Dana-Farber Research Publication, 9.15.2021

Blood Measurable Residual Disease Does Not Preclude Prolonged Progression-Free Survival in CLL Treated with Ibrutinib Wang V, Stone RM E1912 was a randomized phase 3 trial comparing indefinite ibrutinib plus six cycles of rituximab (IR) to six cycles of fludarabine, cyclophosphamide and rituximab (FCR) in untreated younger patients with CLL. We describe measurable residual disease (MRD) levels in E1912 over time and correlate them with clinical outcome. Undetectable MRD rates (< 1 CLL cell per 104 leukocytes) were 29.1%, 30.3%, 23.4% and 8.6% at 3, 12, 24 and 36 months for FCR, and significantly lower at 7.9%, 4.2% and 3.7% at 12, 24 and 36 months for IR, respectively. Undetectable MRD at 3, 12, 24 and 36 months was associated with longer progression-free survival (PFS) for the FCR arm with hazard ratios (MRD detectable / MRD undetectable) of 4.29 (95% CI 1.89 - 9.71), 3.91 (95% CI 1.39 - 11.03), 14.12 (95% CI 1.78 - 111.73), and not estimable (no events among those with undetectable MRD), respectively. For the IR arm, patients with detectable MRD did not have significantly worse PFS compared to those in whom MRD was undetectable; however, PFS was longer for those with MRD levels of less than 10-1 compared to those with MRD levels above this threshold. Our observations provide additional support for the use of MRD as a surrogate endpoint for PFS in patients receiving FCR. For patients on indefinite ibrutinib-based therapy, PFS did not differ significantly by undetectable MRD status, while those with MRD less than 10-1 tend to have longer PFS, although continuation of ibrutinib is very likely required to maintain treatment efficacy.

Journal of Clinical Oncology Beyond the Front Line: Emerging Data for Maintenance Therapy in Pancreatic Cancer Singh H, Perez K, Wolpin BM, Aguirre AJ The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors' suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology, to patients seen in their own clinical practice.

Journal of Clinical Oncology Pertuzumab Plus High-Dose Trastuzumab in Patients with Progressive Brain Metastases and HER2-Positive Metastatic Breast Cancer: Primary Analysis of a Phase II Study Lin NU PURPOSE: Effective therapies are needed for the treatment of patients with human epidermal growth factor receptor-2 (HER2)-positive metastatic breast cancer (MBC) with brain metastases. A trastuzumab radioisotope has been shown to localize in brain metastases of patients with HER2-positive MBC, and intracranial xenograft models have demonstrated a dose-dependent response to trastuzumab. METHODS: In the phase II PATRICIA study (ClinicalTrials.gov identifier: NCT02536339), patients with HER2-positive MBC with CNS metastases and CNS progression despite prior radiotherapy received pertuzumab plus high-dose trastuzumab (6 mg/kg weekly) until CNS or systemic disease progression or unacceptable toxicity. The primary end point was confirmed objective response rate (ORR) in the CNS per Response Assessment in Neuro-Oncology Brain Metastases criteria. Secondary end points included duration of response, clinical benefit rate (complete response plus partial response plus stable disease 4 or 6 months) in the CNS, and safety. RESULTS: Thirty-nine patients were treated for a median (range) of 4.5 (0.3-37.3) months at clinical cutoff. Thirty-seven patients discontinued treatment, most commonly because of CNS progression (n = 27); two remained on treatment. CNS ORR was 11% (95% CI, 3 to 25), with four partial responses (median duration of response, 4.6 months). Clinical benefit rate at 4 months and 6 months was 68% and 51%, respectively. Two patients permanently discontinued study treatment because of adverse events (left ventricular dysfunction [treatment-related] and seizure, both grade 3). No grade 5 adverse events were reported. No new safety signals emerged with either agent. CONCLUSION: Although the CNS ORR was modest, 68% of patients experienced clinical benefit, and two patients had ongoing stable intracranial and extracranial disease for > 2 years. High-dose trastuzumab for HER2-positive CNS metastases may warrant further study.

