A phase 2 clinical trial of neoadjuvant anti-PD-1 ab (Toripalimab) plus axitinib in resectable mucosal melanoma.

9512 Background: The outcome of patients (pts) with resectable mucosal melanoma (MM) is still poor. Toripalimab combined with axitinib has shown impressive results in metastatic MM with an ORR of 48.3% and a median PFS of 7.5 months in a phase 1b trial. It was hypothesized that this combination therapy might cause pathologic response in neoadjuvant setting for resectable MM, so we conducted this single arm phase 2 trial. Methods: Eligible pts were adults (aged 18 to 75) with histologically confirmed resectable (localized or regional lymph node metastasis) MM disease. Exclusion criteria included ocular or unknown primary melanoma, distant metastatic disease or previous use of anti PD-1 ab. Pts received toripalimab 3 mg/kg Q2W plus axitinib 5 mg BID for 8 weeks as neoadjuvant therapy, then surgery and the adjuvant toripalimab 3 mg/kg Q2W starting 2±1week after surgery for totally 52 weeks. The primary end point is pathologic response rate according to the International Neoadjuvant Melanoma Consortium (pCR+pPR, pCR is defined as the complete absence of residual viable tumor and pPR ≤ 50% of viable tumor cells). The secondary end point is RFS in the ITT population. Clinical trial information: NCT04180995. Results: From Aug 2019 to Dec 2020, 21 pts have been eligible and enrolled. Basic characteristics: median age 62 years; M: F 28.6% : 71.4%; primary sites 8 femal genital(1urethra, 7vagina), 5 esophagus, 4 ano-rectal, 4 head & neck(3 nasal,1 oral), in which 47.6% localized disease (T3/4 60%), 52.4% regional lymphatic disease; Gene mutation: 4 cKit (1 amplification), 2 Nras,1 Braf (N581), 1mTOR. This therapy was tolerable with grade 3-4 treatment related AEs of 23.8% (liver dysfunction 14.3%, hyperglycemia 9.5% and hypertension 4.8%). 13 pts had received surgeries (local excision 30.8%, wide excision ± CLND72.7%)and 5 pts still in neoadjuvant treatment. One patient was inoperable for bone metastasis, and 2 pts withdrew for covid 19 epidemic. At a median follow up time of 59 weeks, the pathologic response rate was 28.6% (4/14, 2 pCR, 2pPR). Of the post-surgical specimens, 61.5% (8/13) showed significant TIL infiltration, with 38.5% Brisk and 23.1% Nonbrisk according to the definition of AJCC 8th edition. Plenty of plasma cells, histiocyte and pigment with hyaline fibrosis were also found in responders. No recurrence or metastasis was observed in responders until now, with a RFS reaching more than 58weeks. 5 pts with pNR( > 50% viable tumor cells) got disease progression, with 1 local recurrence, 1 regional lymphatic metastasis, and 3 distant metastases. The median RFS has not been reached. Conclusions: Neoadjuvant toripalimab plus axitinib in resectable MM has shown promising pathologic responses with good tolerance, which supports further investigation of neoadjuvant therapies in MM. Survival is still in follow-up. Clinical trial information: NCT04180995.

Large cell neuroendocrine carcinoma of the urothelial tract (LNEC): The MSKCC experience.

