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Dana-Farber Research Publication 3.1.2022

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March 1, 2022

This twice-monthly newsletter highlights the research endeavors at Dana-Farber Cancer Institute, noting recently published papers available from PubMed where Dana-Farber faculty are listed as first or senior authors.


The Menin-MLL1 Interaction is a Molecular Dependency in NUP98-Rearranged AML

Heikamp EB, Henrich JA, Perner F, Wong EM, Hatton C, Wen Y, Xu H, Uckelmann HJ, Pikman Y, Armstrong SA

Translocations involving the NUP98 gene produce NUP98-fusion proteins and are associated with a poor prognosis in acute myeloid leukemia (AML). MLL1 is a molecular dependency in NUP98-fusion leukemia, and therefore we investigated the efficacy of therapeutic blockade of the menin-MLL1 interaction in NUP98-fusion leukemia models. Using mouse leukemia cell lines driven by NUP98-HOXA9 and NUP98-JARID1A fusion oncoproteins, we demonstrate that NUP98-fusion-driven leukemia is sensitive to the menin-MLL1 inhibitor VTP50469, with an IC50 similar to what we have previously reported for MLL-rearranged and NPM1c leukemia cells. Menin-MLL1 inhibition upregulates markers of differentiation such as CD11b and downregulates expression of proleukemogenic transcription factors such as Meis1 in NUP98-fusion-transformed leukemia cells. We demonstrate that MLL1 and the NUP98 fusion protein itself are evicted from chromatin at a critical set of genes that are essential for the maintenance of the malignant phenotype. In addition to these in vitro studies, we established patient-derived xenograft (PDX) models of NUP98-fusion-driven AML to test the in vivo efficacy of menin-MLL1 inhibition. Treatment with VTP50469 significantly prolongs survival of mice engrafted with NUP98-NSD1 and NUP98-JARID1A leukemias. Gene expression analysis revealed that menin-MLL1 inhibition simultaneously suppresses a proleukemogenic gene expression program, including downregulation of the HOXa cluster, and upregulates tissue-specific markers of differentiation. These preclinical results suggest that menin-MLL1 inhibition may represent a rational, targeted therapy for patients with NUP98-rearranged leukemias.


Venetoclax Plus Dose-Adjusted R-EPOCH for Richter Syndrome

Davids MS, Tyekucheva S, Wang Z, Pazienza S, Montegaard J, Ihuoma U, Lehmberg TZ, Parry EM, Wu CJ, Jacobson CA, Fisher DC, Brown JR

Richter syndrome (RS) of chronic lymphocytic leukemia (CLL) is typically chemoresistant, with a poor prognosis. We hypothesized that the oral Bcl-2 inhibitor venetoclax could sensitize RS to chemoimmunotherapy and improve outcomes. We conducted a single-arm, investigator-sponsored, phase 2 trial of venetoclax plus dose-adjusted rituximab, etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (VR-EPOCH) to determine the rate of complete response (CR). Patients received R-EPOCH for 1 cycle, then after count recovery, accelerated daily venetoclax ramp-up to 400 mg, then VR-EPOCH for up to 5 more 21-day cycles. Responders received venetoclax maintenance or cellular therapy off-study. Twenty-six patients were treated, and 13 of 26 (50%) achieved CR, with 11 achieving undetectable bone marrow minimal residual disease for CLL. Three additional patients achieved partial response (overall response rate, 62%). Median progression-free survival was 10.1 months, and median overall survival was 19.6 months. Hematologic toxicity included grade 3 neutropenia (65%) and thrombocytopenia (50%), with febrile neutropenia in 38%. No patients experienced tumor lysis syndrome with daily venetoclax ramp-up. VR-EPOCH is active in RS, with deeper, more durable responses than historical regimens. Toxicities from intensive chemoimmunotherapy and venetoclax were observed. Our data suggest that studies comparing venetoclax with chemoimmunotherapy to chemoimmunotherapy alone are warranted. This trial was registered at as #NCT03054896.

Cancer Cell

Dangerous Dynamic Duo: Lactic Acid and PD-1 Blockade

Johnson S, Haigis MC, Dougan SK

In this issue of Cancer Cell, Kumagai et al. reveal lactic acid as a mediator of checkpoint blockade resistance. Tumor-derived lactic acid promotes T regulatory cell (Treg) activity and impairs CD8+ T cell function. PD-1 blockade synergizes with lactic acid to enhance Treg suppression and impede antitumor immunity.

Cancer Discovery

An In Vivo CRISPR Screening Platform for Prioritizing Therapeutic Targets in AML

Lin S, Scheidegger NK, Seong BKA, Dharia NV, Kuljanin M, Wechsler CS, Kugener G, Robichaud AL, Conway AS, Mashaka T, Adane B, Ryan JA, Mancias JD, Younger ST, Piccioni F, Letai A, Stegmaier K

CRISPR-Cas9-based genetic screens have successfully identified cell type-dependent liabilities in cancer, including acute myeloid leukemia (AML), a devastating hematologic malignancy with poor overall survival. Because most of these screens have been performed in vitro using established cell lines, evaluating the physiologic relevance of these targets is critical. We have established a CRISPR screening approach using orthotopic xenograft models to validate and prioritize AML-enriched dependencies in vivo, including in CRISPR-competent AML patient-derived xenograft (PDX) models tractable for genome editing. Our integrated pipeline has revealed several targets with translational value, including SLC5A3 as a metabolic vulnerability for AML addicted to exogenous myo-inositol and MARCH5 as a critical guardian to prevent apoptosis in AML. MARCH5 repression enhanced the efficacy of BCL2 inhibitors such as venetoclax, further highlighting the clinical potential of targeting MARCH5 in AML. Our study provides a valuable strategy for discovery and prioritization of new candidate AML therapeutic targets. SIGNIFICANCE: There is an unmet need to improve the clinical outcome of AML. We developed an integrated in vivo screening approach to prioritize and validate AML dependencies with high translational potential. We identified SLC5A3 as a metabolic vulnerability and MARCH5 as a critical apoptosis regulator in AML, both of which represent novel therapeutic opportunities.This article is highlighted in the In This Issue feature, p. 275.

