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Real-world evidence regarding the value of integrating genomic profiling (GP) in managing cancer of unknown primary (CUP) is limited. We assessed this clinical utility using a prospective trial of 158 patients with CUP (10/2016-09/2019) who underwent GP using next-generation sequencing designed to identify genomic alterations (GAs). Only 61 (38.6%) patients had sufficient tissue for successful profiling. GAs were seen in 55 (90.2%) patients; of which GAs with FDA approved genomically-matched therapy were seen in 25 (40.9%) cases. A change in therapy was recommended and implemented (primary endpoint of the study) in 25 (10.1%) and 4 (2.5%) patients of the entire study cohort, respectively. Most common reason for inability to implement the profiling-guided therapy was worsening of performance status (56.3%). Integrating GP in management of CUP is feasible but challenging due to paucity of tissue and aggressive natural history of the disease and requires innovative precision strategies.

Background Human papillomavirus (HPV) types 16/18 drive oncogenesis for most patients with cervical, anal, and penile cancers. MEDI0457, a therapeutic DNA vaccine containing plasmids for E6 and E7 HPV-16/18 viral oncogenes and IL-12 adjuvant, is safe and provokes an immune response against E6/E7. We tested MEDI0457 with the anti-PD-L1 antibody durvalumab for patients with HPV-associated cancers. Methods Patients with recurrent/metastatic, treatment-refractory HPV-16/18 cervical cancer, or rare HPV-associated (anal and penile) cancers were eligible. Prior immune checkpoint inhibition was not permitted. Patients received MEDI0457 7 mg intramuscularly (weeks 1, 3, 7, 12, and every 8 weeks thereafter) and durvalumab 1500 mg intravenously every 4 weeks. The primary endpoint was overall response (RECIST 1.1). In this Simon two-stage phase 2 trial (Ho: p Results Twenty-one patients (12 cervical, 7 anal, and 2 penile) were evaluable for toxicity and 19 for response Overall response rate was 21% (95% CI, 6%-46%) among evaluable patients. Disease control rate was 37% (95% CI, 16%-62%). Median duration of response among responders was 21.8 months (95% CI, 9.7%-not estimable). Median progression-free survival was 4.6 months (95% CI, 2.8%-7.2%). Median overall survival was 17.7 months (95% CI, 7.6%-not estimable). Grades 3-4 treatment-related adverse events occurred in 6 (23%) participants. Conclusions The combination of MEDI0457 and durvalumab demonstrated acceptable safety and tolerability in patients with advanced HPV-16/18 cancers. The low ORR among patients with cervical cancer led to study discontinuation despite a clinically meaningful disease control rate.

Supplementary Data

Purpose:Prognostic uncertainty is a major challenge for cancer of unknown primary (CUP). Current models limit a meaningful patient-provider dialogue. We aimed to establish a nomogram for predicting overall survival (OS) in CUP based on robust clinicopathologic prognostic factors.Experimental Design:We evaluated 521 patients with CUP at MD Anderson Cancer Center (MDACC; Houston, TX; 2012–2016). Baseline variables were analyzed using Cox regression and nomogram developed using significant predictors. Predictive accuracy and discriminatory performance were assessed by calibration curves, concordance probability estimate (CPE ± SE), and concordance statistic (C-index). The model was subjected to bootstrapping and multi-institutional external validations using two independent CUP cohorts: V1 [MDACC (2017), N = 103] and V2 (BC Cancer, Vancouver, Canada and Sarah Cannon Cancer Center/Tennessee Oncology, Nashville, TN; N = 302).Results:Baseline characteristics of entire cohort (N = 926) included: median age (63 years), women (51%), Eastern Cooperative Oncology Group performance status (ECOG PS) 0–1 (64%), adenocarcinomas (52%), ≥3 sites of metastases (30%), and median follow-up duration and OS of 40.1 and 14.7 months, respectively. Five independent prognostic factors were identified: gender, ECOG PS, histology, number of metastatic sites, and neutrophil-lymphocyte ratio. The resulting model predicted OS with CPE of 0.69 [SE: ± 0.01; C-index: 0.71 (95% confidence interval: 0.68–0.74)] outperforming Culine/Seve prognostic models (CPE: 0.59 ± 0.01). CPE for external validation cohorts V1 and V2 were 0.67 (± 0.02) and 0.70 (± 0.01), respectively. Calibration curves for 1-year OS showed strong agreement between nomogram prediction and actual observations in all cohorts.Conclusions:Our user-friendly CUP nomogram integrating commonly available baseline factors provides robust personalized prognostication which can aid clinical decision making and selection/stratification for clinical trials.

