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Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. To assess long-term risk of local tumor regrowth, we report updated organ preservation rate and oncologic outcomes of the OPRA trial (ClinicalTrials.gov identifier: NCT02008656). Patients with stage II/III rectal cancer were randomly assigned to receive induction chemotherapy followed by chemoradiation (INCT-CRT) or chemoradiation followed by consolidation chemotherapy (CRT-CNCT). Patients who achieved a complete or near-complete response after finishing treatment were offered watch-and-wait (WW). Total mesorectal excision (TME) was recommended for those who achieved an incomplete response. The primary end point was disease-free survival (DFS). The secondary end point was TME-free survival. In total, 324 patients were randomly assigned (INCT-CRT, n = 158; CRT-CNCT, n = 166). Median follow-up was 5.1 years. The 5-year DFS rates were 71% (95% CI, 64 to 79) and 69% (95% CI, 62 to 77) for INCT-CRT and CRT-CNCT, respectively ( P = .68). TME-free survival was 39% (95% CI, 32 to 48) in the INCT-CRT group and 54% (95% CI, 46 to 62) in the CRT-CNCT group ( P = .012). Of 81 patients with regrowth, 94% occurred within 2 years and 99% occurred within 3 years. DFS was similar for patients who underwent TME after restaging (64% [95% CI, 53 to 78]) and patients in WW who underwent TME after regrowth (64% [95% CI, 53 to 78]; P = .94). Updated analysis continues to show long-term organ preservation in half of the patients with rectal cancer treated with total neoadjuvant therapy. In patients who enter WW, most cases of tumor regrowth occur in the first 2 years.

Purpose: The safety, pharmacokinetics, and efficacy of elraglusib, a glycogen synthase kinase-3β (GSK-3β) small-molecule inhibitor, as monotherapy or combined with chemotherapy, in patients with relapsed or refractory solid tumors or hematologic malignancies was studied., Patients and Methods: Elraglusib (intravenously twice weekly in 3-week cycles) monotherapy dose escalation was followed by dose escalation with eight chemotherapy regimens (gemcitabine, doxorubicin, lomustine, carboplatin, irinotecan, gemcitabine/nab-paclitaxel, paclitaxel/carboplatin, and pemetrexed/carboplatin) in patients previously exposed to the same chemotherapy., Results: Patients received monotherapy (n = 67) or combination therapy (n = 171) elraglusib doses 1 to 15 mg/kg twice weekly. The initial recommended phase II dose (RP2D) of elraglusib was 15 mg/kg twice weekly and was defined, without dose-limiting toxicity observation, due to fluid volumes necessary for drug administration. The RP2D was subsequently reduced to 9.3 mg/kg once weekly to reduce elraglusib-associated central/peripheral vascular access catheter blockages. Other common elraglusib-related adverse events (AE) included transient visual changes and fatigue. Grade ≥3 treatment-emergent AEs occurred in 55.2% and 71.3% of patients on monotherapy and combination therapy, respectively. Part 1 monotherapy (n = 62) and part 2 combination (n = 138) patients were evaluable for response. In part 1, a patient with melanoma had a complete response, and a patient with acute T-cell leukemia/lymphoma had a partial response (PR). In part 2, seven PRs were observed, and the median progression-free survival and overall survival were 2.1 [95% confidence interval (CI), 2-2.6] and 6.9 (95% CI, 5.7-8.4) months, respectively., Conclusions: Elraglusib had a favorable toxicity profile as monotherapy and combined with chemotherapy and was associated with clinical benefit supporting further clinical evaluation in combination with chemotherapy., (©2023 American Association for Cancer Research.)