Journal of Clinical Oncology Updated Standardized Definitions for Efficacy End Points (STEEP) in Adjuvant Breast Cancer Clinical Trials: STEEP Version 2.0 Tolaney SM, Frank E, Tung NM, Winer EP PURPOSE: The Standardized Definitions for Efficacy End Points (STEEP) criteria, established in 2007, provide standardized definitions of adjuvant breast cancer clinical trial end points. Given the evolution of breast cancer clinical trials and improvements in outcomes, a panel of experts reviewed the STEEP criteria to determine whether modifications are needed. METHODS: We conducted systematic searches of ClinicalTrials.gov for adjuvant systemic and local-regional therapy trials for breast cancer to investigate if the primary end points reported met STEEP criteria. On the basis of common STEEP deviations, we performed a series of simulations to evaluate the effect of excluding non-breast cancer deaths and new nonbreast primary cancers from the invasive disease-free survival end point. RESULTS: Among 11 phase III breast cancer trials with primary efficacy end points, three had primary end points that followed STEEP criteria, four used STEEP definitions but not the corresponding end point names, and four used end points that were not included in the original STEEP manuscript. Simulation modeling demonstrated that inclusion of second nonbreast primary cancer can increase the probability of incorrect inferences, can decrease power to detect clinically relevant efficacy effects, and may mask differences in recurrence rates, especially when recurrence rates are low. CONCLUSION: We recommend an additional end point, invasive breast cancer-free survival, which includes all invasive disease-free survival events except second nonbreast primary cancers. This end point should be considered for trials in which the toxicities of agents are well-known and where the risk of second primary cancer is small. Additionally, we provide end point recommendations for local therapy trials, low-risk populations, noninferiority trials, and trials incorporating patient-reported outcomes.

New England Journal of Medicine Adjuvant Pembrolizumab after Nephrectomy in Renal-Cell Carcinoma Choueiri TK BACKGROUND: Patients with renal-cell carcinoma who undergo nephrectomy have no options for adjuvant therapy to reduce the risk of recurrence that have high levels of supporting evidence. METHODS: In a double-blind, phase 3 trial, we randomly assigned, in a 1:1 ratio, patients with clear-cell renal-cell carcinoma who were at high risk for recurrence after nephrectomy, with or without metastasectomy, to receive either adjuvant pembrolizumab (at a dose of 200 mg) or placebo intravenously once every 3 weeks for up to 17 cycles (approximately 1 year). The primary end point was disease-free survival according to the investigator's assessment. Overall survival was a key secondary end point. Safety was a secondary end point. RESULTS: A total of 496 patients were randomly assigned to receive pembrolizumab, and 498 to receive placebo. At the prespecified interim analysis, the median time from randomization to the data-cutoff date was 24.1 months. Pembrolizumab therapy was associated with significantly longer disease-free survival than placebo (disease-free survival at 24 months, 77.3% vs. 68.1%; hazard ratio for recurrence or death, 0.68; 95% confidence interval [CI], 0.53 to 0.87; P = 0.002 [two-sided]). The estimated percentage of patients who remained alive at 24 months was 96.6% in the pembrolizumab group and 93.5% in the placebo group (hazard ratio for death, 0.54; 95% CI, 0.30 to 0.96). Grade 3 or higher adverse events of any cause occurred in 32.4% of the patients who received pembrolizumab and in 17.7% of those who received placebo. No deaths related to pembrolizumab therapy occurred. CONCLUSIONS: Pembrolizumab treatment led to a significant improvement in disease-free survival as compared with placebo after surgery among patients with kidney cancer who were at high risk for recurrence. (Funded by Merck Sharp and Dohme, a subsidiary of Merck; KEYNOTE-564 ClinicalTrials.gov number, NCT03142334.).