Cancer Discovery

Functional Precision Medicine: Putting Drugs on Patient Cancer Cells and Seeing What Happens

Letai A

For too long, assays exposing patient tumor cells to drugs to identify active therapies have been dismissed as ineffective. In this issue of Cancer Discovery, two groups independently demonstrate clinical utility of such functional precision medicine assays in hematologic malignancies.

Cancer Discovery

Sex-Biased ZRSR2 Mutations in Myeloid Malignancies Impair Plasmacytoid Dendritic Cell Activation and Apoptosis

Togami K, Chung SS, Booth CAG, Kenyon CM, Cabal-Hierro L, Kim SS, Griffin GK, Ghandi M, Li YY, Lovitch SB, Louissaint A Jr, Morgan EA, Weinstock DM, Hammerman PS, Lane AA

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive leukemia of plasmacytoid dendritic cells (pDC). BPDCN occurs at least three times more frequently in men than in women, but the reasons for this sex bias are unknown. Here, studying genomics of primary BPDCN and modeling disease-associated mutations, we link acquired alterations in RNA splicing to abnormal pDC development and inflammatory response through Toll-like receptors. Loss-of-function mutations in ZRSR2, an X chromosome gene encoding a splicing factor, are enriched in BPDCN, and nearly all mutations occur in males. ZRSR2 mutation impairs pDC activation and apoptosis after inflammatory stimuli, associated with intron retention and inability to upregulate the transcription factor IRF7. In vivo, BPDCN-associated mutations promote pDC expansion and signatures of decreased activation. These data support a model in which male-biased mutations in hematopoietic progenitors alter pDC function and confer protection from apoptosis, which may impair immunity and predispose to leukemic transformation. SIGNIFICANCE: Sex bias in cancer is well recognized, but the underlying mechanisms are incompletely defined. We connect X chromosome mutations in ZRSR2 to an extremely male-predominant leukemia. Aberrant RNA splicing induced by ZRSR2 mutation impairs dendritic cell inflammatory signaling, interferon production, and apoptosis, revealing a sex- and lineage-related tumor suppressor pathway.This article is highlighted in the In This Issue feature, p. 275.

Journal of Clinical Oncology

Phase II Study of Copanlisib in Patients with Tumors with PIK3CA Mutations: Results From the NCI-MATCH ECOG-ACRIN Trial (EAY131) Subprotocol Z1F

Zhao F, Gray RJ, Wang V, Flaherty KT

PURPOSE: Activating mutations in PIK3CA are observed across multiple tumor types. The NCI-MATCH (EAY131) is a tumor-agnostic platform trial that enrolls patients to targeted therapies on the basis of matching genomic alterations. Arm Z1F evaluated copanlisib, an α and δ isoform-specific phosphoinositide 3-kinase (PI3K) inhibitor, in patients with PIK3CA mutations (with or without PTEN loss).
PATIENTS AND METHODS: Patients received copanlisib (60 mg intravenous) once weekly on days 1, 8, and 15 in 28-day cycles until progression or toxicity. Patients with KRAS mutations, human epidermal growth factor receptor 2-positive breast cancers, and lymphomas were excluded. The primary end point was centrally assessed objective response rate (ORR); secondary end points included progression-free survival, 6-month progression-free survival, and overall survival.
RESULTS: Thirty-five patients were enrolled, and 25 patients were included in the primary efficacy analysis as prespecified in the protocol. Multiple histologies were enrolled, with gynecologic (n = 6) and gastrointestinal (n = 6) being the most common. Sixty-eight percent of patients had ‚â• 3 lines of prior therapy. The ORR was 16% (4 of 25, 90% CI, 6 to 33) with P = .0341 against a null rate of 5%. The most common reason for protocol discontinuation was disease progression (n = 17, 68%). Grade 3/4 toxicities observed were consistent with reported toxicities for PI3K pathway inhibition. Sixteen patients (53%) had grade 3 toxicities, and one patient (3%) had grade 4 toxicity (CTCAE v5.0). Most common toxicities include hyperglycemia (n = 19), fatigue (n = 12), diarrhea (n = 11), hypertension (n = 10), and nausea (n = 10).
CONCLUSION: The study met its primary end point with an ORR of 16% (P = .0341) with copanlisib showing clinical activity in select tumors with PIK3CA mutation in the refractory setting.

Journal of Clinical Oncology

Trastuzumab Emtansine Plus Pertuzumab Versus Taxane Plus Trastuzumab Plus Pertuzumab After Anthracycline for High-Risk Human Epidermal Growth Factor Receptor 2-Positive Early Breast Cancer: The Phase III KAITLIN Study