Introduction: BRAF + EGFR inhibition induces decreased expression of mismatch repair (MMR) genes in preclinical models of microsatellite stable (MSS), BRAFV600E metastatic colorectal cancer (mCRC) but has not been reported in patients. We evaluated exosomal RNA (exoRNA) isolated from serial blood specimens collected from patients (pts) with MSS, BRAFV600E mCRC treated with encorafenib (E) + cetuximab (C) + nivolumab (N) as a novel blood-based approach to compare differences in gene expression according to treatment response. Methods: Pts with refractory MSS, BRAFV600E mCRC were treated with E (300 mg daily), C (500 mg/m2 q2 weeks), and N (480 mg q4 weeks) on an IRB-approved clinical trial at MD Anderson. Responses to treatment were assessed every 8 weeks (RECIST v1.1). ExoRNA isolated from pretreatment and on-treatment (week 8) blood samples were sequenced (SMART-seq) and deconvoluted (DeMix) in order to estimate cancer-specific gene expression. Previously validated MAPK and interferon (IFN)-γ gene expression signatures were used for measuring transcriptomic changes following treatment with E+C+N. Scores between responders and non-responders were compared by unpaired t-tests. For Gene Set Enrichment Analysis (GSEA), an adjusted false discovery rate (FDR) < 0.25 was applied to find significantly enriched pathways between on-treatment and pretreatment samples separately for responders and non-responders. Results: 26 pts were treated with E+C+N, and 24 were evaluable for response. Overall response rate was 50% (95% confidence interval (CI), 29-71), and median progression-free survival was 7.4 months (95% CI, 6.0-NA). Four pts remained on study > 12 months. Between responders vs non-responders (N=12 each), mean changes in MAPK signature score was decreased (-0.63 vs 0.15, respectively; p=.13). Both patients with response > 18 months demonstrated dramatic increases in IFN-γ score following treatment with E+C+N (+13.1 and +14.6), a trend not observed in all other patients (range, -18.0 to 3.6). Among responders to E+C+N, GSEA analysis demonstrated dynamic pathway changes in normalized enrichment score (NES) for DNA repair (NES -2.3; p-adj=.008), IL6/JAK/STAT3 (NES -2.1, p-adj=.02), and IFN-α response (NES -2.0, p-adj=.03). For non-responders, relative increases in NES were observed for angiogenesis (NES 2.1, p-adj=.02) and IL-2/STAT5 (NES 2.0, p-adj= .02). Conclusions: Transcriptome analysis using exoRNA isolated from serial blood samples is feasible for assessing treatment response in pts with mCRC. Decreased MAPK score in exoRNA may be associated with treatment response to E+C+N in pts with MSS, BRAFV600E mCRC. Changes in immune NES scores following treatment may distinguish responders from non-responders to MAPK + PD-1 blockade and highlight targets for novel immune-mediated combinations for MSS, BRAFV600E mCRC. Citation Format: Van Karlyle Morris, Kimal I. Rajapakshe, Vahid Bahrambeigi, Christine M. Parsehgian, Benny Johnson, Kanwal P. Raghav, Arvind Dasari, Ryan W. Huey, Michael J. Overman, Jason Willis, Michael S. Lee, Robert A. Wolff, Bryan K. Kee, Phat Le, Paola A. Guerrero, Scott Kopetz, Anirban Maitra. Changes in exosomal RNA expression associate with treatment response to BRAF + EGFR + PD-1 blockade in MSS, BRAFV600E colorectal cancer: A liquid biopsy approach [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr B028.

BackgroundCancer of unknown primary (CUP) is an aggressive rare malignancy with limited treatment options. Data regarding clinical activity of immune checkpoint inhibitors in CUP is lacking. Therefore, we evaluated the efficacy of pembrolizumab, a programmed cell death-1 inhibitor, in patients with CUP.MethodsThe study was designed as a phase 2 basket trial for independent rare tumor cohorts including CUP. Adult patients with CUP who had progressed on previous systemic therapy, performance status 0/1 and measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST V.1.1) were eligible. Patients received pembrolizumab (200 mg) intravenously every 21 days. Twenty-nine patients were enrolled and treated between August 2016 and June 2020. The primary endpoint was non-progression rate (NPR) at 27 weeks (NPR-27) per immune-related RECIST. Key prespecified secondary endpoints were confirmed objective response rate (ORR), safety, duration of response (DoR), progression-free survival (PFS) and overall survival (OS). Pretreatment biopsies were examined for biomarkers of response (programmed cell death ligand-1 (PD-L1) expression and tumor infiltrating lymphocytes (TILs)).ResultsAmong 25 (of 29 enrolled) eligible and evaluable patients, 14 (56%) had poorly differentiated carcinoma. Patients received a median of two lines of therapy prior to enrollment. Median follow-up was 27.3 months. NPR-27 was observed in seven patients (28.0% (95% CI: 12.1 to 49.4)). ORR was 20.0% (95% CI: 6.8 to 40.7) with five patients achieving immune-related partial response with median DoR of 14.7 months (95% CI: 9.8 to 19.6). Median PFS and OS were 4.1 (95% CI: 3.1 to 5.1) and 11.3 (95% CI: 5.5 to 17.1) months, respectively. Treatment-related adverse events of any and grade ≥3 were seen in 19 (76%) and 4 (16%) patients, respectively. One (4%) patient had grade 3 immune-related acute kidney injury requiring treatment discontinuation. Neither PD-L1 nor TILs were associated with NPR-27. Both positive PD-L1 staining (44.4% vs 6.3%; p=0.040) and intense TIL infiltration (44.4% vs 6.3%; p=0.040) were associated with response.ConclusionPembrolizumab showed encouraging efficacy in patients with CUP with acceptable safety profile.Trial registration numberNCT02721732.