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Adjuvant nivolumab for resected urothelial carcinoma (September 2021)

In a placebo-controlled phase III trial of over 700 patients with urothelial carcinoma (UC) and high-risk disease after radical cystectomy, one year of adjuvant nivolumab improved disease-free survival (median 21 versus 11 months) [1]. These data led to approval by the US Food and Drug Administration (FDA) for adjuvant nivolumab in patients at high risk for recurrence after undergoing radical resection of UC [2]. This includes patients with muscle-invasive or node-positive disease after receiving neoadjuvant chemotherapy, or those with extravesicular extension or node-positive disease who did not receive neoadjuvant chemotherapy and were ineligible for or refused adjuvant cisplatin-based chemotherapy.

Image-guided intensity-modulated radiation therapy in cervical cancer (October 2021)

For adjuvant radiation for cervical cancer, newer techniques such as intensity- modulated radiation therapy (IMRT) are being evaluated as less toxic options compared with three-dimensional conformal radiation therapy (3D-CRT). In a randomized trial among 300 patients with cervical cancer undergoing postoperative radiation, disease-free survival was similar with image-guided IMRT versus 3D-CRT (77 versus 81 percent), but three-year cumulative incidence of late toxicity was reduced (28 versus 49 percent) [3]. When adjuvant radiation is indicated for cervical cancer, we suggest image-guided IMRT, but 3D-CRT is an acceptable alternative.

Avapritinib for treatment-refractory gastrointestinal stromal tumors with PDGFRA exon 18 D842V mutations (October 2021)

For patients with advanced gastrointestinal stromal tumor (GIST), novel agents are being evaluated in the treatment-refractory setting. In a phase III trial of almost 500 patients with unresectable or metastatic treatment-refractory GIST, the tyrosine kinase inhibitor (TKI) avapritinib resulted in similar progression-free survival (PFS) compared with the antiangiogenesis agent, regorafenib [4]. However, among 13 patients whose tumors harbored a platelet-derived growth factor receptor alpha (PDGFRA) D842V mutation, avapritinib improved progression-free survival (median not reached versus 4.5 months). Objective response rates in this subset were 43 versus 0 percent. Based on these data, we consider avapritinib to be an acceptable option for patients with PDGFRA D842V mutation-positive GIST who have experienced progression on both imatinib and sunitinib.

Fam-trastuzumab deruxtecan in HER2-mutated advanced NSCLC (October 2021)

There is interest in trastuzumab antibody-based conjugates, such as fam-trastuzumab deruxtecan, in advanced HER2-driven non-small cell lung cancer (NSCLC). In a phase 2 study of 91 patients with HER2 mutation-positive NSCLC that had progressed on standard treatment, the agent was associated with a median progression-free survival of 8.2 months, overall survival of 17.8 months, and response rate of 55 percent [5]. Notable toxicities included drug-related interstitial lung disease in 24 patients (2 fatalities). For patients with HER2-mutated advanced NSCLC that have progressed on standard therapy, fam-trastuzumab deruxtecan is an appropriate, though potentially toxic, off-label option.

Belzutifan for von Hippel-Lindau disease-associated tumors (October 2021)

For patients with von Hippel-Lindau (VHL)-associated cancers, systemic treatment options are limited. In a phase II trial of the hypoxia-inducible factor-2alpha inhibitor belzutifan in 61 patients with VHL disease, objective response rates were 49 percent in systemic therapy-naive renal cell carcinoma (RCC), 30 percent in central nervous system (CNS) hemangioblastomas, and 91 percent in pancreatic neuroendocrine tumors (pNET) [6,7]. Based on these data, the US Food and Drug Administration approved belzutifan for adults with VHL disease who require therapy for these tumors, but not immediate surgery. Our general approach is to use belzutifan as an alternative to surveillance for rapidly growing tumors that could become symptomatic if allowed to progress; for tumors not amenable to resection; and to delay or defer local therapies such as surgery or radiation.

1. Bajorin DF, Witjes JA, Gschwend JE, et al. Adjuvant Nivolumab versus Placebo in Muscle-Invasive Urothelial Carcinoma. N Engl J Med. 2021;384(22):2102.

2. Nivolumab: United States Food and Drug Administration (FDA) Prescribing Label https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/125554s097lbl.pdf (Accessed on September 01, 2021).

3. Chopra S, Gupta S, Kannan S, et al. Late Toxicity After Adjuvant Conventional Radiation Versus Image-Guided Intensity-Modulated Radiotherapy for Cervical Cancer (PARCER): A Randomized Controlled Trial. J Clin Oncol. 2021; PMID: 34506246.

4. Kang YK, George S, Jones RL, et al. Avapritinib Versus Regorafenib in Locally Advanced Unresectable or Metastatic GI Stromal Tumor: A Randomized, Open-Label Phase III Study. J Clin Oncol. 2021;39(28):3128. Epub 2021 Aug 3.

5. Li BT, Smit EF, Goto Y, et al. Trastuzumab Deruxtecan in HER2-Mutant Non-Small-Cell Lung Cancer. N Engl J Med. 2021; PMID: 34534430.

6. Jonasch E, Donskov F, Iliopoulous O, et al. Phase 2 study of belzutifan (MK-6482), an oral hypoxia-inducible factor 2[alpha](HIF-2[alpha]) inhibitor, for Von Hippel-Lindau (VHL) disease-associated clear cell renal cell carcinoma (ccRCC). J Clin Oncol. 2021;39;15S.

7. Belzutifan: United States Food and Drug Administration (FDA) Prescribing Label https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/215383s000lbl.pdf (Accessed on August 16, 2021).

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