Background: Recent trials suggest that programmed cell death 1 (PD-1)-directed immunotherapy may be beneficial for some patients with anal squamous cell carcinoma and biomarkers predictive of response are greatly needed., Methods: This multicenter phase II clinical trial (NCT02919969) enrolled patients with metastatic or locally advanced incurable anal squamous cell carcinoma (n=32). Patients received pembrolizumab 200 mg every 3 weeks. The primary endpoint of the trial was objective response rate (ORR). Exploratory objectives included analysis of potential predictive biomarkers including assessment of tumor-associated immune cell populations with multichannel immunofluorescence and analysis of circulating tumor tissue modified viral-human papillomavirus DNA (TTMV-HPV DNA) using serially collected blood samples. To characterize the clinical features of long-term responders, we combined data from our prospective trial with a retrospective cohort of patients with anal cancer treated with anti-PD-1 immunotherapy (n=18)., Results: In the phase II study, the ORR to pembrolizumab monotherapy was 9.4% and the median progression-free survival was 2.2 months. Despite the high level of HPV positivity observed with circulating TTMV-HPV DNA testing, the majority of patients had low levels of tumor-associated CD8+PD-1+ T cells on pretreatment biopsy. Patients who benefited from pembrolizumab had decreasing TTMV-HPV DNA scores and a complete responder's TTMV-HPV DNA became undetectable. Long-term pembrolizumab responses were observed in one patient from the trial (5.3 years) and three patients (2.5, 6, and 8 years) from the retrospective cohort. Long-term responders had HPV-positive tumors, lacked liver metastases, and achieved a radiological complete response., Conclusions: Pembrolizumab has durable efficacy in a rare subset of anal cancers. However, despite persistence of HPV infection, indicated by circulating HPV DNA, most advanced anal cancers have low numbers of tumor-associated CD8+PD-1+ T cells and are resistant to pembrolizumab., Competing Interests: Competing interests: BMH has received honorarium from TD Cowen for consulting. JMC has received funding to her institution for research from Lilly and Sanofi. She has served as a consultant or on advisory boards for Novartis/AAA, Ipsen, Curium, and TerSera. She has received royalties from UpToDate. She owns stock in Merck. JAM received an honorarium for being on the advisory board of Merck. NJM received funding to her institution for research from Bristol Myers Squibb. MBY received research funding from Janssen Pharmaceuticals and fees for peer review services from UpToDate. BR has institutional patents filed on methods for clinical interpretation. EMVA has served in an advisory/consulting role for Tango Therapeutics, Genome Medical, Genomic Life, Enara Bio, Manifold Bio, Monte Rosa, Novartis Institute for Biomedical Research, Riva Therapeutics, and Serinus Bio. He receives research support from Novartis, BMS, and Sanofi. He has investment equity in Tango Therapeutics, Genome Medical, Genomic Life, Syapse, Enara Bio, Manifold Bio, Microsoft, Monte Rosa, Riva Therapeutics, Serinus Bio. He holds institutional patents filed on chromatin mutations and immunotherapy response, and methods for clinical interpretation; intermittent legal consulting on patents for Foaley & Hoag. AP has equity in C2i Genomics XGenomes and Parithera and in the last 36 months, has served as an advisor/consultant for Eli Lilly, Pfizer, Inivata, Biofidelity, Checkmate Pharmaceuticals, FMI, Guardant, Abbvie, Bayer, Delcath, Taiho, CVS, Value Analytics Lab, Seagen, Saga, AZ, Scare, Illumina and Science For America. She receives fees from Up to Date. She has received travel fees from Karkinos Healthcare. She has been on the DSMC for a Roche study and on Steering Committee for Exilixis. She has received research funding to the Institution from PureTech, PMV Pharmaceuticals, Plexxicon, Takeda, BMS, Mirati, Novartis, Erasca, Genentech, and