Avelumab Plus Axitinib Shows Promising Activity in Pretreated Advanced Type B3 Thymoma and Thymic Carcinoma

Article

Patients with advanced type B3 thymoma and thymic carcinoma who progressed after chemotherapy were responsive to treatment with avelumab plus axitinib, according to data from the phase 2 CAVEATT trial.

The anti-angiogenesis drug axitinib (Inlyta) showed tolerable and promising clinical activity in combination with the anti–PD-L1 inhibitor avelumab (Bavencio) in patients with advanced type B3 thymoma and thymic carcinoma who progressed after chemotherapy, according to findings from the single-arm, multicenter phase 2 CAVEATT trial conducted in Italy.

Out of 32 patients enrolled, the overall response rate (ORR) was 34% (90% CI, 21%-50%), comprised entirely of partial responses. No patients had a complete response, 18 (56%) had stable disease, and 2 (6%) had a best response of progressive disease. In target lesions, tumor size reduction from baseline occurred in 66% of patients (n = 21), with no patients experiencing pseudoprogression. The median time to response and duration of response was 3.6 months (interquartile range [IQR], 1.9-5.4) and 5.5 months (90% CI, 3.9-9.2), respectively. The median follow-up for progression-free survival (PFS) was 22.4 months (IQR, 12.3-24.3) and the median PFS was 7.5 months (90% CI, 3.7-10). Moreover, a post-hoc analysis found the disease control rate (DCR) to be 91% (90% CI, 78%-97%).

“The combination of anti-angiogenesis drugs with immune checkpoint inhibitors has previously shown synergistic efficacy in patients with several types of solid tumors, and we reported here, to our knowledge for the first time, evidence of its efficacy and safety in patients with advanced type B3 thymoma and thymic carcinoma,” investigators wrote.

In the overall population, 6-month and 12-month PFS rates were 61.3% (90% CI, 45.3%-73.9%) and 29.0% (90% CI, 16.0%-43.4%), respectively. Median overall survival (OS) was 26.6 months (90% CI, 17-30).

A post-hoc subgroup analysis highlighted ORRs of 47% (90% CI, 27%-68%) and 15% (90% CI, 3%-41%) in patients without (n = 19) and with (n = 13) any prior exposure to antiangiogenic agents. The DCR was 100% (90% CI, 85%-100%) in patients naïve to anti- antiangiogenic treatment vs 77% (90% CI, 51%-93%) in those with prior exposure. Additionally, median PFS was 10 months (90% CI, 7.4-13.1) in patients without prior exposure vs 4.5 months (90% CI, 2.4-7.5) in patients with prior exposure (HR, 0.56; 90% CI, 0.28-1.09).

Patients in the trial were premedicated with oral diphenhydramine at 50 mg and oral paracetamol at 500 mg before administration of intravenous avelumab at 10 mg/kg over 60 minutes every 2 weeks. Oral axitinib was administered at 5 mg twice per day continuously. Treatment discontinuation occurred in cases of confirmed progression, unacceptable toxicity, or upon withdrawal of consent. The trial criteria allowed 2 levels of dose reduction for axitinib, to 3 mg and 2 mg twice daily; no dose reduction was allowed for avelumab.

Most patients experienced grade 1/2 adverse effects (AEs) during treatment, including 3 (9%) grade 1/2 infusion-related reactions associated with avelumab. The most common grade 3/4 AE was hypertension (19%). In total, 8 patients (25%) required reductions in their axitinib dose due to AEs, and 4 (12%) developed serious new-onset immune-related AEs. None of these patients with severe immune-related AEs died from toxicity, but all 4 discontinued treatment.

“This combination could emerge as a standard treatment option in this setting. Despite the treatment combination yielding objective responses both in patients naïve to, and those previously treated with, anti-angiogenic drugs, the good overall response rate observed in the former group suggests that this combination should be considered as a second-line treatment after platinum-based chemotherapy, rather than after progression to an anti-angiogenesis drug, to maximise its potential synergist effect, especially in patients with a higher burden of disease or tumor-related symptoms who need tumor shrinkage,” investigators concluded.

Though the findings showed promise, their generalizability is limited in part by small sample sizes, especially in the subgroup analyses, and relatively immature follow-up. The ongoing multicenter phase 2 PECATI trial (NCT04710628) examining pembrolizumab (Keytruda) plus lenvatinib (Lenvima) in a similar patient population will provide further evidence on the combination of antiangiogenic agents with immune checkpoint inhibitors and may help justify a future randomized clinical trial.

Reference

Conforti F, Zucali PA, Pala L, et al. Avelumab plus axitinib in unresectable or metastatic type B3 thymomas and thymic carcinomas (CAVEATT): a single-arm, multicentre, phase 2 trial. Lancet Oncol. 2022;23(10):1287-1296. doi:10.1016/S1470-2045(22)00542-3

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