LUMINANCE Study Supports Durvalumab Plus Platinum/Etoposide in Frontline Treatment of ES-SCLC

LUMINANCE Study Supports Durvalumab Plus Platinum/Etoposide in Frontline Treatment of ES-SCLC

Data from two separate studies support the use of 5 or more cycles of induction platinum/etoposide (EP) along with durvalumab (Imfinzi) for the first-line treatment of patients with extensive-stage small cell lung cancer (ES-SCLC).¹

In particular, the safety and efficacy data observed with this regimen in the first-line setting in the phase 3b LUMINANCE study (NCT04774380) aligned with outcomes reported in the phase 3 CASPIAN trial (NCT03043872).

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.

References

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

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

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