms adducts and ultimately affects the activities of DNA binding proteins, transcription factors, and DNA repair pathways.8 Lurbinectedin also reshapes the tumor microenvironment leading to activated T cells and antitumor immune responses. This can lead to synergistic effects and improved efficacy when combined with immunotherapy.9 In ES-SCLC, lurbinectedin is dosed at 3.2 mg/m2 intravenously (IV) every 3 weeks.
The ES-SCLC treatment has a high initial response rate but also early progression and becomes chemo-refractory in later lines of therapy.10 The study that brought lurbinectedin as monotherapy into the ES-SCLC treatment landscape was a phase 2 single arm basket trial.11 It included patients with ES-SCLC who received one prior line of therapy. At a median follow-up of 17.1 months, the overall response rate (ORR) was 35.2%.11 Response rates increased as the chemotherapy-free interval increased. Subsequently, the IMforte trial was conducted to determine whether lurbinectedin could synergize with immunotherapy by modifying the tumor microenvironment.
IMforte
IMforte was a randomized, open-label, global phase 3 trial designed to evaluate lurbinectedin plus atezolizumab versus atezolizumab maintenance after first-line induction therapy with standard of care atezolizumab, carboplatin, and etoposide in patients with ES-SCLC.Patients were included if they were Eastern Cooperative Oncology Group (ECOG) 0 or 1 and had an ongoing response or stable disease after four cycles of atezolizumab, carboplatin, and etoposide. Patients were excluded if they had central nervous system (CNS) metastases or consolidative thoracic radiation. Primary granulocyte colony-stimulating factor (G-CSF) prophylaxis was required for patients receiving lurbinectedin. Lurbinectedin was given at a dose of 3.2 mg/m2 IV every 3 weeks, and atezolizumab was given at a dose of 1200 mg IV every 3 weeks. Patients continued therapy until disease progression, unacceptable toxic effects, or withdrawal of consent. The two primary endpoints were independent review facility (IRF) assessed PFS and OS.
Between May 24, 2022, and April 30, 2024, 483 total patients were randomly assigned to lurbinectedin plus atezolizumab (n=242) or atezolizumab (n=241). Baseline characteristics were generally well-balanced between the two arms, except for age, with 49% of patients on lurbinectedin plus atezolizumab below age 65 as compared to 37% for patients on atezolizumab. Most patients were from Europe, the Middle East, or Asia, and <10% of patients were from North America. Of the total population, approximately 15% of patients received prophylactic cranial irradiation (PCI), 33% were current smokers, 26% had an elevated lactate dehydrogenase (LDH), and 87% had a complete or partial response to induction therapy.
The median follow-up was 15 months. At data cutoff, final IRF-assessed PFS showed clinically and statistically significant improvement in the lurbinectedin plus atezolizumab arm versus the atezolizumab arm (median 5.4 versus 2.1 months; HR 0.54, 95% CI 0.43-0.67, p<0.0001). Interim OS was also significantly improved in the lurbinectedin plus atezolizumab arm versus the atezolizumab arm (median 13.2 versus 10.6 months, HR 0.73, 95% CI 0.57-0.95, p=0.017). Lurbinectedin plus atezolizumab showed an OS benefit in most subgroups but not in patients with prior PCI or elevated LDH. North American patients were underrepresented in this trial, and while that subgroup did show a benefit in PFS from lurbinectedin plus atezolizumab versus atezolizumab (HR 0.36, median PFS 3.1 months versus 2.1 months), this was not reflected in OS (HR 1.08, median OS 7.7 months versus 9 months).
Lurbinectedin plus atezolizumab had increased rates of most adverse events when compared to atezolizumab alone. All-cause treatment-related adverse events were 83% in the lurbinectedin plus atezolizumab arm versus 40% in the atezolizumab arm. This included rates of infection (38% vs 26%), hepatitis (10% vs 6%), nausea (36% vs 4%), fatigue (20% vs 8%), anemia (32% vs 7%), neutropenia (11% vs 2%), and thrombocytopenia (13% vs 2%). Rates of grade 3-4 adverse events were higher in the lurbinectedin plus atezolizumab arm (38% vs 22%), as were rates of corticosteroid use (17% vs 8%). There were 12 fatal adverse events in the lurbinectedin plus atezolizumab arm compared to 6 in the atezolizumab arm. Of these fatal events, 2 events were treatment-related in the lurbinectedin plus atezolizumab arm, and one event was considered to be treatment-related in the atezolizumab arm.
Discussion
The benefit of adding lurbinectedin to atezolizumab is based on the aggressiveness of ES-SCLC. Only 240/405 (59%) of the patients who discontinued maintenance treatment received subsequent therapy.12 Many ES-SCLC patients never reach second line treatment after progression, so delaying progression by adding maintenance chemotherapy to immunotherapy appears to improve OS. This benefit in OS was demonstrated despite a worse toxicity profile and more deaths from adverse events.
However, adding lurbinectedin does not necessarily improve long-term outcomes. At approximately 18 months (median follow-up was 15 months), the PFS curves cross. While short-term OS shows a benefit, long-term OS is immature. ES-SCLC remains a difficult to treat disease, and adding maintenance lurbinectedin to atezolizumab may not change a patient’s long-term prognosis.
In addition, patients with CNS metastases were excluded from the trial. This limits the trial’s generalizability, as the CNS is a common site of metastasis for ES-SCLC patients.13 Furthermore, there is evidence from a previously published phase 3 trial that lurbinectedin does not have good penetration into the CNS.14 While maintenance lurbinectedin may help control disease outside the CNS, it is unlikely to control CNS disease.
The results of IMforte show that in patients who are ECOG 0 or 1 without CNS metastases, maintenance lurbinectedin can be added to maintenance atezolizumab after induction to extend OS at the cost of increased toxicity. This trial is practice-changing only for this set of patients, as other patients may be unable to tolerate the adverse events. Data on the immunogenicity of atezolizumab with and without lurbinectedin, as well as quality of life data from this trial, is still pending. While this trial is a step in the right direction, further research is still needed to improve long-term outcomes in all ES-SCLC patients.
References
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