Medline ® Abstracts for References 36-40
Expanded access study of patients with advanced basal cell carcinoma treated with the Hedgehog pathway inhibitor, vismodegib.
Chang AL, Solomon JA, Hainsworth JD, Goldberg L, McKenna E, Day BM, Chen DM, Weiss GJ
J Am Acad Dermatol. 2014;70(1):60.
BACKGROUND: Vismodegib, a first-in-class Hedgehog pathway inhibitor, was US Food and Drug Administration (FDA) approved for advanced basal cell carcinomas (BCCs) based on a single, nonrandomized, phase-II trial. Consequently, additional clinical data are critical to confirm the efficacy and safety of vismodegib.
OBJECTIVE: We sought to assess efficacy and safety of vismodegib, while providing early drug access to patients with advanced BCC and limited treatment options.
METHODS: This was an open-label, multicenter study in patients with advanced BCC inappropriate for radiotherapy or surgery. Patients received 150 mg vismodegib daily until disease progression or intolerable toxicity. Tumor response was assessed via Response Evaluation Criteria in Solid Tumors version 1.0.
RESULTS: A total of 119 patients with advanced BCC took vismodegib for a median of 5.5 months. Objective responses occurred in 46.4% of locallyadvanced BCC and 30.8% of patients with metastatic BCC. Response was negatively associated with prior systemic therapy in patients with locally advanced BCC (P = .002). Mean follow-up for safety was 6.5 months, with muscle spasms (70.6%), dysgeusia (70.6%), alopecia (58.0%), and diarrhea (25.2%) as the most common adverse events.
LIMITATIONS: Abbreviated follow-up time because of study termination upon FDA approval was a limitation.
CONCLUSION: This study provides important clinical data supporting the efficacy and safety of vismodegib. Larger studies are underway to assess predictors of response and long-term outcomes.
Stanford University School of Medicine, Stanford, California. Electronic address: firstname.lastname@example.org.
Palbociclib and Letrozole in Advanced Breast Cancer.
Finn RS, Martin M, Rugo HS, Jones S, Im SA, Gelmon K, Harbeck N, Lipatov ON, Walshe JM, Moulder S, Gauthier E, Lu DR, Randolph S, Diéras V, Slamon DJ
N Engl J Med. 2016;375(20):1925.
BACKGROUND: A phase 2 study showed that progression-free survival was longer with palbociclib plus letrozole than with letrozole alone in the initial treatment of postmenopausal women with estrogen-receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer. We performed a phase 3 study that was designed to confirm and expand the efficacy and safety data for palbociclib plus letrozole for this indication.
METHODS: In this double-blind study, we randomly assigned, in a 2:1 ratio, 666 postmenopausal women with ER-positive, HER2-negative breast cancer, who had not had prior treatment for advanced disease, to receive palbociclib plus letrozole or placebo plus letrozole. The primary end point was progression-free survival, as assessed by the investigators; secondary end points were overall survival, objective response, clinical benefit response, patient-reported outcomes, pharmacokinetic effects, and safety.
RESULTS: The median progression-free survival was 24.8 months (95% confidence interval [CI], 22.1 to not estimable) in the palbociclib-letrozole group, as compared with 14.5 months (95% CI, 12.9 to 17.1) in the placebo-letrozole group (hazard ratio for disease progression or death, 0.58; 95% CI, 0.46 to 0.72; P<0.001). The most common grade 3 or 4 adverse events were neutropenia (occurring in 66.4% of the patients in the palbociclib-letrozole group vs. 1.4% in the placebo-letrozole group), leukopenia (24.8% vs. 0%), anemia (5.4% vs. 1.8%), and fatigue (1.8% vs. 0.5%). Febrile neutropenia was reported in 1.8% of patients in the palbociclib-letrozole group and in none of the patients in the placebo-letrozole group. Permanent discontinuation of any study treatment as a result of adverse events occurred in 43 patients (9.7%) in the palbociclib-letrozole group and in 13 patients (5.9%) in the placebo-letrozole group.
