To investigate the impact of newly identified chromosome 3p21 epigenetic tumor suppressors PBRM1, SETD2, and BAP1 on cancer-specific survival (CSS) of 609 patients with clear cell renal cell carcinoma (ccRCC) from 2 distinct cohorts.Select sequencing on 3p tumor suppressors of 188 patients who underwent resection of primary ccRCC at the Memorial Sloan-Kettering Cancer Center (MSKCC) was conducted to interrogate the genotype-phenotype associations. These findings were compared with analyses of the genomic and clinical dataset from our nonoverlapping The Cancer Genome Atlas (TCGA) cohort of 421 patients with primary ccRCC.3p21 tumor suppressors are frequently mutated in both the MSKCC (PBRM1, 30.3%; SETD2, 7.4%; BAP1, 6.4%) and the TCGA (PBRM1, 33.5%; SETD2, 11.6%; BAP1, 9.7%) cohorts. BAP1 mutations are associated with worse CSS in both cohorts [MSKCC, P = 0.002; HR 7.71; 95% confidence interval (CI)2.08-28.6; TCGA, P = 0.002; HR 2.21; 95% CI 1.35-3.63]. SETD2 are associated with worse CSS in the TCGA cohort (P = 0.036; HR 1.68; 95% CI 1.04-2.73). On the contrary, PBRM1 mutations, the second most common gene mutations of ccRCC, have no impact on CSS.The chromosome 3p21 locus harbors 3 frequently mutated ccRCC tumor suppressor genes. BAP1 and SETD2 mutations (6%-12%) are associated with worse CSS, suggesting their roles in disease progression. PBRM1 mutations (30%-34%) do not impact CSS, implicating its principal role in the tumor initiation. Future efforts should focus on therapeutic interventions and further clinical, pathologic, and molecular interrogation of this novel class of tumor suppressors.
Natural killer (NK) cell-mediated antibody-dependent toxicity is a potent mechanism of action of the anti-GD2 murine monoclonal antibody 3F8 (m3F8). Killer immunoglobulin-like receptor (KIR) and HLA genotypes modulate NK activity and are key prognostic markers in m3F8-treated patients with neuroblastoma. Endogenous NK-cells are suppressed in the setting of high tumor burden and chemotherapy. Allogeneic NK-cells however, demonstrate potent anti-neuroblastoma activity. We report on the results of a phase I clinical trial of haploidentical NK-cells plus m3F8 administered to patients with high-risk neuroblastoma after conditioning chemotherapy. The primary objective was to determine the maximum tolerated NK-cell dose (MTD). Secondary objectives included assessing anti-neuroblastoma activity and its relationship to donor-recipient KIR/HLA genotypes, NK function, and donor NK chimerism. Patients received a lymphodepleting regimen prior to infusion of haploidentical CD3-CD56+ NK-cells, followed by m3F8. Overall and progression free survival (PFS) were assessed from the time of first NK-cell dose. Univariate Cox regression assessed relationship between dose and outcomes. Thirty-five patients received NK-cells at one of five dose levels ranging from <1×106 to 50×106 CD3-CD56+cells/kg. One patient experienced grade 3 hypertension and grade 4 pneumonitis. MTD was not reached. Ten patients (29%) had complete or partial response; 17 (47%) had no response; and eight (23%) had progressive disease. No relationship was found between response and KIR/HLA genotype or between response and FcγRIII receptor polymorphisms. Patients receiving >10×106 CD56+cells/kg had improved PFS (HR: 0.36, 95%CI: 0.15–0.87, p = 0.022). Patient NK-cells displayed high NKG2A expression, leading to inhibition by HLA-E-expressing neuroblastoma cells. Adoptive NK-cell therapy in combination with m3F8 is safe and has anti-neuroblastoma activity at higher cell doses.