Daiichi Sankyo. KN has received research funding to her institution from Pharmavite, Evergrande Group, Janssen, and Revolution Medicines. She has consulted or served on advisory boards for Bayer, Pfizer, and GSK. SK, CDVF, and CK are employed by Naveris, Inc. and may hold equity or stock options in Naveris, Inc. ALC received research funding unrelated to this project from Novocure, Astrazeneca, Amgen, Nucana, Gilead, Tanabe, Seagen. DAR has served in a consulting or advisory role for Boston Scientific, Instylla, Taiho, and AxialTx. SKD received research funding unrelated to this project from Eli Lilly and Company, Novartis Pharmaceuticals, Genocea, and Bristol-Myers Squibb and is a founder, science advisory board member (SAB) and equity holder in Kojin. JMC receives research funding to his institution from Merus, Roche, Servier, and Bristol Myers Squibb. He receives research support from Merck, AstraZeneca, Esperas Pharma, Bayer, Tesaro, Arcus Biosciences, and Apexigen; he has also received honoraria for being on the advisory boards of Incyte and Blueprint Medicines. The remaining authors report no conflicts of interest., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Importance: Assessing clinical tumor response following completion of total neoadjuvant therapy (TNT) in patients with locally advanced rectal cancer is paramount to select patients for watch-and-wait treatment., Objective: To assess organ preservation (OP) and oncologic outcomes according to clinical tumor response grade., Design, Setting, and Participants: This was secondary analysis of the Organ Preservation in Patients with Rectal Adenocarcinoma trial, a phase 2, nonblinded, multicenter, randomized clinical trial. Randomization occurred between April 2014 and March 2020. Eligible participants included patients with stage II or III rectal adenocarcinoma. Data analysis occurred from March 2022 to July 2023., Intervention: Patients were randomized to induction chemotherapy followed by chemoradiation or chemoradiation followed by consolidation chemotherapy. Tumor response was assessed 8 (±4) weeks after TNT by digital rectal examination and endoscopy and categorized by clinical tumor response grade. A 3-tier grading schema that stratifies clinical tumor response into clinical complete response (CCR), near complete response (NCR), and incomplete clinical response (ICR) was devised to maximize patient eligibility for OP., Main Outcomes and Measures: OP and survival rates by clinical tumor response grade were analyzed using the Kaplan-Meier method and log-rank test., Results: There were 304 eligible patients, including 125 patients with a CCR (median [IQR] age, 60.6 [50.4-68.0] years; 76 male [60.8%]), 114 with an NCR (median [IQR] age, 57.6 [49.1-67.9] years; 80 male [70.2%]), and 65 with an ICR (median [IQR] age, 55.5 [47.7-64.2] years; 41 male [63.1%]) based on endoscopic imaging. Age, sex, tumor distance from the anal verge, pathological tumor classification, and clinical nodal classification were similar among the clinical tumor response grades. Median (IQR) follow-up for patients with OP was 4.09 (2.99-4.93) years. The 3-year probability of OP was 77% (95% CI, 70%-85%) for patients with a CCR and 40% (95% CI, 32%-51%) for patients with an NCR (P < .001). Clinical tumor response grade was associated with disease-free survival, local recurrence-free survival, distant metastasis-free survival, and overall survival., Conclusions and Relevance: In this secondary analysis of a randomized clinical trial, most patients with a CCR after TNT achieved OP, with few developing tumor regrowth. Although the probability of tumor regrowth was higher for patients with an NCR compared with patients with a CCR, a significant proportion of patients achieved OP. These findings suggest the 3-tier grading schema can be used to estimate recurrence and survival outcomes in patients with locally advanced rectal cancer who receive TNT., Trial Registration: ClinicalTrials.gov Identifier: NCT02008656.