CONCLUSIONS: Among patients with previously untreated ER-positive, HER2-negative advanced breast cancer, palbociclib combined with letrozole resulted in significantly longer progression-free survival than that with letrozole alone, although the rates of myelotoxic effects were higher with palbociclib-letrozole. (Funded by Pfizer; PALOMA-2 ClinicalTrials.gov number, NCT01740427 .).
From the Department of Medicine, Division of Hematology and Oncology, David Geffen School of Medicine at the University of California, Los Angeles, Santa Monica (R.S.F., D.J.S.), the Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco (H.S.R.), and Pfizer, La Jolla (E.G., D.R.L., S.R.) - all in California; Hospital Gregorio Maranon, Universidad Complutense, Madrid (M.M.); U.S. Oncology Research, The Woodlands, TX (S.J.); Cancer Research Institute, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, South Korea (S.-A.I.); British Columbia Cancer Agency, Vancouver, Canada (K.G.); Brustzentrum der Universität München (LMU), Munich, Germany (N.H.); State Budget Medical Institution Republican Clinical Oncology, Ufa, Russia (O.N.L.); All-Ireland Cooperative Oncology Research Group, Dublin (J.M.W.); M.D. Anderson Cancer Center, University of Texas, Houston (S.M.); and Institut Curie, Paris (V.D.).
Ribociclib as First-Line Therapy for HR-Positive, Advanced Breast Cancer.
Hortobagyi GN, Stemmer SM, Burris HA, Yap YS, Sonke GS, Paluch-Shimon S, Campone M, Blackwell KL, AndréF, Winer EP, Janni W, Verma S, Conte P, Arteaga CL, Cameron DA, Petrakova K, Hart LL, Villanueva C, Chan A, Jakobsen E, Nusch A, Burdaeva O, Grischke EM, Alba E, Wist E, Marschner N, Favret AM, Yardley D, Bachelot T, Tseng LM, Blau S, Xuan F, Souami F, Miller M, Germa C, Hirawat S, O'Shaughnessy J
N Engl J Med. 2016;375(18):1738. Epub 2016 Oct 7.
BACKGROUND: The inhibition of cyclin-dependent kinases 4 and 6 (CDK4/6) could potentially overcome or delay resistance to endocrine therapy in advanced breast cancer that is positive for hormone receptor (HR) and negative for human epidermal growth factor receptor 2 (HER2).
METHODS: In this randomized, placebo-controlled, phase 3 trial, we evaluated the efficacy and safety of the selective CDK4/6 inhibitor ribociclib combined with letrozole for first-line treatment in 668 postmenopausal women with HR-positive, HER2-negative recurrent or metastatic breast cancer who had not received previous systemic therapy for advanced disease. We randomly assigned the patients to receive either ribociclib (600 mg per day on a 3-weeks-on, 1-week-off schedule) plus letrozole (2.5 mg per day) or placebo plus letrozole. The primary end point was investigator-assessed progression-free survival. Secondary end points included overall survival, overall response rate, and safety. A preplanned interim analysis was performed on January 29, 2016, after 243 patients had disease progression or died. Prespecified criteria for superiority required a hazard ratio of 0.56 or less with P<1.29×10(-5).
RESULTS: The duration of progression-free survival was significantly longer in the ribociclib group than in the placebo group (hazard ratio, 0.56; 95% CI, 0.43 to 0.72; P=3.29×10(-6) for superiority). The median duration of follow-up was 15.3 months. After 18 months, the progression-free survival rate was 63.0% (95% confidence interval [CI], 54.6 to 70.3) in the ribociclib group and 42.2% (95% CI, 34.8 to 49.5) in the placebo group. In patients with measurable disease at baseline, the overall response rate was 52.7% and 37.1%, respectively (P<0.001). Common grade 3 or 4 adverse events that were reported in more than 10% of the patients in either group were neutropenia (59.3% in the ribociclib group vs. 0.9% in the placebogroup) and leukopenia (21.0% vs. 0.6%); the rates of discontinuation because of adverse events were 7.5% and 2.1%, respectively.
