| News and publications Rapid heterogeneous adaptations to conformation-specific KRAS inhibition: In Phase I trials with KRAS inhibitors, early results show partial responses in approx. 50% of patients. However, the mechanism by which cancer cells bypass inhibition is unknown. In this study, Xue et al reported a rapid divergent behavior of cancer cells: some populations are sequestered in a quiescent state (low KRAS activity), whereas others bypass this state and resume proliferation. This escape is made possible by newly produced KRAS, maintained active by epidermal growth factor receptor signaling. Cell populations lacking these adaptive changes remain sensitive to drug treatment, whereas others do not. This study is the first to highlight this process, which needs to be overcome for achieving complete durable responses. Results were published in Nature.
AI for diagnosis and grading of prostate cancer: There is an increasing strain due to higher volumes of biopsies, worldwide shortage of pathologists, and intra-/inter-observer variability in grading. To address this, Strom et al developed an artificial intelligence (AI) system by training deep neural networks and evaluating their capacity to predict the presence, extent, and Gleason grade of malignant tissue on several (independent, validation, and internal) data sets. Grading performance of 23 experienced pathologists was also assessed. Results showed an almost 100% capacity of the AI system to differentiate between benign and malignant biopsy cores, a correlation between AI- and pathologist-predicted cancer length, and a comparable grading performance. Results were published in The Lancet Oncology. |
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| Industry A few highlights of industry & academy: BioNTech acquires Neon Therapeutics for $67 million or $2.18 per share. With this acquisition, BioNTech strengthens its global leadership position in T cell therapies by expanding chemmeric antigen receptor (CAR)-T and T-cell receptor (TCR) therapy pipelines through addition and further development of Neon Therapeutics’ neoantigen-specific cell therapies. Merck establishes collaboration with Taiho and Astex, focused on development of small molecule inhibitors against several drug targets. In exchange for providing Merck exclusive global licenses to their drug candidates, Taiho and Astex will receive an upfront payment of $50 million and will be eligible to receive approx. $2.5 billion contingent upon achievement of preset milestones. Leap Therapeutics and BeiGene enter exclusive licensing agreement for clinical development of the anti-Dickopf-1 antibody able to block tumorigenesis. Leap will receive an upfront cash payment of $3 million from BeiGene and will be eligible to receive milestones-related payments for up to $132 million. Leap also entered a second agreement for $27 million equity financing with BeiGene and two institutional investors. Verastem Oncology and Chugai Pharmaceutical enter global licensing agreement to develop and commercialize the CH5126766 RAF/MEK inhibitor for treatment of solid tumors. Verastem has agreed to make an upfront payment of $3 million and royalties to Chugai. BeiGene enters exclusive agreement with EUSA Pharma for development and commercialization of Qarziba (dinutuximab beta) in Greater China, the only EMA-approved targeted immunotherapy for the treatment of high-risk neuroblastoma. EUSA Pharma will receive an upfront nondisclosed payment and be eligible for up to $ 160 million upon achievement of preset milestones. Iovance Biotherapeutics enters exclusive licensing agreement for development of genetically-edited tumor infiltrating lymphocytes using the TALEN technology from Cellectis. Financial terms of the agreement were undisclosed. |
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| EMA The Committee for Medical Products for Human Use (CHMP) adopted a positive opinion for:
New drugs: Darolutamide (Nubeqa, Bayer), an androgen receptor inhibitor, for treatment of prostate cancer. The decision was based on the Phase III ARAMIS trial, whose results reported a median metastasis-free survival of 40.4 versus 18.4 months, in patients receiving darolutamide plus androgen deprivation therapy (ADT) versus placebo plus ADT. New biosimilars: Rituximab (Ruxience, Pfizer), for treatment of non-Hodgkin’s lymphoma, chronic lymphocytic leukemia, rheumatoid arthritis, granulomatosis with polyangiitis and microscopic polyangiitis, and Pemphigus vulgaris New generic medicines: Azacitidine betapharm (Betapharm) and azacitidine trioxide Mylan (Mylan), for treatment of myelodyspastic syndromes, and acute myeloid and chronic myelomonocytic leukemia. Arsenic trioxide Mylan (Mylan Pharmaceuticals) for treatment of acute promyelocytic leukemia. Cinacalcet Accordpharma (Accord Healthcare), for several indications, including treatment of parathyroid carcinoma. Extensions of indications: Rituximab (MabThera, Roche), combined with chemotherapy, for pediatric patients (≥6 months to <18 years) with previously untreated advanced stage CD20+ diffuse large B-cell lymphoma, Burkitt lymphoma/leukemia or Burkitt-like lymphoma. Venetoclax (Venclyxto, AbbVie), combined with obinutuzumab, for treatment of adult patients with previously untreated chronic lymphocytic leukemia.
FDA The FDA granted approval for: Tazemetostat (Tazverik, Epizyme) for treatment of adults and pediatric patients aged ≥16 years with metastatic/locally advanced epithelioid sarcoma not eligible for resection. The accelerated approval was based on the Phase II EZH-202 trial, whose results reported an overall response rate (ORR) of 15% in a previously untreatable patient population. Pembrolizumab (Keytruda, Merck) for treatment of patients with bacillus Calmette-Guerin-unresponsive, high-risk, non-muscle invasive bladder cancer with carcinoma in situ, with/without papillary tumors and ineligible for cystectomy. Approval was based on the Phase II KEYNOTE-057 trial, whose results reported a 41% rate of complete response with a median response duration of 16.2 months. Ayvakit (avapritinib, Blueprint Medicines), for treatment of adults with unresectable/metastatic platelet-derived growth factor receptor alpha exon 18 mutant gastrointestinal stromal tumors. Approval was based on the Phase I NAVIGATOR trial, whose results reported an 84% ORR in these patients.
The FDA also granted breakthrough therapy designation to the following drug to advance its development: APR-246 (Aprea Therapeutics), combined with azacytidine, for treatment of myelodysplastic syndromes with a TP53 mutation.
Guidelines FDA guidance on submission of iPSPs for oncology drugs:
In follow-up to amendments made by the FDARA 2017 Act, the FDA recently published a new draft guidance regarding submission of initial pediatric study plans (iPSPs) for oncology drugs.
Sponsors seeking a full waver of pediatric studies need to comply with the following: prior to 18Aug2020, only the sections provided in Appendix 1 of the Draft iPSP Guidance from 2016 need to be completed. On/after 18Aug2020, sponsors should also submit an abbreviated iPSP.
A product granted orphan designation is exempt from the new FDARA act only if the designation was granted prior to 18Aug2020. Nevertheless, FDA recommends all sponsors to submit an iPSP anyway, to avoid any subsequent requirements.
Lastly, a product intended for treatment of an adult cancer, with a new ingredient relevant to a pediatric cancer, but with an indication listed as “rarely/never occurring in pediatrics”, will qualify for a waiver only if the application is submitted prior to 18Aug2020.
FDA guidance on drug importation into the US:
To lower prescription drug prices in the US, FDA released a proposed rule and draft guidance on drug importation. The rule authorizes states, wholesalers, and pharmacists to submit proposals to import prescription drugs (excluding biologics and infused drugs) from Canada. The draft guidance follows up by describing various pathways to import FDA-approved drugs manufactured abroad and originally intended for sale in a foreign country. |
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