Purpose: High levels of type I T cells are needed for tumor eradication. We evaluated whether the HER2-specific vaccine-primed T cells are readily expanded ex vivo to achieve levels needed for therapeutic infusion., Patients and Methods: Phase I/II nonrandomized trial of escalating doses of ex vivo-expanded HER2-specific T cells after in vivo priming with a multiple peptide-based HER2 intracellular domain (ICD) vaccine. Vaccines were given weekly for a total of three immunizations. Two weeks after the third vaccine, patients underwent leukapheresis for T-cell expansion, then received three escalating cell doses over 7- to 10-day intervals. Booster vaccines were administered after the T-cell infusions. The primary objective was safety. The secondary objectives included extent and persistence of HER2-specific T cells, development of epitope spreading, and clinical response. Patients received a CT scan prior to enrollment and 1 month after the last T-cell infusion., Results: Nineteen patients received T-cell infusions. Treatment was well tolerated. One month after the last T-cell infusion, 82% of patients had significantly augmented T cells to at least one of the immunizing epitopes and 81% of patients demonstrated enhanced intramolecular epitope spreading compared with baseline (P < 0.05). There were no complete responses, one partial response (6%), and eight patients with stable disease (47%), for a disease control rate of 53%. The median survival for those with progressive disease was 20.5 months and for responders (PR+SD) was 45.0 months., Conclusions: Adoptive transfer of HER2 vaccine-primed T cells was feasible, was associated with minimal toxicity, and resulted in an increased overall survival in responding patients. See related commentary by Crosby et al., p. 3256., (©2023 American Association for Cancer Research.)

Background: SEA-CD40 is an investigational, non-fucosylated, humanized monoclonal IgG 1 antibody that activates CD40, an immune-activating tumor necrosis factor receptor superfamily member. SEA-CD40 exhibits enhanced binding to activating FcγRIIIa, possibly enabling greater immune stimulation than other CD40 agonists. A first-in-human phase 1 trial was conducted to examine safety, pharmacokinetics, and pharmacodynamics of SEA-CD40 monotherapy in patients with advanced solid tumors and lymphoma., Methods: SEA-CD40 was administered intravenously to patients with solid tumors or lymphoma in 21-day cycles with standard 3+3 dose escalation at 0.6, 3, 10, 30, 45, and 60 µg/kg. An intensified dosing regimen was also studied. The primary objectives of the study were to evaluate the safety and tolerability and identify the maximum tolerated dose of SEA-CD40. Secondary objectives included evaluation of the pharmacokinetic parameters, antitherapeutic antibodies, pharmacodynamic effects and biomarker response, and antitumor activity., Results: A total of 67 patients received SEA-CD40 including 56 patients with solid tumors and 11 patients with lymphoma. A manageable safety profile was observed, with predominant adverse events of infusion/hypersensitivity reactions (IHRs) reported in 73% of patients. IHRs were primarily ≤grade 2 with an incidence associated with infusion rate. To mitigate IHRs, a standardized infusion approach was implemented with routine premedication and a slowed infusion rate. SEA-CD40 infusion resulted in potent immune activation, illustrated by dose dependent cytokine induction with associated activation and trafficking of innate and adaptive immune cells. Results suggested that doses of 10-30 µg/kg may result in optimal immune activation. SEA-CD40 monotherapy exhibited evidence of antitumor activity, with a partial response in a patient with basal cell carcinoma and a complete response in a patient with follicular lymphoma., Conclusions: SEA-CD40 was tolerable as monotherapy and induced potent dose dependent immune cell activation and trafficking consistent with immune activation. Evidence of monotherapy antitumor activity was observed in patients with solid tumors and lymphoma. Further evaluation of SEA-CD40 is warranted, potentially as a component of a combination regimen., Trial Registration Number: