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Timing of CDK 4/6 inhibition in hormone receptor-positive, HER2-negative advanced breast cancer (June 2023)
Addition of a cyclin-dependent kinase 4/6 inhibitor (CDK 4/6i) to an aromatase inhibitor improves outcomes when used as first-line treatment for hormone receptor-positive, HER2-negative advanced breast cancer; however, whether deferring to the second-line setting is as effective is unknown. In the SONIA trial, 1050 women were randomly assigned to either first-line treatment with a nonsteroidal aromatase inhibitor (NSAI) plus a CDK 4/6i, followed by single-agent fulvestrant upon disease progression, or to first-line treatment with an NSAI, followed by fulvestrant plus a CDK 4/6i upon progression.1 At a median follow-up of 37 months, median overall survival was 46 months in the first-line CDK 4/6i group and 54 months in the second-line CDK 4/6i group. The first-line group remained on CDK 4/6i for 25 months, versus 8.1 months for the second-line group, which was associated with 42 percent more grade >=3 toxicities. Although there were some limitations to this trial and we continue to suggest a CDK 4/6i in the first-line setting, deferring to the second-line setting is a reasonable alternative in select patients.
Gemcitabine plus cisplatin and pembrolizumab for advanced cholangiocarcinoma (June 2023)
Advanced cholangiocarcinoma is an aggressive disease with poor survival outcomes, so there is interest in investigating novel approaches such as the addition of immunotherapy to chemotherapy. In a placebo-controlled phase III trial of over 1000 patients with treatment-naive, locally advanced or metastatic biliary tract cancers, the addition of pembrolizumab to gemcitabine plus cisplatin improved overall survival (median 13 versus 11 months) with an acceptable toxicity profile.2 Based on these data, we consider gemcitabine plus cisplatin and pembrolizumab to be an appropriate initial treatment option in fit patients with advanced or metastatic cholangiocarcinoma and no hyperbilirubinemia.
Pembrolizumab plus enfortumab vedotin for metastatic urothelial carcinoma (July 2023)
For patients with advanced urothelial carcinoma (UC) who are ineligible for cisplatin-based chemotherapy, studies are evaluating novel treatment combinations. In a randomized phase II trial of approximately 150 previously untreated, cisplatin-ineligible patients with UC, the addition of pembrolizumab to enfortumab vedotin (EV) resulted in an objective response rate of 65 versus 45 percent for EV alone, although this difference did not reach statistical significance.3 Based on these data, the US Food and Drug Administration granted accelerated approval for EV plus pembrolizumab in adults with locally advanced or metastatic UC who are ineligible for cisplatin-based chemotherapy.4,5 We consider this combination to be an acceptable option in this population.
Induction chemotherapy for locally advanced nasopharyngeal carcinoma (July 2023)
For patients with locally advanced nasopharyngeal carcinoma (LANPC), contemporary clinical trials have evaluated the overall survival (OS) advantages of adding induction chemotherapy (IC) to chemoradiation (CRT). In a meta-analysis (MAC-NPC) of 28 randomized controlled clinical trials that included over 8000 patients with LANPC, the addition of IC to CRT improved OS at median follow-up of almost eight years, irrespective of whether IC included a taxane (hazard ratio [HR] 0.75) or not (HR 0.81).6 Based on these data, for most patients with LANPC, we continue to recommend IC followed by CRT rather than CRT alone.
1. Sonke G, van Ommen A, Wortelboer N, et al. Primary outcome analysis of the phase 3 SONIA trial (BOOG 2017-03) on selecting the optimal position of cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors for patients with hormone receptor-positive (HR+), HER2-negative (HER2-) advanced breast cancer (ABC). J Clin Oncol. 2023;41, 17S. LBA1000
2. Kelley RK, Ueno M, Yoo C, et al. Pembrolizumab in combination with gemcitabine and cisplatin compared with gemcitabine and cisplatin alone for patients with advanced biliary tract cancer (KEYNOTE-966): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2023;401(10391):1853. Epub 2023 Apr 16.
3. O'Donnell PH, Milowsky MI, Petrylak DP, et al. Enfortumab Vedotin With or Without Pembrolizumab in Cisplatin-Ineligible Patients With Previously Untreated Locally Advanced or Metastatic Urothelial Cancer. J Clin Oncol. 2023
4. Enfortumab vedotin-ejfv for injection. United States Prescribing Information. US National Library of Medicine. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/761137s020lbl.pdf (Accessed on April 12, 2023).
5. Pembrolizumab: United States Food and Drug Administration Prescribing Label https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/125514s136lbl.pdf (Accessed on April 12, 2023).
6. Petit C, Lee A, Ma J, et al. Role of chemotherapy in patients with nasopharynx carcinoma treated with radiotherapy (MAC-NPC): an updated individual patient data network meta-analysis. Lancet Oncol. 2023;24(6):611.
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