Promising ORR Seen With Temozolomide Plus Nivolumab in Previously-Treated ES-SCLC


The combination of temozolomide and nivolumab demonstrated promising overall response rates in patients who previously received chemotherapy for extensive-stage small cell lung cancer.

The combination of temozolomide (Temodar) plus nivolumab (Opdivo) in patients who previously received chemotherapy for extensive-stage small cell lung cancer (ES-SCLC) induced a promising overall response rate (ORR), according to findings from a phase 2 trial (NCT03728361) presented at the 2022 World Conference on Lung Cancer.1

However, investigators found that only those with platinum-sensitive disease realized a benefit with the combination.

Twenty-five patients with ES-SCLC who progressed following first-line chemoimmunotherapy were included in the findings. Patients with treated and untreated brain metastases were part of the cohort.

The ORR was 28% (95% CI, 12%-49%) at a median follow-up of 6.3 months. The response rate among platinum-sensitive patients (n = 15) was 47% (95% CI, 21%-73%) compared with 0% (95% CI, 0%-31%) among platinum-resistant patients (P = .057).

The ORR was 20% (95% CI, 3%-56%) among patients who had brain metastases (n = 10) and 33% (95% CI, 12%-62%) among those who did not (n = 15; P = .659).

The oral alkylating agent temozolomide is approved for the treatment of patients with glioblastoma and patients with refractory anaplastic astrocytoma who have experienced disease progression on a drug regimen containing nitrosourea and procarbazine (Matulane). Its efficacy is associated with the predictive biomarker, MGMT promoter methylation. Because MGMT plays a role in the repair of DNA damage that is caused by alkylating agents, it is known that epigenetic MGMT silencing represents a mechanism of synthetic lethality following temozolomide exposure.

The trial was a multicohort, open-label study conducted at The Ohio State University Comprehensive Cancer Center in Columbus. Data from 28 patients with metastatic neuroendocrine carcinoma were not included in these results.

All enrolled patients in the ES-SCLC cohort (N = 27) received 480 mg nivolumab and 150 mg/m2 temozolomide for 5 days of a 28-day cycle. Two patients were not evaluable for ORR.

The primary end point was best ORR by RECIST v1.1. Progression-free survival (PFS) and overall survival (OS) were secondary end points.

The median patient age was 65 years (range, 56-78) and 63% of the cohort was male. Twenty-three (85%) patients had an ECOG score of 1. All patients were smokers, and 75% had received 2 prior lines of therapy.

The median PFS for all 27 patients was 2.4 months (95% CI, 1.9-3.4). The median OS was 6.3 months (95% CI, 3.7-9.2).

For patients without brain metastases, the median PFS was 2.1 months (95% CI, 1.9-3.5), and the median OS was 5.2 months (95% CI, 3.1-9.2). The median PFS was 3.3 months (95% CI, 1.7-3.7) for patients with brain metastases, and the median OS was 9.0 months (95% CI, 2.0-11.4).

Regarding safety, 96% of patients experienced at least 1 any-grade treatment-related adverse effect (TRAE), and 70% had a grade 3 or higher TRAE. The most common TRAEs of any grade included decreased lymphocyte count (63%), fatigue (59%), anemia (41%), vomiting (41%), weight loss (41%), nausea (33%), decreased platelet count (33%), and generalized muscle weakness (30%).

One treatment-related death was reported due to COVID-19.

In results published in May 2022, temozolomide priming followed by the combination of low-dose ipilimumab (Yervoy) and nivolumab produced durable clinical benefit in microsatellite stable (MSS) and MGMT-silenced metastatic colorectal cancer (mCRC), according to data from a phase 2 MAYA trial (NCT03832621) published in the Journal of Clinical Oncology.2

At a median follow-up of 23.1 months (interquartile range, 14.9-24.6), 12 out of 33 patients achieved a PFS that was longer than 8 months, translating to a 9-month PFS rate of 36% (95% CI, 23%-57%), which met the primary end point of the trial.

Moreover, the median PFS in these patients was 7.0 months (95% CI, 5.5-8.3), and the median OS was 18.4 months (95% CI, 14.9–non-assessable). The 12-month PFS rate was 24% (95% CI, 13%-44%), and the 18-month PFS rate was 20% (95% CI, 10%-41%).

1. Owen DW, Wei L, Brenner B, et al. Efficacy of nivolumab and temozolomide in extensive stage small cell lung cancer after chemo immunotherapy. Presented at: International Association for the Study of Lung Cancer 2022 World Conference on Lung Cancer; August 6-9, 2022; Vienna, Austria. Abstract OA12.04
2. Morano F, Raimondi A, Pagani F, et al. Temozolomide followed by combination with low-dose ipilimumab and nivolumab in patients with microsatellite-stable, o6-methylguanine-dna methyltransferase-silenced metastatic colorectal cancer: the MAYA trial. J Clin Oncol. 2022;40(14):1562-1573. doi: 10.1200/JCO.21.02583
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