Durvalumab Plus Chemo Is Tolerable in Real-World Representative ES-SCLC Population

Niels Reinmuth, MD

First-line durvalumab (Imfinzi) plus up to 6 cycles of platinum and etoposide is safe and tolerable with signals of clinical efficacy consistent with those previously seen in patients with treatment-naïve extensive-stage small cell lung cancer (ES-SCLC), according to preliminary findings from the phase 3b LUMINANCE trial (NCT04774380) that were presented at the 2023 European Lung Cancer Congress.

At a data cutoff date of August 19, 2022, and a median follow-up of 20.6 weeks, 94.1% of patients (n = 48) had experienced adverse effects (AEs) of any cause, and 64.7% of patients (n = 33) had experienced AEs of grade 3 or higher. The incidence of immune-mediated AEs was 13.7% (n = 7), with 3.9% of patients (n = 2) experiencing grade 3/4 immune-mediated AEs.¹

“The early safety and efficacy results from the LUMINANCE study in the first 51 patients enrolled, including those who received more than 4 rounds of chemotherapy, were consistent with those from [the phase 3] CASPIAN [trial (NCT03043872)],” lead study author Niels Reinmuth, MD, of the Asklepios Lung Clinic in Munich-Gauting, Germany, and coauthors, wrote in a poster of the data.

Results from CASPIAN showed that treatment with frontline durvalumab plus chemotherapy resulted in a median overall survival (OS) of 13.0 months vs 10.3 months with chemotherapy alone in patients with ES-SCLC (HR, 0.73; 95% CI, 0.59-0.91; P = .0047).² These findings supported the 2020 FDA approval of the combination in this population. The OS benefit with durvalumab plus chemotherapy in this trial was sustained after a median follow-up of 39.4 months, with a median OS of 12.9 months vs 10.5 months with chemotherapy alone (HR, 0.71; 95% CI, 0.60-0.86; nominal P = .0003).³

However, the patient population enrolled in CASPIAN did not fully represent the real-world population of patients with ES-SCLC, the study authors wrote. Notably, CASPIAN only allowed patients with an ECOG performance status (PS) of 0 or 1. Additionally, although patients in the chemotherapy alone arm could receive up to 6 cycles of chemotherapy, patients in the durvalumab arm could only receive up to 4 cycles of chemotherapy.

The open-label, single-arm, international LUMINANCE trial evaluated the safety and efficacy of the CASPIAN regimen in a more inclusive patient population. LUMINANCE enrolled patients with previously untreated, histologically or cytologically confirmed ES-SCLC who were eligible for platinum-based chemotherapy in the frontline setting and had a life expectancy of at least 12 weeks.¹ Patients could receive durvalumab plus 4 to 6 cycles of chemotherapy and could have a World Health Organization (WHO) PS of 0 to 2. Patients with asymptomatic or treated and stable brain metastases were allowed, and prophylactic cranial irradiation was permitted at any point during the trial at the treating investigator’s discretion.

Patients received durvalumab at 1500 mg plus investigator’s choice of either carboplatin (54.9%; n = 28) or cisplatin (45.1%; n = 23) plus etoposide once every 3 weeks for the investigator’s decision of 4 to 6 cycles, followed by 1500 mg of durvalumab maintenance once every 4 weeks until progressive disease (PD). The primary assessment of LUMINANCE occurred around 16 weeks after the 50th patient was enrolled and included the first 51 patients enrolled.

The primary end point of LUMINANCE was safety and tolerability, including the incidence of grade 3 or higher AEs and immune-mediated AEs. Immune-mediated AEs were defined as those associated with treatment exposure with no clear alternate etiology that required treatment with endocrine therapy or immunosuppressants like systemic corticosteroids. The key secondary efficacy end points were overall response rate (ORR), progression-free survival (PFS), 12-month PFS, duration of response (DOR), 12-month DOR, OS, and 12-month OS. The key secondary safety and tolerability end points were AEs and serious AEs.

Patients had a median age of 64.0 years (range, 27-81), 58.8% (n = 30) were male, and all were White. In total, 43.1% (n = 22), 52.9% (n = 27), and 3.9% (n = 2) had a WHO PS of 0, 1, or 2, respectively. Additionally, 4.0% (n = 2) and 38.0% (n = 19) had baseline brain and liver metastases, respectively.