NCT02376699., Competing Interests: Competing interests: ALC reports receiving commercial research grants from Actuate, Abgenomics, Amgen, AstraZeneca, Novocure, Nucana, and Seagen. DCS reports receiving commercial research grants from Agensys, Atterocor/Millendo, Bayer, Bristol-Myers Squibb, Celgene, F. Hoffman-LaRoche, Incyte, Lilly, MedImmune/AstraZeneca, Millennium/Takeda, Novartis, OncoMed, Merck, Roche/Genentech, Seagen. TP reports receiving commercial research grants from AbbVie, Bayer, Bristol-Myers Squibb, Incyte, Celgene, Genentech; reports receiving honoraria from Lymphoma Connect; and is a consultant/advisory board member for AbbVie, ADCT Therapeutics, AstraZeneca, Bayer, Bristol-Myers Squibb/Celgene, Genentech, Gilead/Kite, Karyopharm, Incyte, Morphosys, Pharmacyclics, Seagen, and TG therapeutics. BDC reports receiving commercial research grants from Clinigen and Galectin Therapeutics; reports receiving honoraria from Merck, Nektar and Clinigen. SG reports receiving commercial research grants from Seagen. AM reports receiving commercial research grants from Incyte, Takeda, Forty Seven Inc/Gilead, Juno pharmaceuticals/Bristol-Myers Squibb, Celgene/Bristol-Myers Squibb, Oncotartis, Innate pharmaceuticals, Seagen, TG Therapeutics, Affimed, Merck, Kite/Gilead, Roche-Genentech, ADC therapeutics, Miragen, Rhizen Pharmaceuticals; reports consultant/advisory board member/speaker bureau for Gilead, AstraZeneca, Pharmacyclics, Seagen, Incyte, Morphosys/Incyte, TG Therapeutics, Carevive, Kyowa Kirin, and Rigel pharmaceuticals. TMK reports receiving commercial research grants from Seagen, Bristol-Myers Squibb, Esai, Soligenix, Jannsen, Pfizer, Exelixis; is a consultant/advisory board member/speaker bureau for Tyme, Merck Sharpe Dome, Amgen, Seagen, Engene, Exelixis, Novartis, Pfizer, Genomic Health, Sanofi, and Bristol-Myers Squibb. SNM was a site investigator for this study. Olivier Rixe reports receiving commercial research grants from Bexion, Kyowa Kirin, Newlink, Rgenix, Oxford biotherapeutics, Daiichi, and Seagen. DLB reports commercial research grants from Seagen, Astellas Pharma US, Rafael Pharmaceuticals, Immunicum AB, and TESARO. TFG reports commercial research grants from Roche-Genentech, Bristol-Myers Squibb, Merck, Incyte, Seagen, Celldex, Evelo, Bayer, Aduro, Pyxis; is a consultant/advisory board member for Roche-Genentech, Merck, AbbVie, Bayer, Jounce, Aduro, Fog Pharma, Adaptimmune, FivePrime, Pyxis, Allogene and holds ownership interest (including patents) in Jounce, Pyxis, Aduro, Evelo, Bristol-Myers Squibb. MG reports commercial research grants from Boehringer Ingelheim, Bristol-Myers Squibb, Checkpoint Therapeutics, Eisai, GSB Pharma, Incyte, Johnson & Johnson, MedImmune, Merck, Moderna Therapeutics, NextCure, Pfizer, Regeneron, Roche/Genentech, Sanofi, Seagen, Silenseed; reports receiving honoraria from Foundation Medicine, Guardant Health; and is a consultant/speaker bureau for Exenex, Bristol-Myers Squibb, Lilly, Merck. HJL reports receiving commercial research grants from Bristol-Myers Squibb, Celgene, Oncternal Therapeutics, Seagen, and Takeda; is a consultant/advisory board member/speaker bureau for Bristol-Myers Squibb, Guidepoint Global, and Aptitude Health. AKG reports receiving commercial research grants from Merck, I-Mab bio, IgM Bio, Takeda, Gilead, AstraZeneca, Agios, Janssen, Bristol-Myers Squibb, Seagen; is a consultant and receives honoraria from Incyte, Kite, Morphosys, ADC, Acrotech, Merck, Karyopharm, Nurix, Cellectar, Janssen, Seagen, Epizyme, I-Mab bio. PC reports receiving commercial research grants from Genetech, ADC Therapeutics; is a consultant/advisory board member/speaker’s bureau for Verastem, Seagen, Amgen, Kite, Bayer, TG Therapeutics, Celgene. EIH reports commercial research grants from Agensys, AIQ, Astellas, AstraZeneca, Bayer, Boehringer, Bristol-Myers Squibb, Calibr, Caris, Celgene, Celldex, Champions, Corcept, Curemeta, Daiichi Sankyo, Dendreon, eFFECTOR, Eisai, Esanik, Five Prime, Fortis, Genentech/Roche, GSK, Ignyta, Infinity, Inovio, Janssen; receives honoraria from AstraZeneca, Bayer, Dendreon, Sanofi, Seagen, is a consultant/speaker bureau for Agensys, AstraZeneca, Bayer, Caris