Excellence in Science

Efficacy of Selpercatinib in RET-Altered Thyroid Cancers

BACKGROUND: RET mutations occur in 70% of medullary thyroid cancers, and RET fusions occur rarely in other thyroid cancers. In patients with RET-altered thyroid cancers, the efficacy and safety of selective RET inhibition are unknown.

RESULTS: In the first 55 consecutively enrolled patients with RET-mutant medullary thyroid cancer who had previously received vandetanib, cabozantinib, or both, the percentage who had a response was 69% (95% confidence interval [CI], 55 to 81), and 1-year progression-free survival was 82% (95% CI, 69 to 90). In 88 patients with RET-mutant medullary thyroid cancer who had not previously received vandetanib or cabozantinib, the percentage who had a response was 73% (95% CI, 62 to 82), and 1-year progression-free survival was 92% (95% CI, 82 to 97). In 19 patients with previously treated RET fusion–positive thyroid cancer, the percentage who had a response was 79% (95% CI, 54 to 94), and 1-year progression-free survival was 64% (95% CI, 37 to 82). The most common adverse events of grade 3 or higher were hypertension (in 21% of the patients), increased alanine aminotransferase level (in 11%), increased aspartate aminotransferase level (in 9%), hyponatremia (in 8%), and diarrhea (in 6%). Of all 531 patients treated, 12 (2%) discontinued selpercatinib owing to drug-related adverse events.

CONCLUSIONS: In this phase 1–2 trial, selpercatinib showed durable efficacy with mainly low-grade toxic effects in patients with medullary thyroid cancer with and without previous vandetanib or cabozantinib treatment. (Funded by Loxo Oncology and others; LIBRETTO-001 ClinicalTrials. gov number, NCT03157128.)

LJ Wirth, E Sherman, B Robinson, B Solomon, H Kang, J Lorch, F Worden, M Brose, J Patel, S Leboulleux, Y Godbert, F Barlesi, JC Morris, TK Owonikoko, DSW Tan, O Gautschi, J Weiss, C de la Fouchardière, ME Burkard, J Laskin, MH Taylor, M Kroiss, J Medioni, JW Goldman, TM Bauer, B Levy, VW Zhu, N Lakhani, V Moreno, K Ebata, M Nguyen, D Heirich, EY Zhu, X Huang, L Yang, J Kherani, SM Rothenberg, A Drilon, V Subbiah, MH Shah, and ME Cabanillas

Read more in The New England Journal of Medicine

Cystine transporter regulation of pentose phosphate pathway dependency and disulfide stress exposes a targetable metabolic vulnerability in cancer

SLC7A11-mediated cystine uptake is critical for maintaining redox balance and cell survival. Here we show that this comes at a significant cost for cancer cells with high levels of SLC7A11. Actively importing cystine is potentially toxic due to its low solubility, forcing cancer cells with high levels of SLC7A11 (SLC7A11^high) to constitutively reduce cystine to the more soluble cysteine. This presents a significant drain on the cellular NADPH pool and renders such cells dependent on the pentose phosphate pathway. Limiting glucose supply to SLC7A11^high cancer cells results in marked accumulation of intracellular cystine, redox system collapse and rapid cell death, which can be rescued by treatments that prevent disulfide accumulation. We further show that inhibitors of glucose transporters selectively kill SLC7A11^high cancer cells and suppress SLC7A11^high tumour growth. Our results identify a coupling between SLC7A11-associated cystine metabolism and the pentose phosphate pathway, and uncover an accompanying metabolic vulnerability for therapeutic targeting in SLC7A11^high cancers.

Xiaoguang Liu, Kellen Olszewski, Yilei Zhang, Esther W. Lim, Jiejun Shi, Xiaoshan Zhang, Jie Zhang, Hyemin Lee, Pranavi Koppula, Guang Lei, Li Zhuang, M. James You, Bingliang Fang, Wei Li, Christian M. Metallo, Masha V. Poyurovsky, and Boyi Gan

Read more in Nature Cell Biology

Comprehensive Molecular Characterization Identifies Distinct Genomic and Immune Hallmarks of Renal Medullary Carcinoma

