Updated Data Solidify First- and Second-Line Standards in Extensive-Stage Small Cell Lung Cancer

Haiying Cheng, MD, PhD

Updated data from the 2020 ASCO Virtual Scientific Program and 2020 ESMO Virtual Congress have provided additional details regarding new standard-of-care options in extensive-stage small cell lung cancer (ES-SCLC), said Haiying Cheng, MD, PhD, who added that the novel agents that have been introduced to the first- and second-line settings have been particularly encouraging advances.

During the 2020 Institutional Perspectives in Cancer webinar on lung cancer, Cheng, an associate professor in the Department of Medicine (Oncology) at the Albert Einstein College of Medicine/Montefiore Medical Center, highlighted new data from key clinical trials in ES-SCLC.

Updated Data Provide Additional Evidence in Support of First- and Second-Line Standards in ES-SCLC

Historically, chemotherapy with platinum and etoposide in the first-line setting and topotecan in the second-line setting were considered the standard treatment options for patients with ES-SCLC. However, the introduction of novel agents such as durvalumab (Imfinzi) and lurbinectedin (Zepzelca) transformed the paradigms.

Updated findings from the phase 3 CASPIAN trial, which were presented during the 2020 ASCO Virtual Scientific Program, demonstrated that the addition of durvalumab to standard chemotherapy continued to improve overall survival (OS) for patients with treatment-naïve ES-SCLC.¹

Based on initial findings from the CASPIAN trial, the FDA approved durvalumab for use in combination with standard-of-care chemotherapy, including etoposide plus carboplatin or cisplatin, for the first-line treatment of adult patients with ES-SCLC.² In the study, durvalumab plus chemotherapy reduced the risk of death by 27% compared with chemotherapy alone (HR, 0.73; 95% CI, 0.591-0.909; P = .0047).³

The randomized, global, open-label, active-controlled, multicenter trial enrolled 805 patients with ES-SCLC who had a World Health Organization performance status (PS) of 0 or 1, a life expectancy of 12 weeks or longer, and measurable disease per RECIST v1.1 criteria. Patients with asymptomatic or treated and stable brain metastases were eligible to participate.

Patients were stratified by planned platinum (carboplatin vs cisplatin). Patients were randomized to receive durvalumab plus tremelimumab and etoposide plus carboplatin/cisplatin (EP) followed by durvalumab alone, durvalumab plus EP (D + EP) followed by durvalumab alone, or EP alone followed by optimal prophylactic cranial irradiation (PCI) at the investigator’s discretion.

The primary end point of CASPIAN was OS, with progression-free survival (PFS), overall response rate (ORR), safety, and patient-reported outcomes serving as secondary end points.

The addition of tremelimumab to D + EP did not demonstrate statistical significance with regard to median OS at 10.4 months vs 10.5 months with EP alone.

However, the updated findings revealed that the median OS with D + EP was 12.9 months (95% CI, 11.3-14.7) compared with 10.5 months (95% CI, 9.3-11.2) with EP (HR, 0.75; 95% CI, 0.62-0.91; P = .0032).

Regarding safety, any-grade all-cause adverse effects (AEs) occurred in 99.2% of patients treated with D + T + EP (n = 266), 98.1% of patients treated with D + EP (n = 265), and 97% of patients treated with EP alone (n = 266). Grade 3/4 AEs were observed in 70.3%, 62.3%, and 62.8% of patients, respectively. Serious AEs occurred in 45.5%, 32.1%, and 36.5% of patients, respectively.

Patients treated with the triplet regimen experienced the highest rate of AEs leading to treatment discontinuation at 21.4% compared with 10.2% with D + EP and 9.4% with EP alone.

Additionally, immune-mediated AEs occurred in 36.1% of patients with D + T + EP, 20% with D + EP, and 2.6% with EP alone.

With the triplet regimen, 10.2% of patients experienced an AE that led to death vs 4.9% with D + EP and 5.6% with EP. Treatment-related AEs (TRAEs) that led to death occurred in 4.5%, 2.3%, and 0.8% of patients, respectively.

In the second-line setting of ES-SCLC, topotecan served as the standard of care from 1996 until 2020, when lurbinectedin entered the armamentarium.

“Lurbinectedin is a selective inhibitor of oncogenic transcription,” Cheng explained. “The drug inhibits angiogenic transcription and can led to tumor cell apoptosis. In addition, by inhibiting activated transcription in tumor-associated macrophages, lurbinectedin also affects the tumor microenvironment.”

In a single-arm, open-label, phase 2 basket trial (NCT2454972), 105 patients with SCLC were treated with 3.2 mg/m2 of lurbinectedin for a 1-hour intravenous infusion every 3 weeks.⁴ 

Eligible patients had a PS of 0 to 2, 1 prior line of chemotherapy, and adequate organ function. Although patients with prior immunotherapy were allowed onto the study, patients with central nervous system metastases were excluded.

Lurbinectedin demonstrated an ORR of 35.2% (95% CI, 26.2%-45.2%) in all patients treated. Additionally, the drug induced a disease control rate (DCR) of 68.6% (95% CI, 58.8%-77.3%).

