Targeting MDSC Differentiation Using ATRA: A Phase I/II Clinical Trial Combining Pembrolizumab and All-Trans Retinoic Acid for Metastatic Melanoma.

PURPOSE: A phase Ib/II clinical trial was conducted to evaluate the safety and efficacy of the combination of all-trans retinoic acid (ATRA) with pembrolizumab in patients with stage IV melanoma. PATIENTS AND METHODS: Anti-PD-1 naïve patients with stage IV melanoma were treated with pembrolizumab plus supplemental ATRA for three days surrounding each of the first four pembrolizumab infusions. The primary objective was to establish the MTD and recommended phase II dose (RP2D) of the combination. The secondary objectives were to describe the safety and toxicity of the combined treatment and to assess antitumor activity in terms of (i) the reduction in circulating myeloid-derived suppressor cell (MDSC) frequency and (ii) progression-free survival (PFS). RESULTS: Twenty-four patients were enrolled, 46% diagnosed with M1a and 29% with M1c stage disease at enrollment. All patients had an ECOG status ≤1, and 75% had received no prior therapies. The combination was well tolerated, with the most common ATRA-related adverse events being headache, fatigue, and nausea. The RP2D was established at 150 mg/m2 ATRA + 200 mg Q3W pembrolizumab. Median PFS was 20.3 months, and the overall response rate was 71%, with 50% of patients experiencing a complete response, and the 1-year overall survival was 80%. The combination effectively lowered the frequency of circulating MDSCs. CONCLUSIONS: With a favorable tolerability and high response rate, this combination is a promising frontline treatment strategy for advanced melanoma. Targeting MDSCs remains an attractive mechanism to enhance the efficacy of immunotherapies, and this combination merits further investigation. See related commentary by Olson and Luke, p. 1167.

Surgical Resection Margin Classifications for High-grade Pleomorphic Soft Tissue Sarcomas of the Extremity or Trunk After Neoadjuvant Cytotoxic Therapy.

Soft tissue sarcomas of the extremities or trunk are often resected after treatment with neoadjuvant radiotherapy. Adequate surgical resection margins for sarcomas after neoadjuvant cytotoxic therapy are not well characterized. Minimum surgical resection margins required for local control of primary, high-grade, pleomorphic soft tissue sarcomas treated with neoadjuvant therapy was assessed by competing risk regression in a series of 166 cases. Optimal tumor clearance was determined to be ≥1 mm. Predictive accuracy of three commonly used resection margin classification schemes (American Joint Committee on Cancer, Musculoskeletal Tumor Society, and the margin distance method) were comparable. However, diagnostic performance of a binary system (positive vs. negative) was more specific than margin distance classification (positive or <1 vs. ≥1 mm from tumor), but less sensitive in predicting local recurrence. The American Joint Committee on Cancer R classification (R0 vs. R1/R2) seems to adequately stratify patients by risk for local recurrence after neoadjuvant therapy and subsequent surgical resection. Furthermore, close but negative resection margins (<1 mm from tumor) appear sufficient for local control of high-grade pleomorphic soft tissue sarcomas of the extremity or trunk in this clinical setting, with minimal reduction in the risk of local recurrence with increasing margin width or surgical clearance.