Renal medullary carcinoma (RMC) is a highly lethal malignancy that mainly afflicts young individuals of African descent and is resistant to all targeted agents used to treat other renal cell carcinomas. Comprehensive genomic and transcriptomic profiling of untreated primary RMC tissues was performed to elucidate the molecular landscape of these tumors. We found that RMC was characterized by high replication stress and an abundance of focal copy-number alterations associated with activation of the stimulator of the cyclic GMP-AMP synthase interferon genes (cGAS-STING) innate immune pathway. Replication stress conferred a therapeutic vulnerability to drugs targeting DNA-damage repair pathways. Elucidation of these previously unknown RMC hallmarks paves the way to new clinical trials for this rare but highly lethal malignancy

P Msaouel, GG Malouf, X Su, H Yao, DN Tripathi, M Soeung, J Gao, P Rao, C Coarfa, CJ Creighton, JP Bertocchio, S Kunnimalaiyaan, AS Multani, J Blando, R He, DD Shapiro, L Perelli, S Srinivasan, F Carbone, PG Pilié, M Karki, RNH Seervai, BH Vokshi, D Lopez-Terrada, EH Cheng, X Tang, W Lu, II Wistuba, TC Thompson, I Davidson, V Giuliani, K Schlacher, A Carugo, TP Heffernan, P Sharma, JA Karam, CG Wood, CL Walker, G Genovese, and NM Tannir

Read more in Cancer Cell

Tucatinib, Trastuzumab, and Capecitabine for HER2-Positive Metastatic Breast Cancer

BACKGROUND: Patients with human epidermal growth factor receptor 2 (HER2)–positive metastatic breast cancer who have disease progression after therapy with multiple HER2-targeted agents have limited treatment options. Tucatinib is an investigational, oral, highly selective inhibitor of the HER2 tyrosine kinase.

RESULTS: Progression-free survival at 1 year was 33.1% in the tucatinib-combination group and 12.3% in the placebo-combination group (hazard ratio for disease progression or death, 0.54; 95% confidence interval [CI], 0.42 to 0.71; P<0.001), and the median duration of progression- free survival was 7.8 months and 5.6 months, respectively. Overall survival at 2 years was 44.9% in the tucatinib-combination group and 26.6% in the placebo-combination group (hazard ratio for death, 0.66; 95% CI, 0.50 to 0.88; P=0.005), and the median overall survival was 21.9 months and 17.4 months, respectively. Among the patients with brain metastases, progression-free survival at 1 year was 24.9% in the tucatinib-combination group and 0% in the placebo-combination group (hazard ratio, 0.48; 95% CI, 0.34 to 0.69; P<0.001), and the median progression- free survival was 7.6 months and 5.4 months, respectively. Common adverse events in the tucatinib group included diarrhea, palmar–plantar erythrodysesthesia syndrome, nausea, fatigue, and vomiting. Diarrhea and elevated aminotransferase levels of grade 3 or higher were more common in the tucatinib-combination group than in the placebo-combination group.

CONCLUSIONS: In heavily pretreated patients with HER2-positive metastatic breast cancer, including those with brain metastases, adding tucatinib to trastuzumab and capecitabine resulted in better progression-free survival and overall survival outcomes than adding placebo; the risks of diarrhea and elevated aminotransferase levels were higher with tucatinib. (Funded by Seattle Genetics; HER2CLIMB ClinicalTrials. gov number, NCT02614794.)

R.K. Murthy, S. Loi, A. Okines, E. Paplomata, E. Hamilton, S.A. Hurvitz, N.U. Lin, V. Borges, V. Abramson, C. Anders, P.L. Bedard, M. Oliveira, E. Jakobsen, T. Bachelot, S.S. Shachar, V. Müller, S. Braga, F.P. Duhoux, R. Greil, D. Cameron, L.A. Carey, G. Curigliano, K. Gelmon, G. Hortobagyi, I. Krop, S. Loibl, M. Pegram, D. Slamon, M.C. Palanca‑Wessels, L. Walker, W. Feng, and E.P. Winer