Krop IE, Winer EP

PURPOSE: We aimed to improve efficacy and reduce toxicity of high-risk human epidermal growth factor receptor 2 (HER2)-positive early breast cancer (EBC) treatment by replacing taxanes and trastuzumab with trastuzumab emtansine (T-DM1).
METHODS: The phase III KAITLIN study (NCT01966471) included adults with excised HER2-positive EBC (node-positive or node-negative, hormone receptor-negative, and tumor > 2.0 cm). Postsurgery, patients were randomly assigned 1:1 to anthracycline-based chemotherapy (three-four cycles) and then 18 cycles of T-DM1 plus pertuzumab (AC-KP) or taxane (three-four cycles) plus trastuzumab plus pertuzumab (AC-THP). Adjuvant radiotherapy/endocrine therapy was permitted. Coprimary end points were invasive disease-free survival (IDFS) in the intention-to-treat node-positive and overall populations with hierarchical testing.
RESULTS: The median follow-up was 57.1 months (interquartile range, 52.1-60.1 months) for AC-THP (n = 918) and 57.0 months (interquartile range, 52.1-59.8 months) for AC-KP (n = 928). There was no significant IDFS difference between arms in the node-positive (n = 1,658; stratified hazard ratio [HR], 0.97; 95% CI, 0.71 to 1.32) or overall population (n = 1846; stratified HR, 0.98; 95% CI, 0.72 to 1.32). In the overall population, the three-year IDFS was 94.2% (95% CI, 92.7 to 95.8) for AC-THP and 93.1% (95% CI, 91.4 to 94.7) for AC-KP. Treatment completion rates (ie, 18 cycles) were 88.4% for AC-THP and 65.0% for AC-KP (difference driven by T-DM1 discontinuation because of laboratory abnormalities [12.5%]). Similar rates of grade ‚â• 3 (55.4% v 51.8%) and serious adverse events (23.3% v 21.4%) occurred with AC-THP and AC-KP, respectively. KP decreased clinically meaningful deterioration in global health status versus THP (stratified HR, 0.71; 95% CI, 0.62 to 0.80).
CONCLUSION: The primary end point was not met. Both arms achieved favorable IDFS. Trastuzumab plus pertuzumab plus chemotherapy remains the standard of care for high-risk HER2-positive EBC.

Journal of Clinical Oncology

Treatment Exposure and Discontinuation in the PALbociclib CoLlaborative Adjuvant Study of Palbociclib With Adjuvant Endocrine Therapy for Hormone Receptor-Positive/Human Epidermal Growth Factor Receptor 2-Negative Early Breast Cancer (PALLAS/AFT-05/ABCSG-42/BIG-14-03)

Mayer EL, Burstein HJ, Winer EP, Metzger Filho O

PURPOSE: The PALLAS study investigated whether the addition of palbociclib, an oral CDK4/6 inhibitor, to adjuvant endocrine therapy (ET) improves invasive disease-free survival (iDFS) in early hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) breast cancer. In this analysis, we evaluated palbociclib exposure and discontinuation in PALLAS.
METHODS: Patients with stage II-III HR+, HER2- disease were randomly assigned to 2 years of palbociclib with adjuvant ET versus ET alone. The primary objective was to compare iDFS between arms. Continuous monitoring of toxicity, dose modifications, and early discontinuation was performed. Association of baseline covariates with time to palbociclib reduction and discontinuation was analyzed with multivariable competing risk models. Landmark and inverse probability weighted per-protocol analyses were performed to assess the impact of drug persistence and exposure on iDFS.
RESULTS: Of the 5,743 patient analysis population (2,840 initiating palbociclib), 1,199 (42.2%) stopped palbociclib before 2 years, the majority (772, 27.2%) for adverse effects, most commonly neutropenia and fatigue. Discontinuation of ET did not differ between arms. Discontinuations for non-protocol-defined reasons were greater in the first 3 months of palbociclib, and in the first calendar year of accrual, and declined over time. No significant relationship was seen between longer palbociclib duration or 70% exposure intensity and improved iDFS. In the weighted per-protocol analysis, no improvement in iDFS was observed in patients receiving palbociclib versus not (hazard ratio 0.89; 95% CI, 0.72 to 1.11).
CONCLUSION: Despite observed rates of discontinuation in PALLAS, analyses suggest that the lack of significant iDFS difference between arms was not directly related to inadequate palbociclib exposure. However, the
discontinuation rate illustrates the challenge of introducing novel adjuvant treatments, and the need for interventions to improve persistence with oral cancer therapies.

Journal of Clinical Oncology

Who Is MB and What Does She Want?

Jacobson JO

My initial glimpse of MB was a virtual one as I reviewed her chart in preparation for her first visit. She was 87, living in a skilled nursing facility, nearly blind, and mostly deaf. She used a wheelchair, had early dementia, and had recently been diagnosed with neglected lung cancer. This is someone who needs to be quickly channeled toward a symptom-based approach, I judged. Pain medication and a brief course of palliative radiation to help for the short term should suffice. Unwillingly, my mind slid back to the long, exhausting days of my internal medicine residency decades ago. I recalled dreading admissions from nursing homes. These patients were widely perceived as old, infirm, difficult to manage, and worst of all, they inevitably presented disposition problems; the nursing homes almost never accepted them back. They could linger in the hospital for weeks on end awaiting placement.

Lancet Oncology

Durvalumab Plus Tremelimumab Alone or in Combination with Low-Dose or Hypofractionated Radiotherapy in Metastatic Non-Small-Cell Lung Cancer Refractory to Previous PD(L)-1 Therapy: An Open-Label, Multicentre, Randomised, Phase 2 Trial

Schoenfeld JD, Giobbie-Hurder A, Ranasinghe S, Kao KZ, Lako A, Tsuji J, Liu Y, Brennick RC, Lyon H, Cibuskis C, Lennon N, Jhaveri A, Yang L, Altreuter J, Gunasti L, Weirather JL, Mak RH, Awad MM, Rodig SJ, Wu CJ, Hodi FS

