LUMINANCE Data Support the Frontline Use of Durvalumab Plus Platinum/Etoposide in ES-SCLC

The safety and efficacy data observed with the administration of 5 or more cycles of induction platinum/etoposide (EP) and concurrent durvalumab (Imfinzi) in patients with extensive-stage small cell lung cancer (ES-SCLC) enrolled in the phase 3b LUMINANCE study (NCT04774380) aligned with outcomes reported in the phase 3 CASPIAN trial (NCT03043872), supporting the use of the regimen in the first-line setting for this population.¹

The findings from the primary analysis of the trial were presented at the 2023 ESMO Immuno-Oncology Congress and showed that 59.2% of patients who received the chemoimmunotherapy combination (n = 152) experienced grade 3 or higher adverse effects (AEs). Immune-mediated AEs occurred in 13.8% of patients, with 3.3% of patients experiencing grade 3 or higher effects.

When broken down further, 59.2% (95% CI, 51.0%-67.1%) of patients experienced these events during the overall AE monitoring period and 56.6% (95% CI, 48.3%-64.6%) had an onset date within the first 6 months. Moreover, 66.7% of the 66 patients who received 1 to 4 cycles of EP experienced grade 3 or higher AEs, as well as 52.9% of the 85 patients who received 5 or more cycles of EP.

Durvalumab plus EP elicited a confirmed overall response rate (ORR) of 65.8% (95% CI, 57.7%-73.3%), with a median duration of response (DOR) of 5.1 months (95% CI, 4.9-5.3). Notably, 35.4% (95% CI, 25.9%-45.1%) of patients continued to respond at 6 months and 15.0% (95% CI, 7.7%-24.6%) continued to respond at 1 year. At a median follow-up of 9.7 months (range, 0.0-15.6), the median progression-free survival (PFS) with the regimen was 6.2 months (95% CI, 5.3-6.5). The 6- and 12-month PFS rates were 55.2% and 11.0%, respectively. At a median follow-up of 9.5 months (range, 0.1-17.5), the median overall survival (OS) was 13.1 months (95% CI, 10.1-not evaluable [NE]); the 12-month OS rate was 55.6%.

In those who received 1 to 4 cycles of EP, the confirmed ORR with the regimen was 47.0% (95% CI, 34.6%-59.7%), and the median DOR was 4.8 months (95% CI, 3.3-5.3). The median PFS was 4.6 months (95% CI, 3.4-4.6) and the median OS was 10.7 months (95% CI, 7.0-NE). In the group of patients who received 5 or more cycles of EP, the confirmed ORR was higher, at 81.2% (95% CI, 71.2%-88.8%), and the median DOR was longer, at 5.2 months (95% CI, 5.-6.3). The median PFS and OS were also prolonged, at 6.5 months (95% CI, 6.3-7.1) and not reached (95% CI, 10.3-NE), respectively.

“The most common [grade 3 or higher] AEs were hematological toxicities, which are typically associated with chemotherapy. The rate of grade 3 or higher AEs was lower in patients who received 5 or more cycles of EP vs 1 to 4 cycles; this is rather likely reflecting a selection bias,” Niels Reinmuth, MD, PhD, leader of the Thoracic Oncology Department at the Asklepios Lung Clinic in Munich-Gauting, Germany, said in a presentation of the data. “In clinical practice, additional cycles of EP would likely be reserved for those who best tolerate the initial 4 cycles. Moreover, numerically better outcomes were observed in patients who received 5 or more cycles of EP.”

Data from the CASPIAN study showed that the use of first-line durvalumab paired with chemotherapy led to a median OS of 13.0 months vs 10.3 months with chemotherapy alone in this population (HR, 0.73; 95% CI, 0.59-0.91; P = .0047).² Based on these findings, in March 2020, the FDA approved the combination in this population. With longer follow-up, a median of 39.4 months, the OS benefit derived with the regimen over chemotherapy alone was maintained, at a median of 12.9 months vs 10.5 months, respectively (HR, 0.71; 95% CI, 0.60-0.86; nominal P = .0003).³

“The results of this study established durvalumab plus EP as a global standard of care. However, like most phase 3 registrational studies, some elements of the study design did not fully reflect real-world clinical practice,” Reinmuth explained.¹ “Eligible patients had to have [a World Health Organization (WHO)] performance status of 0 and 1 and there was a limit for 4 cycles of EP in the durvalumab arm compared to up to 6 cycles in the comparator arm of chemotherapy only.”

The phase 3b LUMINANCE study examined durvalumab in combination with up to 6 cycles of EP in patients with histologically or cytologically confirmed ES-SCLC, including those with a WHO performance status of 2. To be eligible, patients needed to be treatment naive, have a life expectancy of at least 12 weeks, and be eligible to receive frontline platinum-based chemotherapy. Those with asymptomatic or treated stable brain metastases were allowed.

