Molecularly Guided Therapy Outperforms Chemo in Cancer of Unknown Primary

Microscopic photorealistic image of tumor cells - Generated with Adobe Firefly

Comprehensive genomic profiling followed by molecularly guided therapy led to longer progression-free survival (PFS) than standard platinum-based chemotherapy in patients with previously untreated, unfavorable, nonsquamous cancer of unknown primary (CUP) who reached disease control on primary induction chemotherapy, based on data from the phase 2, prospective, randomized CUPISCO study (NCT03498521).^1,2

“Despite recent efforts, effective treatment for unfavorable subset CUP has proven elusive.To our knowledge, CUPISCO is the first randomized study of [molecularly guided therapy] for newly diagnosed unfavorable subset CUP and reports positive results,” wrote authors in the study published in The Lancet.¹ “The results from the CUPISCO study show that, compared with standard platinum-based chemotherapy, [molecularly guided therapy] conferred a significant and clinically meaningful improvement in progression-free survival to patients with previously untreated, unfavorable, nonsquamous CUP who reached disease control during an induction period with 3 platinum-based chemotherapy cycles.”

A total of 436 patients reached disease control with induction chemotherapy between July 10, 2018, and December 9, 2022, and the median follow-up was 24.1 months (IQR, 11.6-35.6). Of these 436, 326 (75%) were assigned to receive molecularly guided therapy and 110 (25%) to receive chemotherapy. In the molecularly guided therapy group, the PFS was 6.1 months (95% CI, 4.7-6.5) vs 4.4 months (range, 4.1-5.6) in the chemotherapy group (HR, 0.72; 95% CI, 0.56-0.92; P =.0079).

In patients with an actionable molecular profile treated with a targeted therapy or atezolizumab (Tecentriq) monotherapy, the PFS was 8.1 months (95% CI, 4.6-8.7) vs 4.7 months (range, 4.0-6.6) with chemotherapy (HR, 0.65; 95% CI, 0.42-0.99). Among patients without an actionable molecular profile, the median PFS was 5.5 months (95% CI, 4.5-6.4) for those treated with atezolizumab vs chemotherapy vs 4.4 months (range, 4.2-5.6) in those treated with chemotherapy (HR, 0.76; 95% CI, 0.54-1.06). Study authors identified that more than two-thirds of patients in the molecularly guided therapy arm did not have an actionable target and were treated with the combination of atezolizumab and chemotherapy according to the guidance of empirical data in other cancer types, and CUPISCO was not sufficiently powered to assess the benefit of adding atezolizumab to chemotherapy.

Interim data for overall survival (OS) were available, and the median OS was 14.7 months (95% CI, 13.3-17.3) in the molecularly guided therapy group vs 11.0 months (range, 9.7-15.4) in the chemotherapy group.

Patients with tumor mutational burden-high or microsatellite instability-high disease treated with atezolizumab saw the highest numerical differences in outcomes. Additionally, large numerical differences were observed in patients with BRAF V600 or K601Ealterations treated with vemurafenib (Zelboraf) and cobimetinib (Cotellic) and in patients with FGFR1, FGFR2, or FGFR3 alterations treated with pemigatinib (Pemazyre).

“The results of the CUPISCO trial suggest that early [comprehensive genomic profiling] by tissue-based or liquid-based testing, or both, and incorporation of [molecularly guided therapies] into the treatment armamentarium of first-line therapy improves progression-free survival in patients with CUP. Given the overall poor prognosis of unfavorable CUP and the high risk of rapid clinical deterioration of patients with this malignancy, the window of opportunity for [molecularly guided therapies] might otherwise be missed,” study authors concluded.

REFERENCES:

1. Krämer A, Bochtler T, Pauli C, et al. Molecularly guided therapy versus chemotherapy after disease control in unfavourable cancer of unknown primary (CUPISCO): an open-label, randomised, phase 2 study. Lancet. 2024; 404, 10452, 527-539. doi:10.1016/S0140-6736(24)00814-6

2. Comprehensive genomic profiling with molecularly-guided therapy results in longer PFS Compared with platinum-based chemotherapy in patients with CUP. News release. ESMO. August 26, 2024. Accessed August 28, 2024. https://tinyurl.com/2s4e8kuz