Nature Communications A Unified Model of Human Hemoglobin Switching Through Single-Cell Genome Editing Shen Y, Verboon JM, Liu N, Marglous S, Nandakumar SK, Voit RA, Fiorini C, Ejaz A, Basak A, Orkin SH, Sankaran VG Key mechanisms of fetal hemoglobin (HbF) regulation and switching have been elucidated through studies of human genetic variation, including mutations in the HBG1/2 promoters, deletions in the Œ?-globin locus, and variation impacting BCL11A. While this has led to substantial insights, there has not been a unified understanding of how these distinct genetically-nominated elements, as well as other key transcription factors such as ZBTB7A, collectively interact to regulate HbF. A key limitation has been the inability to model specific genetic changes in primary isogenic human hematopoietic cells to uncover how each of these act individually and in aggregate. Here, we describe a single-cell genome editing functional assay that enables specific mutations to be recapitulated individually and in combination, providing insights into how multiple mutation-harboring functional elements collectively contribute to HbF expression. In conjunction with quantitative modeling and chromatin capture analyses, we illustrate how these genetic findings enable a comprehensive understanding of how distinct regulatory mechanisms can synergistically modulate HbF expression.

Nature Medicine Inhibition of Hypoxia-Inducible Factor-2a in Renal Cell Carcinoma with Belzutifan: A Phase 1 Trial and Biomarker Analysis Choueiri TK, McDermott DF, Michaelson MD Hypoxia-inducible factor-2? (HIF-2?) is a transcription factor that frequently accumulates in clear cell renal cell carcinoma (ccRCC), resulting in constitutive activation of genes involved in carcinogenesis. Belzutifan (MK-6482, previously known as PT2977) is a potent, selective small molecule inhibitor of HIF-2?. Maximum tolerated dose, safety, pharmacokinetics, pharmacodynamics and anti-tumor activity of belzutifan were evaluated in this first-in-human phase 1 study (NCT02974738). Patients had advanced solid tumors (dose-escalation cohort) or previously treated advanced ccRCC (dose-expansion cohort). Belzutifan was administered orally using a 3 + 3 dose-escalation design, followed by expansion at the recommended phase 2 dose (RP2D) in patients with ccRCC. In the dose-escalation cohort (n = 43), no dose-limiting toxicities occurred at doses up to 160 mg once daily, and the maximum tolerated dose was not reached; the RP2D was 120 mg once daily. Plasma erythropoietin reductions were observed at all doses; erythropoietin concentrations correlated with plasma concentrations of belzutifan. In patients with ccRCC who received 120 mg once daily (n = 55), the confirmed objective response rate was 25% (all partial responses), and the median progression-free survival was 14.5 months. The most common grade ?3 adverse events were anemia (27%) and hypoxia (16%). Belzutifan was well tolerated and demonstrated preliminary anti-tumor activity in heavily pre-treated patients, suggesting that HIF-2? inhibition might offer an effective treatment for ccRCC.

AJR American Journal of Roentgenology Intercostal Brown Adipose Tissue on FDG PET/CT Dabiri BE, Jacene HA

Biochemistry Targeted Degradation of the Oncogenic Phosphatase SHP2 Vemulapalli V, Donovan KA, Rogers JM, Bae M, Lumpkin RJ, Cao R, Henke MT, Fischer ES, Blacklow SC

Bioinformatics Quantification of Aneuploidy in Targeted Sequencing Data Using ASCETS Spurr LF, Touat M, Taylor AM, Dubuc AM, Shih J, Meredith DM, Pisano WV, Meyerson ML, Ligon KL, Cherniack AD, Li YY, Beroukhim R

Blood Advances Activity of mRNA COVID-19 Vaccines in Patients with Lymphoid Malignancies Crombie JL, Sherman AC, Cheng CA, Ryan CE, Zon R, Desjardins M, Baker P, McDonough M, Izaguirre N, Bausk B, Krauss J, Gilboa T, Senussi Y, Walt DR, Davids MS, Brown JR, Armand P, Baden LR, Issa N

Blood Advances Lack of Differential Impact of Del17p on Survival in African Americans Compared to White Patients with Multiple Myeloma: A VA Study Fillmore NR, Cirstea D, Munjuluri A, Do NV, Brophy MT, Munshi NC

