New Drug Updates in Solid Tumors: PARP Inhibitors in Ovarian Cancer, Immunotherapeutics, and Other Agents
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New Drug Updates in Solid Tumors: PARP Inhibitors in Ovarian Cancer, Immunotherapeutics, and Other Agents Edward Li, PharmD, MPH, BCOP University of New England College of Pharmacy Learning Objectives 1. Discuss the pharmacology and indications of medications approved in the year 2016–2017 for the management of patients with solid tumors 2. Recall the pivotal clinical trial data considered by the FDA when approving new oncologics 3. Identify the signs and symptoms of serious or life-threatening adverse effects of newly approved oncology drugs 4. Describe the impact of these agents in advanced practice Financial Disclosure • Edward Li, PharmD, MPH, BCOP, declares that he has served on the speakers bureau for Pfizer and ApoBiologiX and on advisory boards for Pfizer, Eli Lilly, and Mylan. History of Cancer Drug Approvals in the United States 1942: Goodman and Gilman 1975: CMF for 1992: Paclitaxel use nitrogen mustard for NHL breast cancer FDA approved Targeted 1959: FDA approves therapies cyclophosphamide 1940s 1950s 1960s 1970s 1980s 1990s 2000s 1948: Farber 1965: 1978: 1998: 2001: Imatinib uses antifolate in Combination Cisplatin Trastuzumab FDA approved ALL chemo for ALL approved FDA approved ALL = acute lymphoblastic leukemia; CMF = cyclophosphamide, methotreXate and fluorouracil; FDA = US Food and Drug Administration; NHL = non-Hodgkin lymphoma. Adapted from Chabner BA, et al. Nat Rev Cancer 2005;5:65-72. Drug Approvals Impact the Practice Paradigm 1942: Goodman Combination and Gilman use chemo Commercialized Ta rg e te d nitrogen Expansion of regimens chemo era therapy era mustard for oral oncolytics invented begins begins NHL 1960 // 1980 1990 2000 2010 Cancer treatment paradigm Cisplatin (1978) Supportive care management: CINV Filgrastim (1991) Supportive care management: febrile neutropenia Trastuzumab (1998), imatinib (2000), gefitinib (2003), etc. Cancer pharmacogenomics 18 oral agents approved 2011–2014 PO adherence/monitoring CINV = chemotherapy-induced nausea and vomiting. Era of Immuno-Oncology First immune checkpoint First oncolytic inhibitor approved virus approved CAR T cells Cytokines First autologous cellular (interferons), etc. Expansion of PD- therapy approved First PD-1 inhibitor 1/PD-L1 indications approved 2000 // 2010 // 2012 // 2015 2016 2017 Survival outcomes Cancer treatment paradigm Severe immune-related adverse events Adverse event monitoring and treatment Serious discussion on pseudoprogression Immune-related response criteria Storage and handling Infrastructure needs IO becomes mainstream Cost containment Intensive monitoring CRS CAR = chimeric antigen receptor; CRS = cytokine-release syndrome; IO = immuno-oncology; PD-1 = programmed cell death protein 1; PD-L1 = programmed death-ligand 1. New Drug Approvals: December 2016 to September 2017 Established Mechanism Novel Mechanism Generic Brand Approval Date Generic Brand Approval Date Rucaparib Rubraca December 19, 2016 Olaratumab Lartruvo October 20, 2016 Ribociclib Kisqali March 13, 2017 Avelumab Bavencio March 23, 2017 Niraparib Zejula March 27, 2017 Brigatinib Alunbrig April 28, 2017 Durvalumab Imfinzi May 1, 2017 Neratinib NerlynX July 17, 2017 Olaparib tabs Lynparza August 17, 2017* Abemaciclib Ver z enio September 28, 2017 *Original FDA approval date: Dec. 19, 2014 US Food and Drug Administration, Hematology/Oncology (Cancer) Approvals & Safety Notifications, https://www.fda.gov/drugs/informationondrugs/approveddrugs/ucm279174.htm. Other Important Regulatory Events Generic Brand Event Description Event Description Date Nivolumab Opdivo Expanded indication Urothelial carcinoma Feb. 2, 2017 Osimertinib Tagrisso Acc à Reg approval T790M+ NSCLC Mar. 30, 2017 HR+, HER2-, initial advanced/metastatic breast Palbociclib Ibrance Acc à Reg approval Mar. 31, 2017 cancer with AI Regorafenib Stivarga Expanded indication Hepatocellular carcinoma Apr. 27, 2017 Accelerated Metastatic nonsquamous NSCLC with Pembrolizumab Keytruda May 10, 2017 approval carboplatin/pembrolizumab Pembrolizumab Keytruda Regular approval Urothelial carcinoma May 18, 2017 Accelerated Pembrolizumab Keytruda MSI-H or dMMR solid tumors May 23, 2017 approval Ceritinib Zykadia Acc à Reg approval ALK+ NSCLC May 26, 2017 AI = aromatase inhibitor; ALK = anaplastic lymphoma kinase; dMMR = mismatch repair deficient; HR = hormone receptor; HER2 = human epidermal growth factor receptor 2; MSI-H = microsatellite instability high; NSCLC = non–small call lung cancer. US Food and Drug Administration, Hematology/Oncology (Cancer) Approvals & Safety Notifications, https://www.fda.gov/drugs/informationondrugs/approveddrugs/ucm279174.htm. Other Important Regulatory Events Generic Brand Event Description