4526 Background: LNEC is a rare, poorly characterized entity morphologically resembling small cell NEC of the urothelial tract (SNEC). Methods: Pure and partial LNEC and SNEC cases were identified by histopathologic re-review; clinical outcomes were compared. A subset was sequenced with MSK-IMPACT (279-505 genes). Results: Between 1992-2020, 43 patients (pts) with LNEC were identified (42 bladder, 1 upper tract); 19 (44%) had concomitant SNEC. LNEC cases were compared to 192 SNEC without LNEC (SNEC-only) (Table 1). Compared to SNEC-only pts, LNEC pts experienced longer overall survival (OS), adjusting for age and M0 vs M1 (median OS not reached vs 22.4 months [mos]; HR 0.34, 95% CI 0.16-0.74, p =.006). Neoadjuvant chemo (NAC) use increased over time. Pathologic response rate (<ypT2N0) after NAC was 25% for LNEC and 50% for SNEC-only (p =.13); the ypT0N0 rate was 25% for LNEC and 40% for SNEC-only (p =.52). Perioperative chemo did not improve OS compared to surgery alone in LNEC, adjusting for age and concurrent SNEC (HR 1.46, 95% CI 0.12-17.5, p =.76), but was associated with longer OS among SNEC-only pts (n = 98; HR 0.39, 95% CI 0.22-0.69, p =.001). Two M1 LNEC pts received immunotherapy (IO) in the first-line: 1 atezolizumab, 1 atezolizumab + chemo. Both remained free of progression on IO at a follow-up of 20 and 12 mos, respectively. Of 18 sequenced LNEC tumors, 89% had TERT promoter alterations (alts), similar to 85% seen in 52 SNEC tumors. All LNEC tumors had alts of TP53 or RB1, and 10 (56%) had both. Median tumor mutational burden (TMB) was 14 (IQR 8-38) in LNEC and 30 (IQR 15-55) in SNEC. Epigenetic modifiers were altered in 78% LNEC and 79% SNEC. Two LNEC pts had ERCC2 alts and received platinum chemo; both were alive at last follow-up from NEC diagnosis of 30.7-39.1 mos. Conclusions: LNEC pts experienced longer OS compared to pts with SNEC-only in this cohort, but did not appear more chemo-sensitive. Genomic profiles of LNEC and SNEC-only tumors were similar; TERT promoter mutations suggest a potential urothelial precursor. Further investigation of IO for LNEC is warranted.[Table: see text]

Efficacy and safety-in analysis of short-course radiation followed by mFOLFOX-6 plus avelumab for locally advanced rectal adenocarcinoma

Background Neoadjuvant chemotherapy and short-course radiotherapy followed by resection has been gaining recognition in the treatment of rectal cancer. Avelumab is a fully human immunoglobulin that binds Programmed Death-Ligand 1 (PD-L1) and prevents the suppression of the cytotoxic T cell immune response. This phase II trial evaluates the safety and pathologic response rate of short-course radiation followed by 6 cycles of mFOLFOX6 with avelumab in patients with locally advanced rectal cancer (LARC). Methods This study is prospective single-arm, multicenter phase II trial adopting Simon’s two-stage. Short-course radiation is given over 5 fractions to a total dose of 25 Gy. mFOLFOX6 plus avelumab (10 mg/kg) are given every 2 weeks for 6 cycles. Total mesorectal excision is performed 3–4 weeks after the last cycle of avelumab. Follow up after surgery is done every 3 months to a total of 36 months. Adverse event data collection is recorded at every visit. Results 13 out of 44 patients with LARC were enrolled in the first stage of the study (30% from total sample size). All patients met the inclusion criteria and received the full short-course radiation course followed by 6 cycles of mFOLFOX6 plus avelumab. 12 out of the 13 patients completed TME while one patient had progression of disease and was dropped out of the study. The sample consisted of 9 (69%) males and 4 (31%) females with median age of 62 (33–73) years. The first interim analysis revealed that 3 (25%) patients achieved pathologic complete response (pCR) (tumor regression grade, TRG 0) out of 12. While 3 (25%) patients had near pCR with TRG 1. In total, 6 out of 12 patients (50%) had a major pathologic response. All patients were found to be MMR proficient. The protocol regimen was well tolerated with no serious adverse events of grade 4 reported. Conclusion In patients with LARC, neoadjuvant radiation followed by mFOLFOX6 with avelumab is safe with a promising pathologic response rate. Trial Registration Number and Date of Registration ClinicalTrials.gov NCT03503630, April 20, 2018. https://clinicaltrials.gov/ct2/show/NCT03503630?term=NCT03503630&draw=2&rank=1.

Short-course radiation followed by mFOLFOX-6 plus avelumab for locally advanced rectal adenocarcinoma.

