OBR Daily Commentary

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Merck and Eisai Receive Complete Response Letter for KEYTRUDA® (pembrolizumab) plus LENVIMA® (lenvatinib) Combination as First-Line Treatment for Unresectable Hepatocellular Carcinoma

(Merck) July 8, 2020 - Merck, known as MSD outside the United States and Canada, and Eisai today announced that the U.S. Food and Drug Administration (FDA) has issued a Complete Response Letter (CRL) regarding Merck’s and Eisai’s applications seeking accelerated approval of KEYTRUDA, Merck’s anti-PD-1 therapy, plus LENVIMA, the orally available multiple receptor tyrosine kinase inhibitor discovered by Eisai, for the first-line treatment of patients with unresectable hepatocellular carcinoma (HCC). The applications were based on data from the Phase 1b KEYNOTE-524/Study 116 trial, which showed clinically meaningful efficacy in the single-arm setting.

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Howard S. Hochster, MD (Posted: July 08, 2020)

quotesWhile a "complete response" is great for our patients, the Complete Response Letter was less auspicious for the sponsors. The FDA turned down the application for approval which was based on a 100 patient uncontrolled study, especially in light of the IMBrave 150 randomized, global phase 3 with atezo-bev. Thanks to the FDA for maintaining some standards requiring controlled trials!! Especially since 30% of patients went off study for AEs. Fortunately, the phase 3 LEAP-002 is underway and should provide specific data on the benefit of adding anti-PD1 to lenvatinib. We look forward to those data.quotes

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FDA Approves Pembrolizumab For Adults and Children With TMB-H Solid Tumors

(FDA.gov) June 17, 2020 - On June 16, 2020, the Food and Drug Administration granted accelerated approval to pembrolizumab (KEYTRUDA, Merck & Co., Inc.) for the treatment of adult and pediatric patients with unresectable or metastatic tumor mutational burden-high (TMB-H) [≥10 mutations/megabase (mut/Mb)] solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options. Today, the FDA also approved the FoundationOneCDx assay (Foundation Medicine, Inc.) as a companion diagnostic for pembrolizumab.

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Howard S. Hochster, MD (Posted: June 19, 2020)

quotesAnother, but far more problematic approval for Pembro. Which tumors actually have high TMB but not MSI-H? Out of 750+ screened, 102 fit this category for mutations of > 10 mut/MB but only 70 if the cutoff is 13. For the 102, most of the tumors were SCLC, followed by cervix, endometrial and anal cancer. These basically had about a 30% RR but many of these would receive anti-PD1 anyway. It would be useful to know how many of these are hypermutated tumors due to POLE and similar mutations. All in all, this is likely to be a very rare happening in any tumor where we aren't already using anti-PD1 as SOC.quotes

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UroGen Gets FDA Nod for Low-Grade Upper Tract Urothelial Cancer Drug

(Xconomy New York) Apr 15, 2020 - The FDA on Wednesday approved a drug developed by UroGen Pharma to treat low-grade upper tract urothelial cancer, which rarely spreads but often recurs and can cause kidney damage in some patients. Urothelial cancer is the most common type of bladder cancer. Upper tract urothelial cancer (UCTC), however, affects the lining of the urinary system, arising in the lining of the kidney or in the ureter, the skinny tube that links that kidney to the bladder. In some patients the tumors block the ureter or kidney, which can cause swelling and infections that may impair kidney function.

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Howard S. Hochster, MD (Posted: April 19, 2020)

quotesThe FDA has approved a new formulation of Mitomycin C (MMC) in hydrogel (4 mg/ml) solution for instillation in the ureter or calyces to treat low grade Upper Urinary Tract Urothelial Cancer. This will certainly be of great benefit to some patients with these tumors. The approval is based on a single arm multi-center trial with no controls, based on the primary endpoint of CR by ureteroscopy and cytology at 3 months. Despite UroGEN calling this OLYMPUS study a "phase 3 trial" it meets no definition of "Phase 3." The study showed 58% of patients had CR at 3 months (later timepoints not yet revealed) and the approval is apparently based on historical controls and the fact that standard practice frequently involves nephrectomy. This finding is not unexpected, given the activity of MMC in NMIBC and it approval. This is another in a series of "better mousetrap" formulations of active drugs making FDA approval without appropriate controls. Why not a standard MMC solution as a control group? Or even the much more available and less expensive Gemcitabine, which is equally active in NMIBC? How much does the hydrogel contribute? This is unknown. The FDA should really require the parent drug as the comparison in such re-formulated agents including nab-paclitaxel and lipsomal irinotecan. It is no service to the oncology community to approve drugs based on activity similar to the parent compound compared with inferior controls, and without a direct comparison. These create very expensive new drugs with unknown advantages. We should know exactly how much better such improved formulations are compared with the parent for the extra cost. FDA: please consider appropriate controls!quotes

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Meet the Editorial Board

Prostate Cancer
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Tomasz M. Beer, MD, FACP

Professor of Medicine, Division of Hematology/Medical O...

Community Oncology
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Dean Gesme, MD

FACP FACPE FASCO President, Minnesota Oncology...

Breast Cancer
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Debu Tripathy, MD

Professor and Chair, Department of Breast Medical Oncol...

Lung Cancer
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H. Jack West, MD

Associate Clinical Professor, Medical Oncology Executi...

Gastrointestinal Cancers
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Howard S. Hochster, MD

Distinguished Professor of Medicine, Rutgers Robert Woo...

Radiation Oncology
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Howard Sandler, MD, MS, FASTRO

Ronald H. Bloom Chair in Cancer Therapeutics Professo...

Editor-In-Chief
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Robert A. Figlin, MD., FACP

Steven Spielberg Family Chair in Hematology Oncology P...

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Stephen M. Schleicher, M.D., MBA

Community Oncology, Medical Oncologist, OneOncology...

Health Policy
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Ted Okon

Executive Director Community Oncology Alliance...

Community Oncology
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Thomas Marsland, MD

Vice President Integrated Community Oncology Network ...

Health Policy
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William McGivney, PhD

National Health Policy Expert...