BACKGROUND: Patients with non-small-cell lung cancer (NSCLC) that is resistant to PD-1 and PD-L1 (PD[L]-1)-targeted therapy have poor outcomes. Studies suggest that radiotherapy could enhance antitumour immunity. Therefore, we investigated the potential benefit of PD-L1 (durvalumab) and CTLA-4 (tremelimumab) inhibition alone or combined with radiotherapy.
METHODS: This open-label, multicentre, randomised, phase 2 trial was done by the National Cancer Institute Experimental Therapeutics Clinical Trials Network at 18 US sites. Patients aged 18 years or older with metastatic NSCLC, an Eastern Cooperative Oncology Group performance status of 0 or 1, and progression during previous PD(L)-1 therapy were eligible. They were randomly assigned (1:1:1) in a web-based system by the study statistician using a permuted block scheme (block sizes of three or six) without stratification to receive either durvalumab (1500 mg intravenously every 4 weeks for a maximum of 13 cycles) plus tremelimumab (75 mg intravenously every 4 weeks for a maximum of four cycles) alone or with low-dose (0¬?5 Gy delivered twice per day, repeated for 2 days during each of the first four cycles of therapy) or hypofractionated radiotherapy (24 Gy total delivered over three 8-Gy fractions during the first cycle only), 1 week after initial durvalumab-tremelimumab administration. Study treatment was continued until 1 year or until progression. The primary endpoint was overall response rate (best locally assessed confirmed response of a partial or complete response) and, along with safety, was analysed in patients who received at least one dose of study therapy. The trial is registered with, NCT02888743, and is now complete.
FINDINGS: Between Aug 24, 2017, and March 29, 2019, 90 patients were enrolled and randomly assigned, of whom 78 (26 per group) were treated. This trial was stopped due to futility assessed in an interim analysis. At a median follow-up of 12¬?4 months (IQR 7¬?8-15¬?1), there were no differences in overall response rates between the durvalumab-tremelimumab alone group (three [11¬?5%, 90% CI 1¬?2-21¬?8] of 26 patients) and the low-dose radiotherapy group (two [7¬?7%, 0¬?0-16¬?3] of 26 patients; p=0¬?64) or the hypofractionated radiotherapy group (three [11¬?5%, 1¬?2-21¬?8] of 26 patients; p=0¬?99). The most common grade 3-4 adverse events were dyspnoea (two [8%] in the durvalumab-tremelimumab alone group; three [12%] in the low-dose radiotherapy group; and three [12%] in the hypofractionated radiotherapy group) and hyponatraemia (one [4%] in the durvalumab-tremelimumab alone group vs two [8%] in the low-dose radiotherapy group vs three [12%] in the hypofractionated radiotherapy group). Treatment-related serious adverse events occurred in one (4%) patient in the durvalumab-tremelimumab alone group (maculopapular rash), five (19%) patients in the low-dose radiotherapy group (abdominal pain, diarrhoea, dyspnoea, hypokalemia, and respiratory failure), and four (15%) patients in the hypofractionated group (adrenal insufficiency, colitis, diarrhoea, and hyponatremia). In the low-dose radiotherapy group, there was one death from respiratory failure potentially related to study therapy.
INTERPRETATION: Radiotherapy did not increase responses to combined PD-L1 plus CTLA-4 inhibition in patients with NSCLC resistant to PD(L)-1 therapy. However, PD-L1 plus CTLA-4 therapy could be a treatment option for some patients. Future studies should refine predictive biomarkers in this setting.
FUNDING: The US National Institutes of Health and the Dana-Farber Cancer Institute.

Lancet Oncology

Isatuximab Plus Pomalidomide and Low-Dose Dexamethasone Versus Pomalidomide and Low-Dose Dexamethasone in Patients with Relapsed and Refractory Multiple Myeloma (ICARIA-MM): Follow-Up Analysis of a Randomised, Phase 3 Study

Richardson PG, Anderson KC

BACKGROUND: The primary analysis of the ICARIA-MM study showed significant improvement in progression-free survival with addition of isatuximab to pomalidomide-dexamethasone in relapsed and refractory multiple myeloma. Here, we report a prespecified updated overall survival analysis at 24 months after the primary analysis.
METHODS: In this randomised, multicentre, open-label, phase 3 study adult patients (aged 18 years) with relapsed and refractory multiple myeloma who had received at least two previous lines of therapy, including lenalidomide and a proteasome inhibitor, and had an Eastern Cooperative Oncology Group performance status of 0-2 were recruited from 102 hospitals in 24 countries across Europe, North America, and the Asia-Pacific regions. Patients were excluded if they had anti-CD38 refractory disease or previously received pomalidomide. Patients were randomly assigned (1:1), using an interactive response technology with permuted blocked randomisation (block size of four) and stratified by number of previous treatment lines (2-3 vs >3) and aged (FINDINGS: Between Jan 10, 2017, and Feb 2, 2018, 387 patients were screened and 307 randomly assigned to either the isatuximab (n=154) or control group (n=153). Median follow-up at data cutoff (Oct 1, 2020) was 35¬?3 months (IQR 33¬?5-37¬?4). Median overall survival was 24¬?6 months (95% CI 20¬?3-31¬?3) in the isatuximab group and 17¬?7 months (14¬?4-26¬?2) in the control group (hazard ratio 0¬?76 [95% CI 0¬?57-1¬?01]; one-sided log-rank p=0¬?028, not crossing prespecified stopping boundary). The most common grade 3 or worse treatment-emergent adverse events in the isatuximab group versus the control group were neutropenia (76 [50%] of 152 patients vs 52 [35%] of 149 patients), pneumonia (35 [23%] vs 31 [21%]), and thrombocytopenia (20 [13%] vs 18 [12%]). Serious treatment-emergent adverse events were observed in 111 (73%) patients in the isatuximab group and 90 (60%) patients in the control group. Two (1%) treatment-related deaths occurred in the isatuximab group (one due to sepsis and one due to cerebellar infarction) and two (1%) occurred in the control group (one due to pneumonia and one due to urinary tract infection).
INTERPRETATION: Addition of isatuximab plus pomalidomide-dexamethasone resulted in a 6¬?9-month difference in median overall survival compared with pomalidomide-dexamethasone and is a new standard of care for lenalidomide-refractory and proteasome inhibitor-refractory or relapsed multiple myeloma. Final overall survival analysis follow-up is ongoing.
FUNDING: Sanofi.