Centers of Excellence, Dendreon, Sanofi. JT reports receiving commercial research grants from Merck, Pfizer, Trillium, Hoffmann-LaRoche, Five Prime, Novartis, Incyte, Xencor; is a consultant for Regeneron, Aveo, and Neoleukin. JEG-O reports commercial research grants from Genentech, MedImmune, NanoCarrier, Pfizer, Seagen; and is a consultant for Bayer, Chimerix. S. Ansari, A. Topletz-Erickson, M. W. Schmitt, are employees of and hold ownership interest (including patents) in Seagen. CJ and PZ are former employees and hold ownership interest in Seagen. No potential conflicts of interest were disclosed by the other authors., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: Pancreatic ductal adenocarcinoma (PDA) is the third most common cause of cancer death in the United States. Most patients who undergo resection develop recurrence. Standard treatment confers a median overall survival (OS) of 24 months. Exposure to alternate regimens may prevent chemoresistance. This study evaluated multiagent perioperative therapy for potentially resectable PDA patients to improve OS., Methods: A single center, phase 2, trial of patients with resectable or borderline resectable PDA. Patients received neoadjuvant therapy with induction chemotherapy (gemcitabine, docetaxel, capecitabine) for 3 cycles, chemoradiation (intensity-modulated radiation therapy with capecitabine and oxaliplatin) followed by surgery, and 2 months of adjuvant gemcitabine and oxaliplatin and 2 months of gemcitabine. The primary endpoint was OS. The secondary endpoint was recurrence-free survival (RFS)., Results: Thirty-two eligible patients were enrolled. Twenty-two patients underwent surgical resection. After a median follow-up of 56.8 months, mOS was 31.6 months (95% confidence interval [CI], 14.2-58.1) for all patients, 58.1 months (95% CI, 31.6 to NR) for those who completed surgery. The mRFS was 31.3 months (95% CI, 12.5 to NR)., Conclusions: Perioperative therapy with GTX, chemoradiotherapy, and adjuvant GemOx/Gem resulted in promising survival of 58 months for patients who underwent resection and may represent another treatment option for PDA., Competing Interests: Conflict of Interest: The authors declare no conflict of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: Prospective data on the efficacy of a watch-and-wait strategy to achieve organ preservation in patients with locally advanced rectal cancer treated with total neoadjuvant therapy are limited., Methods: In this prospective, randomized phase II trial, we assessed the outcomes of 324 patients with stage II or III rectal adenocarcinoma treated with induction chemotherapy followed by chemoradiotherapy (INCT-CRT) or chemoradiotherapy followed by consolidation chemotherapy (CRT-CNCT) and either total mesorectal excision (TME) or watch-and-wait on the basis of tumor response. Patients in both groups received 4 months of infusional fluorouracil-leucovorin-oxaliplatin or capecitabine-oxaliplatin and 5,000 to 5,600 cGy of radiation combined with either continuous infusion fluorouracil or capecitabine during radiotherapy. The trial was designed as two stand-alone studies with disease-free survival (DFS) as the primary end point for both groups, with a comparison to a null hypothesis on the basis of historical data. The secondary end point was TME-free survival., Results: Median follow-up was 3 years. Three-year DFS was 76% (95% CI, 69 to 84) for the INCT-CRT group and 76% (95% CI, 69 to 83) for the CRT-CNCT group, in line with the 3-year DFS rate (75%) observed historically. Three-year TME-free survival was 41% (95% CI, 33 to 50) in the INCT-CRT group and 53% (95% CI, 45 to 62) in the CRT-CNCT group. No differences were found between groups in local recurrence-free survival, distant metastasis-free survival, or overall survival. Patients who underwent TME after restaging and patients who underwent TME after regrowth had similar DFS rates., Conclusion: Organ preservation is achievable in half of the patients with rectal cancer treated with total neoadjuvant therapy, without an apparent detriment in survival, compared with historical controls treated with chemoradiotherapy, TME, and postoperative chemotherapy.