At the data cutoff date, 70.6% (n = 36) and 25.5% (n = 13) of patients were still receiving durvalumab and chemotherapy, respectively. The median number of durvalumab doses during the durvalumab plus chemotherapy treatment period was 5.0 (range, 1-6), with 41.2% (n = 21), 58.8% (n = 30), and 47.1% (n = 24) of patients receiving up to 4, at least 5, and 6 doses, respectively. The median number of chemotherapy cycles based on etoposide exposure was 5.0 (range, 1-6), with 39.2% (n = 20), 56.9% (n = 29), and 47.1% (n = 24) receiving up to 4, at least 5, and 6 cycles, respectively. Chemotherapy cycle data were missing from 2 patients.

In total, 27.5% of patients (n = 14) experienced serious AEs. Additionally, 43.1% (n = 22) and 15.7% (n = 8) of patients had AEs leading to treatment interruption and discontinuation, respectively. Three patients had AEs leading to death, 1 each from acute kidney injury, cerebrovascular/pneumonia accident, and sepsis/pneumonia. Per the investigator, the acute kidney injury and sepsis/pneumonia were deemed possibly related to the chemotherapy, and none of the AEs with an outcome of death were determined to be related to durvalumab.

The most common AEs were anemia (all-grade, 60.8%; grade ≥ 3, 9.8%), neutropenia (41.2%; 37.3%), increased gamma-glutamyltransferase (21.6%; 7.8%), hypomagnesemia (all-grade, 17.6%), nausea (all-grade, 17.6%), thrombocytopenia (17.6%; 7.8%), alopecia (all-grade, 15.7%), leukopenia (15.7%; 5.9%), decreased neutrophil counts (15.7%; 15.7%), hyperthyroidism (all-grade, 13.7%), hyponatremia (13.7%; 7.8%), increased alanine aminotransferase (ALT; 11.8%; 3.9%), increased aspartate aminotransferase (AST; all-grade, 11.8%), constipation (all-grade, 11.8%), dyspnea (11.8%; 5.9%), decreased white blood cell counts (grade ≥ 3, 5.9%), hyperglycemia (grade ≥ 3, 3.9%), decreased lymphocyte counts (grade ≥ 3, 3.9%), pneumonia (grade ≥ 3, 3.9%), and sepsis (grade ≥ 3, 3.9%).

The incidence of AEs in patients who received up to 4 and at least 5 cycles of chemotherapy was 95.0% (n = 19) and 93.1% (n = 27), respectively. Of the patients who received 4 or fewer cycles, 85.0% had AEs at a maximum of grade 3 or higher, and 10.0% had AEs at a maximum of grade 2. Of the patients who received 5 or more cycles, 48.3% had AEs at a maximum of grade 3 or higher, and 44.8% had AEs at a maximum of grade 2.

“This likely suggests that, in clinical practice, additional cycles are reserved for those who best tolerate cycles 1 through 4, as might be expected,” the study authors wrote.

The most common immune-mediated AEs were hypothyroidism (5.9%; n = 3), increased ALT (3.9%; n = 2), hyperthyroidism (3.9%), increased AST (2.0%; n = 1), and increased blood creatinine (2.0%).

Of the 51 patients included in the primary analysis, the confirmed ORR was 58.8% (95% CI, 44.2%-72.4%). In total, 58.8% of patients (n = 30) achieved a partial response, including the 2 patients with a WHO PS of 2; 25.5% of patients (n = 13) achieved stable disease for at least 6 weeks; and 7.8% of patients (n = 4) each had PD or were not evaluable for response.

“Overall, these preliminary findings from the LUMINANCE study further support using durvalumab plus chemotherapy as a first treatment for patients with ES-SCLC,” the study authors concluded.

The ORR, PFS, DOR, and OS for all 152 patients enrolled in LUMINANCE will be assessed with longer follow-up.

Disclosures: Dr Reinmuth reports honoraria from Amgen, AstraZeneca, Bristol-Myers Squibb, Boehringer-Ingelheim, Daiichi Sankyo, GlaxoSmithKline, Hoffmann-La Roche, Janssen, Lilly, MSD, Merck, Pfizer, Symphogen, and Takeda; and consulting fees from AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, Hoffmann-La Roche, MSD, Merck, and Pfizer.

References

1. Reinmuth N, de Marinis F, Leighl N, Sadow S, Davey K, Özgüroglu M, et al. Preliminary results from LUMINANCE: a phase 3b, single-arm study of 1L durvalumab (D) + platinum-etoposide (EP) for patients with extensive-stage SCLC (ES-SCLC). Presented at: 2023 European Lung Cancer Congress; March 29-April 1, 2023; Copenhagen, Denmark. Abstract 170P.
2. Imfinzi approved in the US for extensive-stage small cell lung cancer. News release. AstraZeneca. Published March 30, 2020. Accessed April 11, 2023. https://www.astrazeneca.com/media-centre/press-releases
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