Lancet Oncology

Patient-Reported Outcomes with First-Line Nivolumab Plus Cabozantinib Versus Sunitinib in Patients with Advanced Renal Cell Carcinoma Treated in CheckMate 9ER: An Open-Label, Randomised, Phase 3 Trial

Choueiri TK

BACKGROUND: In the CheckMate 9ER trial, patients with advanced renal cell carcinoma who received first-line nivolumab plus cabozantinib had significantly better progression-free survival compared with those given sunitinib. In this study, we aimed to describe the patient-reported outcome (PRO) results from CheckMate 9ER.
METHODS: In this open-label, randomised, phase 3 trial done in 125 cancer centres, urology centres, and hospitals across 18 countries, patients aged 18 years or older with previously untreated advanced renal cell carcinoma with a clear-cell component, a Karnofsky performance status of 70% or more, and available tumour tissue were randomly assigned (1:1) via interactive response technology to nivolumab 240 mg intravenously every 2 weeks plus oral cabozantinib 40 mg per day, or oral sunitinib 50 mg per day monotherapy for 4 weeks in 6-week cycles. The primary endpoint of progression-free survival was reported previously. PROs were analysed as prespecified exploratory endpoints at common timepoints (at baseline and every 6 weeks) until week 115. Disease-related symptoms were evaluated using the 19-item Functional Assessment of Cancer Therapy-Kidney Symptom Index (FKSI-19), and global health status was assessed with the three-level EQ-5D (EQ-5D-3L) visual analogue scale (VAS) and UK utility index. PRO analyses were done in the intention-to-treat population. Change from baseline was assessed using mixed-model repeated measures. A time-to-deterioration analysis was done for first and confirmed deterioration events. This study is registered with, NCT03141177, and is closed to recruitment.
FINDINGS: Between Sept 11, 2017, and May 14, 2019, 323 patients were randomly assigned to nivolumab plus cabozantinib and 328 to sunitinib. Median follow-up was 23¬?5 months (IQR 21¬?0-26¬?5). At baseline, patients in both groups reported low symptom burden (FKSI-19 disease-related symptoms version 1 mean scores at baseline were 30¬?24 [SD 5¬?19] for the nivolumab plus cabozantinib group and 30¬?06 [5¬?03] for the sunitinib group). Change from baseline in PRO scores indicated that nivolumab plus cabozantinib was associated with more favourable outcomes versus sunitinib (treatment difference 2¬?38 [95% CI 1¬?20-3¬?56], nominal p<0¬?0001, effect size 0¬?33 [95% CI 0¬?17-0¬?50] for FKSI-19 total score; 1¬?33 [0¬?84-1¬?83], nominal p<0¬?0001, 0¬?45 [0¬?28-0¬?61] for FKSI-19 disease-related symptoms version 1; 3¬?48 [1¬?58-5¬?39], nominal p=0¬?0004, 0¬?30 [0¬?14-0¬?47] for EQ-5D-3L VAS; and 0¬?04 [0¬?01-0¬?07], nominal p=0¬?0036, 0¬?25 [0¬?08-0¬?41] for EQ-5D-3L UK utility index), reaching significance at most timepoints. Nivolumab plus cabozantinib was associated with decreased risk of clinically meaningful deterioration for FKSI-19 total score compared with sunitinib (first deterioration event hazard ratio 0¬?70 [95% CI 0¬?56-0¬?86], nominal p=0¬?0007; confirmed deterioration event 0¬?63 [0¬?50-0¬?80], nominal p=0¬?0001).
INTERPRETATION: PROs were maintained or improved with nivolumab plus cabozantinib versus sunitinib. Compared with sunitinib, nivolumab plus cabozantinib significantly delayed time to deterioration of patient-reported outcome scores. These results suggest a benefit for nivolumab plus cabozantinib compared with sunitinib in the treatment of patients with advanced renal cell carcinoma.
FUNDING: Bristol Myers Squibb.

Lancet Oncology

Safety of Adjuvant CDK4/6 Inhibitors During the COVID-19 Pandemic

Mayer EL

During the COVID-19 pandemic, it was observed that patients with cancer who were undergoing treatment had an increased risk of contracting COVID-19, and a more severe course of infection, compared with individuals who did not have a history of cancer. As this increased risk was not associated with more frequent exposure to health-care systems, it was thought to reflect a weakened immune system caused by the disease itself or anticancer treatment.

Lancet Oncology

Therapeutic Avenues for Cancer Neuroscience: Translational Frontiers and Clinical Opportunities

Shi DD, Guo JA, Hoffman HI, Su J, Mino-Kenudson M, Barth JL, Schenkel JM, Loeffler JS, Shih HA, Hong TS, Wo JY, Aguirre AJ, Wen PY, Hwang WL

With increasing attention on the essential roles of the tumour microenvironment in recent years, the nervous system has emerged as a novel and crucial facilitator of cancer growth. In this Review, we describe the foundational, translational, and clinical advances illustrating how nerves contribute to tumour proliferation, stress adaptation, immunomodulation, metastasis, electrical hyperactivity and seizures, and neuropathic pain. Collectively, this expanding knowledge base reveals multiple therapeutic avenues for cancer neuroscience that warrant further exploration in clinical studies. We discuss the available clinical data, including ongoing trials investigating novel agents targeting the tumour-nerve axis, and the therapeutic potential for repurposing existing neuroactive drugs as an anti-cancer approach, particularly in combination with established treatment regimens. Lastly, we discuss the clinical challenges of these treatment strategies and highlight unanswered questions and future directions in the burgeoning field of cancer neuroscience.