Event Description Date Dabrafenib + Tafinlar + Regular approval BRAF V600E mutated NSCLC June 22, 2017 trametinib Mekinist Nivolumab Opdivo Accelerated approval MSI-H or dMMR met colorectal cancer Aug. 1, 2017 Bevacizumab- Mvasi Biosimilar approval CRC, NSCLC, GBM, RCC, cervical Sep. 14, 2017 awwb CabazitaXel Jevtana Lower dose CRPC in combination with prednisone Sep. 14, 2017 PD-L1+, advanced/metastatic gastric/GE junction Pembrolizumab Keytruda Accelerated approval Sep. 22, 2017 adenocarcinoma Nivolumab Opdivo Accelerated approval Hepatocellular carcinoma Sep. 22, 2017 CRC = colorectal cancer; CRPC = castration-resistant prostate cancer; GBM = glioblastoma; GE = gastroesophageal; RCC = renal cell carcinoma. US Food and Drug Administration, Hematology/Oncology (Cancer) Approvals & Safety Notifications, https://www.fda.gov/drugs/informationondrugs/approveddrugs/ucm279174.htm. New Drug Approvals: December 2016 to September 2017 Route of Administration Generic Brand Approval Date Rucaparib Rubraca December 19, 2016 Ribociclib Kisqali March 13, 2017 Avelumab Bavencio March 23, 2017 Niraparib Zejula March 27, 2017 Parenteral (IV) Brigatinib Alunbrig April 28, 2017 Oral administration administration Durvalumab Imfinzi May 1, 2017 Neratinib NerlynX July 17, 2017 Olaparib tabs Lynparza August 17, 2017* September 28, Abemaciclib Verzenio *Original FDA approval date: Dec. 19, 2014 2017 US Food and Drug Administration, Hematology/Oncology (Cancer) Approvals & Safety Notifications, https://www.fda.gov/drugs/informationondrugs/approveddrugs/ucm279174.htm. New Drug Approvals: December 2016 to September 2017 PARP Inhibitors FDA-Approved Indications Generic Brand Approval Date Rucaparib Rubraca December 19, 2016 Monotherapy for the treatment of patients with Ribociclib Kisqali March 13, 2017 deleterious BRCA mutation (germline and/or somatic) associated advanced ovarian cancer; Avelumab Bavencio March 23, 2017 treated with two or more chemotherapies Niraparib Zejula March 27, 2017 Brigatinib Alunbrig April 28, 2017 Maintenance treatment of recurrent epithelial ovarian, fallopian tube, or primary peritoneal Durvalumab Imfinzi May 1, 2017 cancer who are in a complete or partial Neratinib Nerlynx July 17, 2017 response to platinum-based chemotherapy Olaparib tabs Lynparza August 17, 2017* *Original FDA approval date: Dec. 19, 2014 Abemaciclib Ver zenio September 28, 2017 PARP = poly ( ADP-ribose) polymerase. US Food and Drug Administration, Hematology/Oncology (Cancer) Approvals & Safety Notifications, https://www.fda.gov/drugs/informationondrugs/approveddrugs/ucm279174.htm. Pharmacology of PARP Inhibition Role in Synthetic Lethality Other Functions of PARP Reprinted by permission from Macmillan Publishers Ltd: Sonnenblick A, et al. Nat Rev Clin Oncol 2015;12:27-41, copyright 2015. PARP Inhibitor Clinical Trials (Landmark) Agent (Activity) Study Design Dosing Reference Rucaparib Phase 2 open-label study of rucaparib in 600 mg orally twice daily NCT018913441 (PARP 1/2) recurrent platinum-sensitive disease (3+ continuously as monotherapy lines of chemo) stratified according to homologous recombination deficiency (n = 206) Niraparib Randomized phase 3 study of niraparib vs. Niraparib 300 mg orally daily NCT018472742 (PARP 1/2) placebo for maintenance in recurrent, within 8 weeks after completing platinum-sensitive disease (n = 553) last dose of platinum-based chemotherapy Olaparib Randomized phase 2 study of olaparib vs. Olaparib 400 mg orally twice daily NCT007535453 (PARP 1/2/3) placebo for maintenance in recurrent, within 8 weeks after completing platinum-sensitive disease (n = 265) last dose of platinum-based chemotherapy 1. Swisher EM, et al. Lancet Oncol 2017;18:75-87; 2. Mirza MR, et al. N Engl J Med 2016;375:2154-64; 3. Ledermann JA, et al. Lancet Oncol 2016;17:1579-89. Rucaparib for Recurrence: ARIEL2 BRCA Wild-Type and BRCA Wild-Type and BRCA Mutation+ LOH High LOH Low Outcome n = 40 n = 82 n = 70 ORR, % 80% 29% 10% Progression-free survival Median 12.8 months 5.7 months 5.2 months HR (vs. LOH-low) 0.27 0.62 -- (95% CI) (0.16–0.44) (0.42–0.90) -- p value < .0001 .011 -- Duration of response 9.2 months 10.8 months 5.6 months Median 6.4–12.9 5.7–NR 4.6–8.5 (95% CI) .013 .022 p value (vs. LOH-low) CI = confidence interval; HR = hazard ratio; LOH = loss of heterozygosity; ORR = objective response rate. Swisher EM, et al. Lancet Oncol 2017;18:75-87. Niraparib, Olaparib for Maintenance Mirza et al., 2016 Ledermann et al., 2016 Phase 3 Phase 2 Outcome Niraparib Niraparib (BRCA mutations vs. BRCA BRCA wt and Niraparib Olaparib Olaparib wild-type) mut(+) HRD BRCA wt BRCA mut(+) BRCA wt Progression-free survival HR 0.27 0.38 0.45 0.18 0.54 (95% CI) (0.17–0.41) (0.24–0.59) (0.34–0.61) (0.10–0.31) (0.34–0.85) Median, mo (vs. placebo) 21.0 vs. 5.5 12.9 vs. 3.8 9.3 vs. 3.9 11.2 vs. 4.3 7.4 vs. 5.5 p-value p < .001 p