Read more in The New England Journal of Medicine

B cells and tertiary lymphoid structures promote immunotherapy response

Treatment with immune checkpoint blockade (ICB) has revolutionized cancer therapy. Until now, predictive biomarkers and strategies to augment clinical response have largely focused on the T cell compartment. However, other immune subsets may also contribute to anti-tumour immunity, although these have been less well-studied in ICB treatment. A previously conducted neoadjuvant ICB trial in patients with melanoma showed via targeted expression profiling that B cell signatures were enriched in the tumours of patients who respond to treatment versus non-responding patients. To build on this, here we performed bulk RNA sequencing and found that B cell markers were the most differentially expressed genes in the tumours of responders versus non-responders. Our findings were corroborated using a computational method (MCP-counter) to estimate the immune and stromal composition in this and two other ICB-treated cohorts (patients with melanoma and renal cell carcinoma). Histological evaluation highlighted the localization of B cells within tertiary lymphoid structures. We assessed the potential functional contributions of B cells via bulk and single-cell RNA sequencing, which demonstrate clonal expansion and unique functional states of B cells in responders. Mass cytometry showed that switched memory B cells were enriched in the tumours of responders. Together, these data provide insights into the potential role of B cells and tertiary lymphoid structures in the response to ICB treatment, with implications for the development of biomarkers and therapeutic targets.

BA Helmink, SM Reddy, J Gao, S Zhang, R Basar, R Thakur, K Yizhak, M Sade-Feldman, J Blando, G Han, V Gopalakrishnan, Y Xi, H Zhao, RN Amaria, HA Tawbi, AP Cogdil, W Liu, VS LeBleu, FG Kugeratski, S Patel, MA Davies, P Hwu, JE Lee, JE Gershenwald, A Lucci, R Arora, S Woodman, E Keung, PO Gaudreau, A Reuben, CN Spencer, EM Burton, LE Haydu, AJ Lazar, R Zapassodi, CW Hudgens, DA Ledesma, S Ong, M Bailey, S Warren, D Rao, O Krijgsman, EA Rozeman, D Peeper, CU Blank, TN Schumacher, LH Butterfield, MA Zelazowska, KM McBride, R Kalluri, J Allison, F Petitprez, W Herman Fridman, C Sautès-Fridman, N Hacohen, K Rezvani, P Sharma, MT Tetzlaff, L Wang, and JA Wargo

Read more in Nature

Patient-Reported Outcomes Through 5 Years for Active Surveillance, Surgery, Brachytherapy, or External Beam Radiation With or Without Androgen Deprivation Therapy for Localized Prostate Cancer

IMPORTANCE: Understanding adverse effects of contemporary treatment approaches for men with favorable-risk and unfavorable-risk localized prostate cancer could inform treatment selection.

RESULTS:  A total of 2005 men met inclusion criteria and completed the baseline and at least 1 postbaseline survey (median [interquartile range] age, 64 [59-70] years; 1529 of 1993 participants [77%] were non-Hispanic white). For men with favorable-risk prostate cancer, nerve-sparing prostatectomy was associated with worse urinary incontinence at 5 years (adjusted mean difference, -10.9 [95% CI, -14.2 to -7.6]) and sexual function at 3 years (adjusted mean difference, -15.2 [95% CI, -18.8 to -11.5]) compared with active surveillance. Low-dose-rate brachytherapy was associated with worse urinary irritative (adjusted mean difference, -7.0 [95% CI, -10.1 to -3.9]), sexual (adjusted mean difference, -10.1 [95% CI, -14.6 to -5.7]), and bowel (adjusted mean difference, -5.0 [95% CI, -7.6 to -2.4]) function at 1 year compared with active surveillance. EBRT was associated with urinary, sexual, and bowel function changes not clinically different from active surveillance at any time point through 5 years. For men with unfavorable-risk disease, EBRT with ADT was associated with lower hormonal function at 6 months (adjusted mean difference, -5.3 [95% CI, -8.2 to -2.4]) and bowel function at 1 year (adjusted mean difference, -4.1 [95% CI, -6.3 to -1.9]), but better sexual function at 5 years (adjusted mean difference, 12.5 [95% CI, 6.2-18.7]) and incontinence at each time point through 5 years (adjusted mean difference, 23.2 [95% CI, 17.7- 28.7]), than prostatectomy.