Nature Communications

PPM1D Mutations are Oncogenic Drivers of De Novo Diffuse Midline Glioma Formation

Khadka P, Lu S, Buchan G, Gionet G, Dubois F, Shih J, Zhang S, Greenwald NF, Zack T, Shapira O, Pelton K, Georgis Y, Jarmale S, Melanson R, Bonanno K, Schoolcraft K, Miller PG, Condurat AL, Gonzalez EM, Qian K, Morin E, Lupien LE, Rendo V, Digiacomo J, Wang D, Zhou K, Kumbhani R, Sinai CE, Becker S, Schneider R, Vogelzang J, Krug K, Goodale A, Abid T, Kalani Z, Piccioni F, Beroukhim R, Persky NS, Root DE, Ebert BL, Kieran MW, Keshishian H, Ligon KL, Carr SA, Bandopadhayay P

The role of PPM1D mutations in de novo gliomagenesis has not been systematically explored. Here we analyze whole genome sequences of 170 pediatric high-grade gliomas and find that truncating mutations in PPM1D that increase the stability of its phosphatase are clonal driver events in 11% of Diffuse Midline Gliomas (DMGs) and are enriched in primary pontine tumors. Through the development of DMG mouse models, we show that PPM1D mutations potentiate gliomagenesis and that PPM1D phosphatase activity is required for in vivo oncogenesis. Finally, we apply integrative phosphoproteomic and functional genomics assays and find that oncogenic effects of PPM1D truncation converge on regulators of cell cycle, DNA damage response, and p53 pathways, revealing therapeutic vulnerabilities including MDM2 inhibition.


Tissue Eosinophils Express the IL-33 Receptor ST2 and Type 2 Cytokines in Patients with Eosinophilic Esophagitis

Uchida AM, Lenehan PJ, Vimalathas P, Miller KC, Valencia-Yang M, Qiang L, Canha LA, Ali LR, Dougan M, Garber JJ, Dougan SK

American Journal of Hematology

Phase 2 Studies of Lenalidomide, Subcutaneous Bortezomib, and Dexamethasone as Induction Therapy in Patients with Newly Diagnosed Multiple Myeloma

Laubach JP, Yee AJ, Rosenblatt J, DiPietro H, Cummings K, Savell A, Masone K, Guerrero Garcia T, Bianchi G, Richardson PG

American Journal of Transplantation

Ex Vivo Generation of Regulatory T Cells from Liver Transplant Recipients Using Costimulation Blockade

Shimozawa K, Contreras-Ruiz L, Sousa S, Zhang R, Bhatia U, Crisalli KC, Brennan LL, Turka LA, Markmann JF, Guinan EC

Annals of Surgical Oncology

Optimizing Axillary Management in Clinical T1-2N0 Mastectomy Patients with Positive Sentinel Lymph Nodes

Kantor O, Means J, Grossmith S, Dey T, Bellon JR, Mittendorf EA, King TA

Blood Advances

Abatacept for GVHD Prophylaxis Can Reduce Racial Disparities by Abrogating the Impact of Mismatching in Unrelated Donor Stem Cell Transplantation

Bratrude B, Betz K, Duncan C, Kean LS, Horan JT

Blood Advances

Response and Survival Predictors in a Cohort of 319 Patients with Waldenström Macroglobulinemia Treated with Ibrutinib Monotherapy

Castillo JJ, Sarosiek SR, Gustine JN, Flynn CA, Leventoff CR, White TP, Meid K, Guerrera ML, Kofides A, Liu X, Munshi M, Tsakmaklis N, Hunter ZR, Patterson CJ, Branagan AR, Treon SP

BMC Women’s Health

Cardiometabolic Risk Factors, Physical Activity, and Postmenopausal Breast Cancer Mortality: Results from the Women's Health Initiative

Dieli-Conwright CM, Manson JE

British Journal of Haematology

A British View on the Management of Waldenström Macroglobulinemia - Response to Pratt Et Al

Castillo JJ

British Journal of Haematology

Patient-Reported Outcomes in Relapsed/Refractory Multiple Myeloma Treated with Melflufen Plus Dexamethasone: Analyses from the Phase II HORIZON Study

Laubach J, Nadeem O, Richardson PG

Breast Cancer Research and Treatment

Perceptions of Patients and Medical Oncologists Toward Biospecimen Donation in the Setting of Abnormal Breast Imaging Findings

Seah DS, Tayob N, Leone JP, Hu J, Yin J, Hughes M, Scott SM, Lederman RI, Frank E, Sohl JJ, Erick TK, Peppercorn J, Winer EP, Silverman SG, Come SE, Lin NU

Cancer Epidemiology, Biomarkers and Prevention

Regular Aspirin Use and Mortality in Patients with Multiple Myeloma

Marinac CR, Lee DH, Rebbeck TR, Rosner B, Bustoros M, Ghobrial IM, Birmann BM

Cancer Immunology Research

Linking a Trio of Molecular Features in Clear-Cell Renal Cell Carcinoma

Labaki C, Van Allen EM, Choueiri TK

Cancer Immunology Research

Spatial Organization and Prognostic Significance of NK and NKT-like Cells via Multimarker Analysis of the Colorectal Cancer Microenvironment

Väyrynen JP, Haruki K, Lau MC, Väyrynen SA, Ugai T, Akimoto N, Zhong R, Zhao M, Dias Costa A, Bell P, Takashima Y, Fujiyoshi K, Arima K, Kishikawa J, Shi SS, Twombly TS, Song M, Wu K, Chan AT, Zhang X, Meyerhardt JA, Giannakis M, Ogino S, Nowak JA