6048 Background: Recurrent/metastatic adenoid cystic carcinoma (R/M ACC) is a rare salivary gland cancer (SGC) without standard treatments. The multitargeted, antiangiogenic kinase inhibitor lenvatinib (len) has activity in R/M ACC, but immune checkpoint inhibitor (ICI) therapies lack efficacy. Hypothesizing that VEGFR inhibition can enhance ICI-induced responses, we conducted a phase II trial evaluating len plus the programmed death-1 (PD-1) inhibitor pembrolizumab (pem) in two R/M SGC cohorts: ACC and non-ACC. Here we report results from the completed ACC cohort. Methods: Patients (Pts) with R/M ACC were enrolled. RECIST v1.1 measurable disease and evidence of progression on imaging performed within 6 months of enrollment were required; any number of prior therapies was allowed. Pts were treated with len 20 mg orally daily and pem 200 mg intravenously every 3 weeks (21-day cycles). The primary objective was to evaluate best overall response rate (ORR), seeking an ORR improvement with len+pem from 15% (previously reported with len alone) to 35%. In the first stage, > 3 confirmed complete and partial responses (cCRs+ cPRs) were required among 17 pts to continue to the second stage; > 8 responses among 32 total pts would have been considered positive (1-sided alpha 0.1, power 0.9). Secondary objectives included evaluating progression-free survival (PFS) and safety/tolerability per CTCAE v5.0 criteria. Results: 17 R/M ACC pts were enrolled and evaluable for the primary objective. One pt had a cPR for an ORR of 6%, failing to meet the rule for progression to the second stage. Thirteen (76%) pts had stable disease and 2 (12%) progression of disease as best response; 1 pt did not have response assessed. Thirteen (76%) pts experienced some degree of regression in RECIST target lesions (TLs; -1.9% to –42.8%), including 5 (29%) with > -20% regression. Eleven (65%) pts were progression-free for > 24 weeks. Twelve (71%) pts experienced at least one > Grade 3 adverse event related to study treatment. Sixteen pts had at least one treatment interruption or len dose reduction; 2 pts received only 1 cycle of therapy. Five pts were treated beyond first progression without observation of subsequent response. Quality of life data and correlative tissue studies are ongoing. Conclusions: The trial failed to demonstrate that len+pem produces a greater ORR in patients with R/M ACC than what was previously reported with len alone. Further investigation into the biology mediating ICI-resistance and development of novel approaches to augment the efficacy of immune-based therapies in ACC are needed. (Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA provided lenvatinib and pembrolizumab for the study.) Clinical trial information: NCT04209660 .
343 Background: Germline single-nucleotide variations (SNVs) in DNA repair genes may have a role in response to platinum-based chemotherapy in bladder cancer (BC). As a pilot project we created a discovery cohort using an extreme phenotype model of BC response to neoadjuvant chemotherapy; we identified candidate SNVs in DNA repair genes via whole exome sequencing, and sought to replicate these findings in a validation cohort. Methods: We sequenced exomes of a discovery cohort with ≥ cT2 BC and neoadjuvant chemotherapy [6 complete responders (CR, pT0N0 and 1 year disease free interval) vs. 9 non-responders]. We identified SNVs within 377 DNA repair pathway genes. We filtered for SNVs with high impact effects, and moderate impact missense variants. The discovery phase resulted in 16 candidate SNVs which we genotyped (matrix-assisted laser desorption/ionization-time of flight) within a validation cohort of 303 BC patients treated with platinum-based neoadjuvant or first-line chemotherapy. Primary outcome was pathologic (neoadjuvant) or radiographic (first-line) CR, with secondary outcome CR+partial response (PR; RECIST criteria or pathologic downstaging). We used additive genetic model and logistic regression to analyze association between individual SNVs and both CR and CR+PR. Multivariate models included MSK risk score for CR or chemotherapy (cis- vs carboplatin) for CR+PR. Results: We included 303 patients (186 neoadjuvant, 117 first-line; 272 cisplatin, 31 carboplatin), median age 64, including 67 (22%) CR and 153 (50%) CR+PR. Genotyping was adequate for analysis in 14 of 16 SNVs—none were associated with CR. SNVs associated with CR+PR were rs2072454 (EGFR, p=0.031 unadjusted, p=0.035 adjusted for chemotherapy) and rs1805321 (PMS2, p=0.014 unadjusted, p=0.019 adjusted for chemotherapy). Findings were not significant after adjusting for multiple comparisons. Conclusions: Using an extreme phenotype model we identified SNVs in genes of the DNA repair pathway that may have an association with platinum-based chemotherapy response in BC. A larger validation study is required to increase power and reduce the impact of multiple testing prior to confirming significance.