CONCLUSIONS: Among patients receiving initial systemic treatment for HR-positive, HER2-negative advanced breast cancer, the duration of progression-free survival was significantly longer among those receiving ribociclib plus letrozole than among those receiving placebo plus letrozole, with a higher rate of myelosuppression in the ribociclib group. (Funded by Novartis Pharmaceuticals; ClinicalTrials.gov number, NCT01958021 .).
From the University of Texas M.D. Anderson Cancer Center, Houston (G.N.H.), and Texas Oncology-Baylor Charles A. Sammons Cancer Center and the U.S. Oncology Network, Dallas (J.O.) - all in Texas; Davidoff Center, Rabin Medical Center, Tel Aviv University, Tel Aviv (S.M.S.), and Sheba Medical Center, Ramat Gan (S.P.-S.) - both in Israel; the Sarah Cannon Research Institute (H.A.B., D.Y.), Vanderbilt-Ingram Cancer Center (C.L.A.), and Tennessee Oncology (D.Y.) - all in Nashville; National Cancer Center Singapore, Singapore (Y.-S.Y.); Netherlands Cancer Institute and BOOG Study Center, Amsterdam (G.S.S.); Institut de Cancérologie de l'Ouest/RenéGauducheau, Saint-Herblain (M.C.), Institut Gustave Roussy, UniversitéParis Sud, Villejuif (F.A.), University Hospital of Besançon, Besançon (C.V.), and Centre Léon Bérard, Lyon (T.B.) - all in France; Duke University Medical Center, Durham, NC (K.L.B.); Dana-Farber Cancer Institute, Boston (E.P.W.); University of Ulm, Ulm (W.J.), Onkologische Pr
RASopathic alopecia: hair changes associated with vemurafenib therapy.
Piraccini BM, Patrizi A, Fanti PA, Starace M, Bruni F, Melotti B, Misciali C, Dika E
J Am Acad Dermatol. 2015 Apr;72(4):738-41.
Dermatology, Department of Experimental, Diagnostic, and Specialty Medicine, University of Bologna, Italy.
Alopecia with endocrine therapies in patients with cancer.
Saggar V, Wu S, Dickler MN, Lacouture ME
BACKGROUND: Whereas the frequency of alopecia to cytotoxic chemotherapies has been well described, the incidence of alopecia during endocrine therapies (i.e., anti-estrogens, aromatase inhibitors) has not been investigated. Endocrine agents are widely used in the treatment and prevention of many solid tumors, principally those of the breast and prostate. Adherence to these therapies is suboptimal, in part because of toxicities. We performed a systematic analysis of the literature to ascertain the incidence and risk for alopecia in patients receiving endocrine therapies.
METHODS: An independent search of citations was conducted using the PubMed database for all literature as of February 2013. Phase II-III studies using the terms "tamoxifen," "toremifene," "raloxifene," "anastrozole," "letrozole," "exemestane," "fulvestrant," "leuprolide," "flutamide," "bicalutamide," "nilutamide," "fluoxymesterone," "estradiol," "octreotide," "megestrol," "medroxyprogesterone acetate," "enzalutamide," and "abiraterone" were searched.
RESULTS: Data from 19,430 patients in 35 clinical trials were available for analysis. Of these, 13,415 patients had received endocrine treatments and 6,015 patients served as controls. The incidence of all-grade alopecia ranged from 0% to 25%, with an overall incidence of 4.4% (95% confidence interval: 3.3%-5.9%). The highest incidence of all-grade alopecia was observed in patients treated with tamoxifen in a phase II trial (25.4%); similarly, the overall incidence of grade 2 alopecia by meta-analysis was highest with tamoxifen (6.4%). The overall relative risk of alopecia in comparison with placebo was 12.88 (p<.001), with selective estrogen receptor modulators having the highest risk.
CONCLUSION: Alopecia is a common yet underreported adverse event of endocrine-based cancer therapies. Their long-term use heightens the importance of this condition on patients' quality of life. These findings are critical for pretherapy counseling, the identification of risk factors, and the development of interventions that could enhance adherence and mitigate this psychosocially difficult event.
School of Medicine, New York University Langone Medical Center, New York, New York, USA;