BACKGROUND
To determine the safety and maximum-tolerated dose of concurrent sunitinib and image-guided radiotherapy (IGRT) followed by maintenance sunitinib in oligometastastic patients. METHODS: Eligible patients had 1 to 5 sites of metastatic cancer measuring ≤6 cm. The most common treatment sites were bone, liver, and lung. Patients were treated with concurrent sunitinib (Day 1 through Day 28) and IGRT (40-50 Gy in 10 fractions starting on Day 8) followed by maintenance sunitinib (50 mg daily, 4 weeks on/2 weeks off starting on Day 43). The starting dose was sunitinib 25 mg and IGRT 40 Gy. Doses were escalated in a ping-pong design with incremental increases in either sunitinib or IGRT. RESULTS: Twenty-one patients with 36 metastatic lesions were enrolled, with a median follow-up of 10 months. No dose limiting toxicities (DLT) were noted at dose levels 1 or 2 (SU 37.5 mg/RT 40 Gy). One of 10 patients at dose level 3 (SU 37.5 mg/RT 50 Gy) and 2 of 5 patients at dose level 4 (SU 50 mg/RT 50 Gy) experienced DLTs comprising grade 4 myelosuppression and grade 3 nausea. At last follow-up, 8 patients are alive without evidence of progression. The 1-year local, progression-free, and overall survival were 85%, 44%, and 75%, respectively. CONCLUSIONS: Addition of SU (25 to 37.5 mg) to IGRT is tolerable in patients with oligome-tastases, without potentiation of RT toxicity. On the basis of promising antitumor responses observed with this novel combination, a multi-institutional phase 2 trial using SU 37.5 mg/RT 50 Gy is ongoing.
Summary
Whole exome sequencing of cutaneous melanoma has led to the detection of P29 mutations in RAC1 in 5–9% of samples, but the role of RAC1 P29 mutations in melanoma biology remains unclear. Using reverse phase protein array analysis to examine the changes in protein/phospho-protein expression, we identified cyclin B1, PD-L1, Ets-1, and Syk as being selectively upregulated with RAC1 P29S expression and downregulated with RAC1 P29S depletion. Using the melanoma patient samples in TCGA, we found PD-L1 expression to be significantly increased in RAC1 P29S patients compared to RAC1 WT as well as other RAC1 mutants. The finding that PD-L1 is upregulated suggests that oncogenic RAC1 P29S may promote suppression of the antitumor immune response. This is a new insight into the biological function of RAC1 P29S mutations with potential clinical implications as PD-L1 is a candidate biomarker for increased benefit from treatment with anti-PD1 or anti-PD-L1 antibodies.
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