Objectives: To compare the efficacy and safety of algenpantucel-L [HyperAcute-Pancreas algenpantucel-L (HAPa); IND# 12311] immunotherapy combined with standard of care (SOC) chemotherapy and chemoradiation to SOC chemotherapy and chemoradiation therapy alone in patients with borderline resectable or locally advanced pancreatic ductal adenocarcinoma (PDAC)., Summary Background Data: To date, immunotherapy has not been shown to benefit patients with borderline resectable or locally advanced unresectable PDAC. HAPa is a cancer vaccine consisting of allogeneic pancreatic cancer cells engineered to express the murine α(1,3)GT gene., Methods: A multicenter, phase 3, open label, randomized (1:1) trial of patients with borderline resectable or locally advanced unresectable PDAC. Patients received neoadjuvant SOC chemotherapy (FOLFIRINOX or gemcitabine/nab-paclitaxel) followed by chemoradiation (standard group) or the same standard neoadjuvant regimen combined with HAPa immunotherapy (experimental group). The primary outcome was overall survival., Results: Between May 2013 and December 2015, 303 patients were randomized from 32 sites. Median (interquartile range) overall survival was 14.9 (12.2-17.8) months in the standard group (N = 158) and 14.3 (12.6-16.3) months in the experimental group (N = 145) [hazard ratio (HR) 1.02, 95% confidence intervals 0.66-1.58; P = 0.98]. Median progression-free survival was 13.4 months in the standard group and 12.4 months in the experimental group (HR 1.33, 95% confidence intervals 0.72-1.78; P = 0.59). Grade 3 or higher adverse events occurred in 105 of 140 patients (75%) in the standard group and in 115 of 142 patients (81%) in the experimental group (P > 0.05)., Conclusions: Algenpantucel-L immunotherapy did not improve survival in patients with borderline resectable or locally advanced unresectable PDAC receiving SOC neoadjuvant chemotherapy and chemoradiation., Trial Registration: ClinicalTrials.gov Identifier: NCT01836432., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Background: No therapies for targeting KRAS mutations in cancer have been approved. The KRAS p.G12C mutation occurs in 13% of non-small-cell lung cancers (NSCLCs) and in 1 to 3% of colorectal cancers and other cancers. Sotorasib is a small molecule that selectively and irreversibly targets KRAS G12C ., Methods: We conducted a phase 1 trial of sotorasib in patients with advanced solid tumors harboring the KRAS p.G12C mutation. Patients received sotorasib orally once daily. The primary end point was safety. Key secondary end points were pharmacokinetics and objective response, as assessed according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1., Results: A total of 129 patients (59 with NSCLC, 42 with colorectal cancer, and 28 with other tumors) were included in dose escalation and expansion cohorts. Patients had received a median of 3 (range, 0 to 11) previous lines of anticancer therapies for metastatic disease. No dose-limiting toxic effects or treatment-related deaths were observed. A total of 73 patients (56.6%) had treatment-related adverse events; 15 patients (11.6%) had grade 3 or 4 events. In the subgroup with NSCLC, 32.2% (19 patients) had a confirmed objective response (complete or partial response) and 88.1% (52 patients) had disease control (objective response or stable disease); the median progression-free survival was 6.3 months (range, 0.0+ to 14.9 [with + indicating that the value includes patient data that were censored at data cutoff]). In the subgroup with colorectal cancer, 7.1% (3 patients) had a confirmed response, and 73.8% (31 patients) had disease control; the median progression-free survival was 4.0 months (range, 0.0+ to 11.1+). Responses were also observed in patients with pancreatic, endometrial, and appendiceal cancers and melanoma., Conclusions: Sotorasib showed encouraging anticancer activity in patients with heavily pretreated advanced solid tumors harboring the KRAS p.G12C mutation. Grade 3 or 4 treatment-related toxic effects occurred in 11.6% of the patients. (Funded by Amgen and others; CodeBreaK100 ClinicalTrials.gov number, NCT03600883.)., (Copyright © 2020 Massachusetts Medical Society.)