Cancer Research

A Novel HER2-Selective Kinase Inhibitor is Effective in HER2 Mutant and Amplified Non-Small Cell Lung Cancer

Son J, Jang J, Beyett TS, Eum Y, Haikala HM, Verano A, Lin M, Hatcher JM, Kwiatkowski NP, Eser PÖ, Poitras MJ, Wang S, Xu M, Gokhale PC, Eck MJ, Jänne PA


Spatial and Genomic Correlates of HIV-1 Integration Site Targeting

Singh PK, Bedwell GJ, Engelman AN


Light-Controllable Binary Switch Activation of CAR T Cells

Kobayashi A, Nobili A, Neier SC, Distel RJ, Novina CD

Clinical Cancer Research

Clinical Significance of PIK3CA and ESR1 Mutations in circulating tumor DNA: Analysis from the MONARCH 2 Study of Abemaciclib Plus Fulvestrant

Tolaney SM

Clinical Breast Cancer

Feasibility of an Online Patient Community to Support Older Women with Newly Diagnosed Breast Cancer

Occhiogrosso RH, Ren S, Tayob N, Li T, Gagnon HC, Freedman RA

Clinical Cancer Research

Microenvironment is a Key Determinant of Immune Checkpoint Inhibitor Response

Anderson KC, Tai YT

Clinical Cancer Research

Neoadjuvant and Adjuvant Nivolumab and Lirilumab in Patients with Recurrent, Resectable Squamous Cell Carcinoma of the Head and Neck

Hanna GJ, O'Neill A, Shin KY, Wong K, Jo VY, Quinn CT, Cutler JM, Flynn M, Lizotte PH, Annino DJ Jr, Goguen LA, Rettig EM, Sethi RKV, Lorch JH, Schoenfeld JD, Margalit DN, Tishler RB, Desai AM, Cavanaugh ME, Paweletz CP, Egloff AM, Uppaluri R, Haddad RI

Clinical Cancer Research

Phase 1b Clinical Trial with Alpelisib plus Olaparib for Patients with Advanced Triple-Negative Breast Cancer

Batalini F, Xiong N, Tayob N, Polak M, Shapiro GI, Adalsteinsson V, Winer EP, Konstantinopoulos PA, D'Andrea AD, Matulonis UA, Wulf GM, Mayer EL

Clinical Cancer Research

Praluzatamab Ravtansine, a CD166-Targeting Antibody-Drug Conjugate, in Patients with Advanced Solid Tumors: An Open-Label Phase 1/2 Trial

Liu JF

Clinical Cancer Research

Updated Integrated Analysis of the Efficacy and Safety of Entrectinib in Patients with NTRK Fusion-Positive Solid Tumors

Demetri GD, Lin JJ

Clinical Gastroenterology and Hepatology

The Performance of AFP, AFP-3, DCP as Biomarkers for Detection of Hepatocellular Carcinoma (HCC). A Phase 3 Biomarker Study in the United States

Tayob N

Clinical Oncology (Royal College of Radiologists)

Hidden in Plain Sight: Clinical Informaticians are the Oncology Subspecialists You Did Not Know You Needed

Kim E, Bitterman DS, Kann BH, Mak RH, Upadhyay VA, Zhang HM

Current Opinion in Immunology

CBASS Phage Defense and Evolution of Antiviral Nucleotide Signaling

Duncan-Lowey B, Kranzusch PJ

Expert Review of Anticancer Therapy

Understanding resistance to immune checkpoint inhibitors in Advanced Breast Cancer

Tarantino P, Garrido-Castro AC, McAllister SS, Guerriero JL, Mittendorf E, Tolaney SM

Gynecologic Oncology

Patient Reported Outcomes for Cisplatin and Radiation Followed by Carboplatin/Paclitaxel Versus Carboplatin/Paclitaxel for Locally Advanced Endometrial Carcinoma: An NRG Oncology Study

Matulonis UA

Health Communication

Beyond Educating the Masses: The Role of Public Health Communication in Addressing Socioeconomic- and Residence-based Disparities in Tobacco Risk Perception

Bekalu MA, Gundersen DA, Viswanath K

Hematology/Oncology Clinics of North America

Biology and Treatment of Meningiomas: A Reappraisal

McFaline-Figueroa JR, Bi WL

Hematology/Oncology Clinics of North America

Is There a Role for Immunotherapy in Central Nervous System Cancers?

Reardon DA

Hematology/Oncology Clinics of North America

Primary Central Nervous System Lymphomas

Chukwueke U, Nayak L

International Journal of Radiation Oncology, Biology, Physics

Boosting the Abscopal Effect Using Immunogenic Biomaterials with Varying Radiation Therapy Field Sizes

Yasmin-Karim S, Ziberi B, Wirtz J, Bih N, Moreau M, Guthier R, Ainsworth V, Makrigiorgos GM, Wei X, Nguyen PL, Ngwa W

Journal of Cell Biology

Sarm1 Activation Produces cADPR to Increase Intra-Axonal Ca++ and Promote Axon Degeneration in PIPN

Li Y, Pazyra-Murphy MF, Tang S, Bergholz JS, Jiang T, Zhao JJ, Segal RA

Journal of Clinical Investigation

Colorectal Cancer: The Facts in the Case of the Microbiota

Clay SL, Fonseca-Pereira D, Garrett WS

Journal of Clinical Investigation

Clonal Hematopoiesis in Sickle Cell Disease

Liggett LA, Cato LD, Williams DA, Natarajan P, Sankaran VG

Journal of ImmunoTherapy of Cancer

Soluble PD-L1 as an Early Marker of Progressive Disease on Nivolumab

Mahoney KM, Yuan L, McDermott DF, Stephen Hodi F, Choueiri TK, Freeman GJ

Journal of Pain and Symptom Management

Development, Implementation, and Outcomes of a Serious Illness Care Community of Practice

Maloney FL, Hawrusik R, Paquette E, Takahashi K, Downey N, Paladino J, Bernacki RE

Journal of Palliative Medicine

"Good Grief": An Opportunity to Grow, Integrate, or Something Else?

