FDA Approval Summary: Vemurafenib for Treatment of Unresectable or Metastatic Melanoma with the BRAFV600E Mutation

Kim, Geoffrey; McKee, Amy E.; Ning, Yang‐Min; Hazarika, Maitreyee; Theoret, Marc R.; Johnson, John R.; Xu, Qiang; Tang, Shenghui; Sridhara, Rajeshwari; Jiang, Xiaoping; He, Kun; Roscoe, Donna; McGuinn, W. David; Helms, Whitney S.; Russell, Anne Marie; Miksinski, Sarah Pope; Zirkelbach, Jeanne Fourie; Earp, Justin; Liu, Qi; Ibrahim, Amna; Justice, Robert; Pazdur, Richard

doi:10.1158/1078-0432.ccr-14-0776

Cited by 172 publications

(119 citation statements)

References 21 publications

(19 reference statements)

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“…This clinical manifestation was very suggestive of rheumatoid arthritis. Vemurafenib has been associated with arthralgias 48 but we had never observed this toxicity to the degree seen in these patients, and the symptoms persisted for many months after discontinuation of the agents. Of interest, we had observed the same arthritic phenomenon in the patients we had previously reported who sustained CRs to temozolomide post IL-2 suggestive of a relationship.…”

Section: Discussionmentioning

confidence: 53%

Durable complete responses off all treatment in patients with metastatic malignant melanoma after sequential immunotherapy followed by a finite course of BRAF inhibitor therapy

Wyluda

Cheng

Schell

et al. 2015

Cancer Biology & Therapy

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Drabick (2015) Durable complete responses off all treatment in patients with metastatic malignant melanoma after sequential immunotherapy followed by a finite course of BRAF inhibitor therapy, Cancer Biology & Therapy, 16:5, 662-670, DOI: 10.1080/15384047.2015 We report 3 cases of durable complete response (CR) in patients with BRAF-mutated metastatic melanoma who were initially treated unsuccessfully with sequential immunotherapies (high dose interleukin 2 followed by ipilimumab with or without concurrent radiation therapy). After progression during or post immunotherapy, these patients were given BRAF inhibitor therapy and developed rapid CRs. Based on the concomitant presence of autoimmune manifestations (including vitiligo and hypophysitis), we postulated that there was a synergistic effect between the prior immune therapy and the BRAF targeting agents. Accordingly, the inhibitors were gradually weaned off beginning at 3 months and were stopped completely at 9-12 months. The three patients remain well and in CR off of all therapy at up to 15 months radiographic follow-up. The institution of the BRAF therapy was associated with development of severe rheumatoid-like arthritis in 2 patients which persisted for months after discontinuation of therapy, suggesting it was not merely a known toxicity of BRAF inhibitors (arthralgias). On immunologic analysis, these patients had high levels of non-T-regulatory, CD4 positive effector phenotype T-cells, which persisted after completion of therapy. Of note, we had previously reported a similar phenomenon in patients with metastatic melanoma who failed high dose interleukin-2 and were then placed on a finite course of temozolomide with rapid complete responses that have remained durable for many years after discontinuation of temozolomide. We postulate that a finite course of cytotoxic or targeted therapy specific for melanoma given after apparent failure of prior immunotherapy can result in complete and durable remissions that may persist long after the specific cytotoxic or targeted agents have been discontinued suggesting the existence of sequence specific synergism between immunotherapy and these agents. Here, we discuss these cases in the context of the literature on synergy between conventional or targeted cytotoxic therapy and immunotherapy in cancer treatment.

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Section: Discussionmentioning

confidence: 53%

Durable complete responses off all treatment in patients with metastatic malignant melanoma after sequential immunotherapy followed by a finite course of BRAF inhibitor therapy

Wyluda

Cheng

Schell

et al. 2015

Cancer Biology & Therapy

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“…The mutated form of the protein is the target of several therapeutic development programs because it has increased kinase activity believed to be responsible for driving cancer growth. On August 2011, vemurafenib (Zelboraf Ò , Hoffmann-LaRoche) was approved by FDA for the treatment of patients with unresectable or metastatic melanoma with the BRAF V600E mutation as detected by an FDA-approved test [14]. The vemurafenib approval occurred concurrently with the FDA approval of the cobas Ò 4800 BRAF V600 Mutation Test (Roche Molecular Systems, Inc.…”

Section: Retrospective Assignment Of Cutoffs In Pivotal Trialmentioning

confidence: 99%

“…However, what was apparent at the conclusion of the vemurafenib trial was that the test displayed limited cross-reactivity to V600K, resulting in the enrollment of some V600K patients (estimated at approximately 5% of the enrolled population). Some treatment effect was observed in the V600K population and HoffmanLaRoche continued to study the effect in this population [14,15].…”

Section: Retrospective Assignment Of Cutoffs In Pivotal Trialmentioning

confidence: 99%

“…Overall, although the test displayed this unintended crossreactivity, it was successful as a companion diagnostic for vemurafenib because Hoffmann LaRoche and RMS had committed to a successful codevelopment path: the test intended for marketing was the test used in the strongly positive therapeutic product clinical trial, and all patient specimens that were tested to determine patient eligibility were screened using the RMS test intended for marketing [14][15][16][17][18]. Therefore, the treatment effect in the population -as selected by the test -was known.…”

Section: Retrospective Assignment Of Cutoffs In Pivotal Trialmentioning

confidence: 99%

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Companion diagnostics: a regulatory perspective from the last 5 years of molecular companion diagnostic approvals

Roscoe

Philip³

2015

Expert Review of Molecular Diagnostics

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Companion diagnostics are essential for the safe and effective use of the corresponding therapeutic products. The US FDA has approved a number of companion diagnostics used to select cancer patients for treatment with contemporaneously approved novel therapeutics. The processes of co-development and co-approval of a therapeutic product and its companion diagnostic have been a learning experience that continues to evolve. Using several companion diagnostics as examples, this article describes the challenges associated with the scientific, clinical and regulatory hurdles faced by FDA and industry alike. Taken together, this discussion is intended to assist manufacturers toward a successful companion diagnostics development plan.

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“…Ever since the discovery of BRAF mutations, vemurafenib (Hoffman-La Roche, Basel, Switzerland) [12], dabrafenib (GlaxoSmithKline, Brentford, England) [13], and trametinib (GlaxoSmithKline) [14] have been approved for the treatment of V600 mutations in melanoma. However, results in CRC were less conclusive and clinical experience with BRAF inhibition in CRC suggests significant differences in response compared with melanoma [15].…”

Section: Introductionmentioning

confidence: 99%

B-type proto-oncogene-mutated tumors of colon cancer

Temraz

Alameddine

Shamseddine

2015

Current Opinion in Oncology

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FDA Approval Summary: Vemurafenib for Treatment of Unresectable or Metastatic Melanoma with the BRAFV600E Mutation

Abstract: On August 17, 2011, the U.S. Food and Drug Administration (FDA) approved vemurafenib tablets (Zelboraf, Hoffmann-LaRoche Inc.)

Cited by 172 publications

References 21 publications

Durable complete responses off all treatment in patients with metastatic malignant melanoma after sequential immunotherapy followed by a finite course of BRAF inhibitor therapy

Durable complete responses off all treatment in patients with metastatic malignant melanoma after sequential immunotherapy followed by a finite course of BRAF inhibitor therapy

Companion diagnostics: a regulatory perspective from the last 5 years of molecular companion diagnostic approvals

B-type proto-oncogene-mutated tumors of colon cancer

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