Pancreatic ductal adenocarcinoma (PDAC) remains a deadly disease with few effective treatment options. Our knowledge of molecular alterations in PDAC has significantly grown and helped identify new therapeutic targets. The success of immune checkpoint inhibition in mismatch repair deficient tumors, PARP inhibitors for tumors with DNA repair defects, and targeting hyaluronan with PEGPH20 in patients with high expressing (hyaluronan-high) tumors are examples of promising biomarker-driven therapies. We review the major biological mechanisms in PDAC and discuss current and future directions for molecularly targeted therapies in this disease., (Copyright © 2018 Elsevier Inc. All rights reserved.)

We previously demonstrated vast expansion of hypoxic areas in the leukemic microenvironment and provided a rationale for using hypoxia-activated prodrugs. PR104 is a phosphate ester that is rapidly hydrolyzed in vivo to the corresponding alcohol PR-104A and further reduced to the amine and hydroxyl-amine nitrogen mustards that induce DNA cross-linking in hypoxic cells under low oxygen concentrations. In this phase I/II study, patients with relapsed/refractory acute myeloid leukemia (n=40) after 1 or 2 prior treatments or acute lymphoblastic leukemia (n=10) after any number of prior treatments received PR104; dose ranged from 1.1 to 4 g/m(2). The most common treatment-related grade 3/4 adverse events were myelosuppression (anemia 62%, neutropenia 50%, thrombocytopenia 46%), febrile neutropenia (40%), infection (24%), and enterocolitis (14%). Ten of 31 patients with acute myeloid leukemia (32%) and 2 of 10 patients with acute lymphoblastic leukemia (20%) who received 3 g/m(2) or 4 g/m(2) had a response (complete response, n=1; complete response without platelet recovery, n=5; morphological leukemia-free state, n=6). The extent of hypoxia was evaluated by the hypoxia tracer pimonidazole administered prior to a bone marrow biopsy and by immunohistochemical assessments of hypoxia-inducible factor alpha and carbonic anhydrase IX. A high fraction of leukemic cells expressed these markers, and PR104 administration resulted in measurable decrease of the proportions of hypoxic cells. These findings indicate that hypoxia is a prevalent feature of the leukemic microenvironment and that targeting hypoxia with hypoxia-activated prodrugs warrants further evaluation in acute leukemia. The trial is registered at clinicaltrials.gov identifier: 01037556., (Copyright© Ferrata Storti Foundation.)

Various human malignancies are immunogenic and recent cancer vaccine trials have demonstrated potential survival benefit. Breast cancer is immunogenic and there are several tumor associated antigens for which breast cancer vaccines have been developed. Breast cancer vaccines are designed to stimulate the immune response at various steps in the native antigen processing pathway for immunosurveillance. Human epidermal growth factor receptor 2 (HER-2/neu), mucin 1 (MUC-1), and human telomerase reverse transcriptase (hTERT) are some of the most studied antigens actively being targeted for vaccination in breast cancer patients. These vaccines are designed to elicit cytotoxic and/or helper T cell responses. Over the last several years, there has been reported progress in human clinical trials for these antigens. Cancer vaccines have repeatedly been shown to be safe with production of minimal toxicity. Recent clinical advances in the development of cancer vaccines demonstrate the potential clinical benefit that cancer vaccines hold.