Bloomhardt H, Frechette E

Journal of Sleep Research

A Population-Based Psychometric Analysis of the Insomnia Severity Index in Black Women with and without a History of Cancer

Yusufov M, Recklitis C, Zhou ES

Journal of Virology

Analysis of Glycosylation and Disulfide Bonding of Wild-Type SARS-CoV-2 Spike Glycoprotein

Zhang S, Anang S, Sodroski JG

JCO Precision Oncology

Phase Ib SEASTAR Study: Combining Rucaparib and Sacituzumab Govitecan in Patients with Cancer with or without Mutations in Homologous Recombination Repair Genes

Jeselsohn R, Shapiro GI

JCO Precision Oncology

Phase II Study of Taselisib in PIK3CA-Mutated Solid Tumors Other Than Breast and Squamous Lung Cancer: Results From the NCI-MATCH ECOG-ACRIN Trial (EAY131) Subprotocol I

Krop IE, Jegede OA, Gray RJ, Wang V, Flaherty KT

Lancet Haematology

Consensus Guidelines and Recommendations for Infection Prevention in Multiple Myeloma: A Report from the International Myeloma Working Group

Raje NS, O'Donnell E, Yee A, Branagan A, Anderson KC, Prabhala RH, Munshi NC

Lancet Public Health

Work and Worker Health in the Post-Pandemic World: A Public Health Perspective

Peters SE, Dennerlein JT, Wagner GR, Sorensen G


Long-Term Follow-Up of Ibrutinib Monotherapy in Treatment-Naive Patients with Waldenström Macroglobulinemia

Castillo JJ, Meid K, Gustine JN, Leventoff C, White T, Flynn CA, Sarosiek S, Demos MG, Guerrera ML, Kofides A, Liu X, Munshi M, Tsakmaklis N, Xu L, Yang G, Branagan AR, O'Donnell E, Raje N, Yee AJ, Patterson CJ, Hunter ZR, Treon SP


Targeting Serine Hydroxymethyltransferases 1 and 2 for T-Cell Acute Lymphoblastic Leukemia Therapy

Pikman Y, Ocasio-Martinez N, Alexe G, Dimitrov B, Kitara S, Robichaud AL, Conway AS, Ross L, Qi J, Vander Heiden MG, Stegmaier K


YBX1 Mediates Translation of Oncogenic Transcripts to Control Cell Competition in AML

Perner F, Xiong Y, Todorova K, Hatton C, Murphy C, Armstrong SA, Mandinova A

Melanoma Research

Sensitivity of Treatment-Free Survival to Subgroup Analyses in Patients with Advanced Melanoma Treated with Immune Checkpoint Inhibitors

Mantia CM, Werner L, McDermott DF, Regan MM

Molecular Cancer Research

Building Tools for Machine Learning and Artificial Intelligence in Cancer Research: Best Practices and a Case Study with the PathML Toolkit for Computational Pathology

Rosenthal J, Carelli R, Brundage D, Halbert E, Nyman J, Hari SN, Van Allen EM, Umeton R, Loda M

Molecular Cancer Therapeutics

Combination of Type I and Type II MET Tyrosine Kinase Inhibitors as Therapeutic Approach to Prevent Resistance

Bahcall M, Paweletz CP, Kuang Y, Taus LJ, Dholakia KH, Lau CJ, Gokhale PC, Chopade PR, Hong F, Wei Z, Köhler J, Kirschmeier PT, Guo S, Wang S, Jänne PA


The Use of External Control Data for Predictions and Futility Interim Analyses in Clinical Trials

Ventz S, Rahman R, Wen PY, Alexander BM, Trippa L

Palliative Medicine

"I Think That She Would Have Wanted. . .": Qualitative Interviews with Bereaved Caregivers Reveal Complexity in Measuring Goal-Concordant Care at the End of Life

Durieux BN, Berrier A, Gray TF, Lakin JR, Cunningham R, Morris SE, Tulsky JA, Sanders JJ

Pediatric Blood and Cancer

Anatomic Patterns of Relapse and Progression Following Treatment with (131) I-MIBG in Relapsed or Refractory Neuroblastoma

DuBois SG, Haas-Kogan DA

Pediatric Blood and Cancer

Early Parental Knowledge of Late Effect Risks in Children with Cancer

Carpenter K, Scavotto M, McGovern A, Kenney LB, Mack JW, Greenzang KA

Prostate Cancer

MRI-Based Radiotherapy Planning to Reduce Rectal Dose in Excess of Tolerance

Schmidt DR, Bhagwat M, Glazer DI, Moteabbed M, McMahon E, Loffredo MJ, Tempany CM, D'Amico AV

Prostate Cancer and Prostatic Diseases

Outcomes in Men with Metastatic Castration-Resistant Prostate Cancer Who Received Sipuleucel-T and No Immediate Subsequent Therapy: Experience at Dana Farber and in the PROCEED Registry

Wei XX, Kwak L, Hamid A, He M, Sweeney C, Choudhury AD


The Effects of a Clinic-Based Weight Loss Program on Health-Related Quality of Life and Weight Maintenance in Cancer Survivors: A Randomized Controlled Trial

Giobbie-Hurder A, Mayer EL, Tolaney SM, Partridge AH, Ligibel JA