CONCLUSIONS AND RELEVANCE: In this cohort of men with localized prostate cancer, most functional differences associated with contemporary management options attenuated by 5 years. However, men undergoing prostatectomy reported clinically meaningful worse incontinence through 5 years compared with all other options, and men undergoing prostatectomy for unfavorable-risk disease reported worse sexual function at 5 years compared

Karen E. Hoffman, David F. Penson, Zhiguo Zhao, Li-Ching Huang, Ralph Conwill, Aaron A. Laviana, Daniel D. Joyce, Amy N. Luckenbaugh, Michael Goodman, Ann S. Hamilton, Xiao-Cheng Wu, Lisa E. Paddock, Antoinette Stroup, Matthew R. Cooperberg, Mia Hashibe, Brock B. O’Neil, Sherrie H. Kaplan, Sheldon Greenfield, Tatsuki Koyama, Daniel A. Barocas

Read more in JAMA

B cells are associated with survival and immunotherapy response in sarcoma

Soft-tissue sarcomas represent a heterogeneous group of cancer, with more than 50 histological subtypes. The clinical presentation of patients with different subtypes is often atypical, and responses to therapies such as immune checkpoint blockade vary widely. To explain this clinical variability, here we study gene expression profiles in 608 tumours across subtypes of soft-tissue sarcoma. We establish an immune-based classification on the basis of the composition of the tumour microenvironment and identify five distinct phenotypes: immune-low (A and B), immune-high (D and E), and highly vascularized (C) groups. In situ analysis of an independent validation cohort shows that class E was characterized by the presence of tertiary lymphoid structures that contain T cells and follicular dendritic cells and are particularly rich in B cells. B cells are the strongest prognostic factor even in the context of high or low CD8⁺ T cells and cytotoxic contents. The class-E group demonstrated improved survival and a high response rate to PD1 blockade with pembrolizumab in a phase 2 clinical trial. Together, this work confirms the immune subtypes in patients with soft-tissue sarcoma, and unravels the potential of B-cell-rich tertiary lymphoid structures to guide clinical decision-making and treatments, which could have broader applications in other diseases.

Florent Petitprez, Aurélien de Reyniès, Emily Z. Keung, Tom Wei-Wu Chen, Cheng-Ming Sun, Julien Calderaro, Yung-Ming Jeng, Li-Ping Hsiao, Laetitia Lacroix, Antoine Bougoüin, Marco Moreira, Guillaume Lacroix, Ivo Natario, Julien Adam, Carlo Lucchesi, Yec’han Laizet, Maud Toulmonde, Melissa A. Burgess, Vanessa Bolejack, Denise Reinke, Khalid M. Wani, Wei-Lien Wang, Alexander J. Lazar, Christina L. Roland, Jennifer A. Wargo, Antoine Italiano, Catherine Sautès-Fridman, Hussein A. Tawbi, and Wolf H. Fridman

Read more in Nature

Pan-Cancer Landscape and Analysis of ERBB2 Mutations Identifies Poziotinib as a Clinically Active Inhibitor and Enhancer of T-DM1 Activity

We characterized the landscape and drug sensitivity of ERBB2 (HER2) mutations in cancers. In 11 datasets (n = 211,726), ERBB2 mutational hotspots varied across 25 tumor types. Common HER2 mutants yielded differential sen­sitivities to eleven EGFR/HER2 tyrosine kinase inhibitors (TKIs) in vitro, and molecular dynamics simulations revealed that mutants with a reduced drug-binding pock­et volume were associated with decreased affinity for larger TKIs. Overall, poziotinib was the most potent HER2 mutant-selective TKI tested. Phase II clinical testing in ERBB2 exon 20-mutant non-small cell lung cancer resulted in a con­firmed objective response rate of 42% in the first 12 evaluable pa­tients. In pre-clinical models, pozi­otinib upregulated HER2 cell-sur­face expression and potentiated the activity of T-DM1, resulting in complete tumor regression with combination treatment.

Jacqulyne P. Robichaux, Yasir Y. Elamin, R.S.K. Vijayan, Monique B. Nilsson, Lemei Hu, Junqin He, Fahao Zhang, Marlese Pisegna, Alissa Poteete, Huiying Sun, Shuai Li, Ting Chen, Han Han, Marcelo Vailati Negrao, Jordi Rodon Ahnert, Lixia Diao, Jing Wang, Xiuning Le, Funda Meric-Bernstam, Mark Routbort, Brent Roeck, Zane Yang, Victoria M. Raymond, Richard B. Lanman, Garrett M. Frampton, Vincent A. Miller, Alexa B.Schrock, Lee A. Albacker, Kwok-kin Wong, Jason B. Cross and John V. Heymach

Read more in Cancer Cell