A total of 152 patients received treatment with durvalumab at 1500 mg plus EP every 3 weeks for 4 to 6 cycles and then single-agent durvalumab at 1500 mg every 4 weeks until disease progression. EP was comprised of investigator’s choice of carboplatin or cisplatin paired with etoposide.

The primary end points of the trial were incidence of grade 3 or higher AEs and incidence of immune-mediated AEs. Important secondary end points included investigator-assessed ORR, PFS, and DOR all by RECIST v1.1 criteria; OS; and AEs, serious AEs (SAEs), and AEs resulting in treatment discontinuation.

The data cutoff date for the primary analysis was June 12, 2023, and the median follow-up was 8.6 months (range, 0.1-17.5).

The median patient age was 64 years (range, 27-83) and most patients were male (64.5%) and White (99.3%). In terms of WHO performance status, 52.0% had a status of 0, 44.7% had a status of 1, and 3.3% had a status of 2. Most patients were former (67.5%) or current (29.8%) smokers. Moreover, 6.8% of patients had brain or central nervous system metastases and 27.7% had liver metastases.

At the data cutoff, 23.7% of patients were still receiving durvalumab. The median number of doses received was 8.5 (range, 1-19) and the median total duration was 29.6 weeks (range, 1.1-74.7). More than half of patients received carboplatin (63.8%) as their platinum agent, and 38.8% received cisplatin. The median number of EP cycles received was 5.0 (range, 1-6), with 87.5% of patients having received 4 or more cycles, 55.9% having received 5 or more cycles, and 48.7% having received 6 cycles.

Additional safety data showed that SAEs occurred in 32.2% of patients. Moreover, 14.5% of AEs resulted in treatment discontinuation, and 9.9% resulted in death. Of the 15 AEs that led to death, 4 were determined to potentially be related to EP, and none were determined to be potentially related to durvalumab

The most common AEs experienced by 10% or more of patients included anemia (56.6%), neutropenia (34.2%), nausea (24.3%), constipation (20.4%), fatigue (15.8%), thrombocytopenia (15.1%), leukopenia (14.5%), alopecia (13.2%), increased blood creatinine (11.8%), hypomagnesemia (11.8%), diarrhea (10.5%), hyperthyroidism (10.5%), hyponatremia (10.5%), hypothyroidism (10.5%), decreased neutrophil count (10.5%), and decreased white blood cell (WBC) count (10.5%).

The most common grade 3 or higher AEs with an incidence of higher than 2.5% included neutropenia (26.3%), anemia (9.9%), decreased neutrophil count (7.9%), thrombocytopenia (6.6%), leukopenia (5.9%), increased gamma-glutamyltransferase (5.3%), pneumonia (5.3%), hyponatremia (4.6%), dyspnea (3.9%), decreased WBC count (3.9%), increased alanine aminotransferase (ALT; 3.3%), hypokalemia (3.3%), acute kidney injury (2.6%), hyperglycemia (2.6%), decreased platelet count (2.6%), and upper abdominal pain (2.6%).

The most common immune-mediated AEs included hypothyroidism (6.6%), hyperthyroidism (3.3%), increased ALT (1.3%), arthralgia (0.7%), increased aspartate aminotransferase (0.7%), increased blood creatinine (0.7%), dermatitis (0.7%), hypertransaminasemia (0.7%), pneumonitis (0.7%), pruritus (0.7%), rash (0.7%), and thyroiditis (0.7%). No immune-mediated AEs led to death.

Editor’s Note: Dr Reinmuth disclosed that he serves on the Speaker’s Bureau for Amgen, AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Daiichi Sankyo, Hoffman-La Roche, Janssen, Lilly, MSD, Merck, Pfizer, and Takeda. He also is an advisory board member for Amgen, AstraZeneca, Bristol Myers Squibb, Daiichi Sankyo, Janssen, MSD, Merck, Pfizer, Sanofi, Symphogen, and Takeda. The LUMINANCE study was funded by AstraZeneca.

References

1. Reinmuth N, Özgüroglu, Leighl NB, et al. LBA2 – First-line (1L) durvalumab plus platinum-etoposide for patients with extensive-stage SCLC (ES-SCLC): primary results from the phase 3b LUMINANCE study. Ann Oncol. 2023;20(suppl 1):100535. doi:10.1016/iotech/iotech100535
2. Imfinzi approved in the US for extensive-stage small cell lung cancer. News release. AstraZeneca. Published March 30, 2020. Accessed January 4, 2024. https://www.astrazeneca.com/media-centre/press-releases/2020/imfinzi-approved-in-the-us-for-extensive-stage-small-cell-lung-cancer.html#modal-historic-confirmation
3. Paz-Ares L, Chen Y, Reinmuth N, et al. Durvalumab, with or without tremelimumab, plus platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer: 3-year overall survival update from CASPIAN. ESMO Open. 2022;7(2):100408. doi:10.1016/j.esmoop.2022.100408