139 Background: Total neoadjuvant treatment (TNT) for locally advanced rectal cancer is becoming an accepted approach over the last few years with increasing pathologic complete response (pCR) and compliance of patients for chemotherapy in comparison with the current standard of care i.e., fluoropyrimidine based chemoradiation followed by surgery and adjuvant chemotherapy. Sequential use checkpoint inhibitors after radiation therapy (RT) has demonstrated synergistic effect in vivo leading to decrease in size of irradiated and non-irradiated secondary tumors outside the radiation field (abscopal effect). Methods: This is an investigator initiated; open-label, single-arm multicenter phase II study, adopting Simon’s two-stage aiming at evaluating the pCR rate and safety of using short-course radiation therapy (25 Grays in 5 fractions), followed by 6 cycles of mFOLFOX-6 plus Avelumab (anti PDL1), then total mesorectal excision(TME) in patients with locally-advanced, potentially resectable rectal adenocarcinoma. Results: 13 out of 44 patients were accrued from 20, July till 28, Dec 2018 in the first stage of the study (30% from total sample size). They all met the inclusion criteria and received full protocol treatment. 12 out of the 13 completed TME. 1 of the 13 had progression of disease, so surgery was aborted and patient was dropped out the study. The sample consisted of 9 (69%) males and 4 (31%) females with median age of 62 (33.0, 73.0) years. The first interim analysis revealed 3 patients (25%) achieved pCR (tumor regression grade: TRG = 0) out of 12 as compared to the historical control group with pCR of 16%. For the rest of the patients, 3 (25%) had major pathologic response rate (pRR) with TRG = 1 (< 10% viable cells is tumor bed).In total, 6 out of 12 patients (50%) had major pathologic response rate. As for safety, no serious adverse events of grade 3 and 4 were reported. Conclusions: Based on the first interim analysis results, incorporation of Avelumab and short course radiotherapy is tolerable in patients with locally advanced rectal cancer treated with TNT. The study will resume recruitment to reach the target accrual. Clinical trial information: NCT03503630.

Pathologic response rate (pCR) and near-pathologic response rate (near-pCR) with docetaxel-carboplatin (TCarb) in early triple-negative breast cancer.

277 Background: Triple-negative breast cancer (TNBC) is associated with a poor prognosis unless a pathological complete response is achieved (Liedtke C et al. 2008: J Clin Oncol 26:1275-1281) or almost achieved (Symmans WF. 2007: J Clin Oncol 25:4414-4422). Sensitivity to platin compounds has been demonstrated in BRCA1-positive settings (Byrski T et al. 2010: J Clin Oncol 20:28:375-9; Silver DP. 2010: J Clin Oncol 28:1145-1153) with only limited numbers of patients (Byrski T et al. 2010: J Clin Oncol 20:28:375-9) or in sporadic breast cancer with heterogeneous cohorts (Sikov WM et al 2009: J Clin Oncol 27:4693-4700; Chang HR et al. 2010: Cancer 15; 116:4227-4237). Methods: This pivotal trial was to assess the efficacy of platinum and taxane-based combination therapy without the use of anthracyclines. 27 patients with primary TNBC (majority of them cT2, two cT3 and one cT4a) had to be unsuitable for standard anthracycline-based chemotherapy. They received 6 cycles, respectively in two cases only 5 cycles, of carboplatin AUC 6 and docetaxel 75 mg/m2 q3w. The primary endpoint was the pCR-rate, secondary endpoint toxicity. Results: 20 out of 27 (74%) patients had pathological complete response (52%) or near-complete response (22%)—ypT1mic and ypT1a—both being associated with a good prognosis. Seven remaining patients had still good partial response, leaving only low residual cancer burden, which was defined as ypT1. Treatment was well-tolerated: grade III and IV toxicities were neutropenia, thrombopenia, oedema, nausea, joint pain, nail changes, fatigue, hypertension, and alopecia. Conclusions: These results show a high efficacy of carboplatin AUC6 and docetaxel 75 mg/m2 q3w and good feasibility as primary chemotherapy for TNBC with a pCR- and near-pCR-rate of 74% and total response rate of 100%. The incorporation of anthracyclines and parp-inhibitors into further trial designs could enhance the efficacy of these compounds. The omission of exposure to anthracyclines in patients with considerable heart disease risks seems to be feasible with a good pCR-rate, the latter being a surrogate-marker for long-term survival.