Cancer Causes and Control Statins to Mitigate Cardiotoxicity in Cancer Patients Treated with Anthracyclines and/or Trastuzumab: A Systematic Review and Meta-Analysis Papatheodorou SI, Nohria A, Asnani A, Partridge AH

Cancer Management and Research Prognostic Factors in Hormone Receptor-Positive/Human Epidermal Growth Factor Receptor 2-Negative (HR+/HER2-) Advanced Breast Cancer: A Systematic Literature Review Tolaney SM

Critical Reviews in Oncology/Hematology Neurotoxicities of Novel Non-Steroidal Anti-Androgens for Prostate Cancer: A Systematic Review and Meta-Analysis Bakouny Z, Braun DA, Berchuck JE, Hirsch L, Lee Y, Trinh QD, Choueiri TK

Current Treatment Options in Oncology How to Sequence Therapies in Waldenström Macroglobulinemia Sarosiek S, Treon SP, Castillo JJ

Expert Opinion on Emerging Drugs The Future of Antibody Therapy in Chronic Lymphocytic Leukemia Crombie JL, Brown JR

Gynecologic Oncology Perceived Patient-Centered Communication, Quality of Life, and Symptom Burden in Individuals with Ovarian Cancer Pozzar RA, Xiong N, Hong F, Wright AA, Underhill-Blazey ML, Tulsky JA, Hammer MJ, Berry DL

Haematologica Allogeneic Hematopoietic Cell Transplantation Outcomes in Patients with Richter's Transformation Kim HT, Baker PO, Parry E, Davids M, Ho VT, Cutler C, Koreth J, Gooptu M, Romee R, Nikiforow S, Antin JH, Ritz J, Soiffer RJ, Wu CJ, Brown JR

International Journal of Radiation Oncology, Biology, Physics Prospective Clinical Investigation of the Efficacy of Combination Radiotherapy with Immune Checkpoint Inhibition Akama-Garren EH, Schoenfeld JD

Journal of Immunotherapy Long-term Overall Survival and Predictors in Anti-PD-1-naive Melanoma Patients with Brain Metastases Treated with Immune Checkpoint Inhibitors in the Real-world Setting: A Multicohort Study Naik GS, Buchbinder EI, Cohen JV, Manos MP, Bowling P, Aizer AA, Schoenfeld JD, Lawrence DP, Haq R, Hodi FS, Sullivan RJ, Ott PA

NPJ Breast Cancer Nivolumab in Combination with Cabozantinib for Metastatic Triple-Negative Breast Cancer: A Phase II and Biomarker Study Barroso-Sousa R, Keenan TE, Li T, Tayob N, Trippa L, Pastorello RG, Richardson Iii ET, Dillon D, Amoozgar Z, Overmoyer B, Schnitt SJ, Winer EP, Mittendorf EA, Van Allen E, Duda DG, Tolaney SM

Oncologist Trifluridine/Tipiracil (FTD/TPI) and Regorafenib in Patients with Metastatic Colorectal Cancer (mCRC): A Retrospective Study at a Tertiary Oncology Center Patel AK, Abhyankar R, Brais LK, Ng K, Fuchs CS

Oncotarget Correction: HDAC6 Inhibitor WT161 Downregulates Growth Factor Receptors in Breast Cancer Hideshima T, Mazitschek R, Qi J, Mimura N, Tseng JC, Kung AL, Bradner JE, Anderson KC

Pediatrics The Case of Billy Best: 25 Years Later Marron JM, Meyer EC

RSC Medicinal Chemistry Selective Degradation-Inducing Probes for Studying Cereblon (CRBN) Biology Powell CE, Du G, Bushman JW, He Z, Zhang T, Fischer ES, Gray NS

Scientific Reports Effect of Aerobic and Resistance Exercise on the Mitochondrial Peptide MOTS-c in Hispanic and Non-Hispanic White Breast Cancer Survivors Dieli-Conwright CM, Norris MK