At a median follow-up of 17.1 months, the median duration of response was 5.3 months (95% CI, 4.1-6.4), and the median PFS was 3.5 months (95% CI, 2.6-4.3). The median OS was 9.3 months (95% CI, 6.3-11.8), with a mortality rate of 63%. The 6-month OS rate was 67.1% (95% CI, 57.6%-76.7%), and the 12-month OS rate was 34.2% (95% CI, 23.2%-45.1%).

Patients were stratified by chemotherapy-free interval: less than 90 days (n = 45) and 90 days or more (n = 60). In the less than 90 days cohort, the ORR was 22.2% (95% CI, 11.2%-37.1%) vs 45% (95% CI, 32.1%-58.4%) in the 90 days or more cohort. The DCRs were 51.1% (95% CI, 35.8%-66.3%) and 81.7% (95% CI, 69.6%-90.5%), respectively.

“Although the median overall survival was much shorter in the patients with chemotherapy-resistant disease, those patients are generally considered to have a very poor prognosis regardless of treatment,” said Cheng.

The most common grade 3 or 4 AEs were mainly hematologic in nature, including neutropenia 46%), leukopenia (29%), anemia (9%), and thrombocytopenia (7%). Treatment-related non-hematologic AEs included grade 3 or 4 fatigue (7%) and neutropenia (5%).

Additionally, during the 2020 ASCO Virtual Scientific Program, findings from a pooled safety analysis of the basket trial and the randomized phase 3 CORAIL trial concurred that the toxicities associated with lurbinectedin are predictable and manageable.⁵

Based on findings from the basket trial, lurbinectedin was granted accelerated approved by the FDA on June 15, 2020 for the treatment of patients with metastatic SCLC with disease progression following platinum-based chemotherapy.⁶

The confirmatory, randomized phase 3 ATLANTIS trial (NCT02566993) of lurbinectedin plus doxorubicin versus topotecan plus CAV [cyclophosphamide, doxorubicin, and vincristine] is ongoing.⁷

Prognostic Biomarkers Inform Long-Term Survival With Atezolizumab in ES-SCLC

In the phase 3 IMpower133 trial, the addition of atezolizumab (Tecentriq) to frontline carboplatin and etoposide improved median OS and PFS compared with placebo and carboplatin/etoposide in patients with ES-SCLC.⁸ In the intent-to-treat population, the median OS was 12.3 months (95% CI, 10.8-15.8) in the atezolizumab group (n = 201) versus 10.3 months (95% CI, 9.3-11.3) in the placebo group (n = 202; HR, 0.76; 95% CI, 0.60-0.95; P = .0154).

Additionally, with longer follow-up, findings showed that atezolizumab plus carboplatin/etoposide induced persistent OS benefit.

A study, which was presented during the 2020 ESMO Virtual Congress, characterized long-term survivors, defined as patients who lived 18 months or longer since randomization to the first-line atezolizumab regimen.⁹

More long-term survivors were treated with the atezolizumab regimen (33.5%) vs the placebo regimen (20.4%).

Additionally, the univariate and multivariate Cox models revealed that ECOG PS, lactate dehydrogenase level, and sum of longest diameters of the target lesions have prognostic significance on survival outcomes for this patient population.

Further, exploratory analyses suggest that patients with ES-SCLC can benefit from atezolizumab plus chemotherapy, irrespective of patient and disease characteristics.

Negative Immunotherapy Trial Leaves Open Opportunities in Limited-Stage SCLC

During the 2020 ESMO Virtual Congress, results from the randomized phase 2 ETOP/IFCT 4-12 STIMULI trial showed that the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) did not improve PFS compared with observation alone in patients with limited stage (LS)-SCLC.¹⁰

The trial enrolled 153 patients with treatment-naïve, stage I to IIIB SCLC. Patients with 1 prior chemotherapy cycle were eligible to participate.

Patients received chemoradiotherapy in the form of 4 cycles of cisplatin or carboplatin plus etoposide with concurrent radiotherapy. Additionally, PCI was given after chemoradiotherapy.

If patients did not have progressive disease after chemoradiotherapy, they were randomized to immunotherapy consolidation with nivolumab plus ipilimumab followed by nivolumab maintenance for up to 12 months or observation without maintenance.

At a median follow-up of 22.7 months, the results showed a 10.7-month median PFS with nivolumab/ipilimumab (95% CI, 7.0–not estimable [NE]) vs a 14.5-month PFS with observation (95% CI, 8.2-NE), failing to meet the primary end point of the study. The median OS was not reached with the combination (95% CI, 22.4-NE) compared with 31.6 months with observation (95% CI, 26.1-NE).

The trial accrued half of the expected enrollment, which was a study limitation, said Cheng.

Although the trial was negative, translational work is ongoing to identify biomarker-defined subgroups that may benefit from consolidation immunotherapy.

References

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7. Clinical trial of lurbinectedin (PM01183)/doxorubicin versus CAV or topotecan as treatment in patients with small-cell lung cancer (ATLANTIS). ClinicalTrials.gov. Updated March 10, 2020. Accessed November 2, 2020. https://bit.ly/3oORpRg​
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