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FDA & EMA Oncology Drugs and Diagnostics Recommended for Approval in 2019

EMA BOTH* FDA Total 126 20 131 ° New active Newsubstance 30 13 48 Anti-Cancer 29 8 36 #

Total 57 Anti-Cancer Medicines Approved in 2019 * Also tallied in totals reported for EMA and FDA ° Includes 18 diagnostic agents or assays, of which 3 (#) are for use in cancer

16 1 7 33 IMMUNO- RADIO- CHEMO- SMALL- THERAPIES THERAPEUTICS THERAPIES MOLECULES

2019 was a prolific year, yielding higher numbers of positive recommendations/approvals than 2018 for both the European Medicines Agency (EMA) and the Food and Drug Administration (FDA) (2019: EMA: 126, FDA: 131 vs 2018: EMA: 84, FDA: 103; Figure 1; see also: Blog Approvals 2018). This is partly due to the increase in positive recommendations/approvals of anti-cancer drugs (2018: 44 vs 2019: 57), with an increase in the number of compounds approved by both the EMA and the FDA (2018: 5 vs 2019: 8). While the numbers of positive recommendations/approvals of immunotherapies, chemotherapies and radiotherapeutics were similar between the two years (2018: 18, 6 and 1 vs 2019: 16, 7 and 1), the number of positive recommendations/approvals for small molecules increased substantially (Figure 1; 2018: 9; 2019: 33). During 2019, a continued focus of both agencies constituted immunotherapies, with an overall of 16 compounds receiving positive recommendations/approvals in 2019 (Figure 1). Overlapping approvals include: Bavencio® (avelumab, Merck) for renal cancer (with FDA having approved the treatment in combination with Inlyta® [axitinib, Pfizer]), Cyramza® (ramucirumab, Eli Lilly) for hepatocellular carcinoma (HCC), Darzalex® (daratumumab, Janssen Biotech) for multiple myeloma (MM), Tecentriq® (atezolizumab, Roche) for non- small cell lung cancer (NSCLC), Polivy® (polatuzumab vedotin-piiq, Genentech) for diffuse large B cell lymphoma (DLBCL) and Keytruda® (pembrolizumab, Merck) for NSCLC, renal cancer, and metastatic/unresectable recurrent head and neck squamous cell carcinoma (HNSCC) (Figure 2). While in 2018 there were no positive recommendations/approvals regarding diagnostic agents or assays for use in cancer (see: Blog Approvals 2018), in 2019 three such approvals were given (Figure 2) for the following diagnostics: • MyChoice®CDx(Myriad), the first FDA-approved tumor test that determines homologous recombination deficiency status by detecting breast cancer gene (BRCA)1 and BRCA2 variants and is able to assess genomic instability using three critical biomarkers: loss of heterozygosity, telomeric allelic imbalance and large- scale state transitions; • Ga 68 DOTATOC (Advanced Accelerator Applications), a radioactive diagnostic agent for the detection of specific types of tumors called somatostatin receptor- positive neuroendocrine tumors; • PD-L1 IHC 22C3 pharmDx (Agilent Biotechnologies Inc.), the only FDA-approved companion diagnostic assay that helps to identify patients with esophageal squamous cell carcinoma that are eligible to receive second-line treatment with Keytruda® (pembrolizumab, Merck). Agilent has also announced that PD-L1 IHC 22C3 pharmDxhas been marked as CE-IVD (Conformité Européene- In Vitro Diagnostic) for use in HNSCC in Europe.

In terms of orphan drug/accelerated approvals and assessments, 2019 registered lower numbers as compared with 2018 (Figure 3, see also: Blog Approvals 2018). Of the eight compounds designated as orphan drug and eight receiving accelerated approval or recommendation in 2019, five received both designations simultaneously: Brukinsa® (zanubrutinib, BeiGene) for mantle cell lymphoma (MCL), Polivy® (polatuzumab vedotin- piiq, Genentech) for DLBCL, Rozlytrek® (entrectinib, Roche) for NSCLC, Xospata® (gilteritinib, Astellas Pharma) for acute myeloid leukemia (AML) and Xpovio® (selinexor, KaryoPharm Therapeutics) for relapsed/refractory MM (Figure 4).

In 2019, Keytruda® received multiple approvals for extending its therapeutic indications from the FDA and EMA, closing the year with 21 indications in total (see also: keytruda.com; Figure 4). This pattern may continue in 2020, with Keytruda® making a promising start with an FDA approval on January 8 for the treatment of patients with high- risk, non-muscle invasivebladder cancer(see: FDA Approval Keytruda). Similar to 2018, the majority of anti-cancer drugs were developed for the treatment of patients with blood cancers (e.g. MM), followed by breast and lung cancers (Figure 4). Indications included primarily diseases that are difficult to treat or with few treatment options, including relapsed,refractory, chronic, advanced and metastaticcancers.

The FDA approved 20 compounds as first-in-class, a designation received by drugs with a new and unique mechanism for treating a medical condition. These included the following five innovative anti-cancer therapies: Balversa® (erdafitinib, Janssen Oncology) as the first fibroblast growth factor receptor (FGFR) kinase inhibitor and Padcev®(enfortumab vedotin- ejfv, Seattle Genetics) as the first ADC directed against nectin-4, both approved for treatment of locally advanced or metastatic bladder cancer. Furthermore, Xpovio® (selinexor, KaryoPharm Therapeutics) was approved in combination with dexamethasone for the treatment of relapsed or refractory MM as the first approval of a nuclear export inhibitor given thus far by the FDA for any indication. Two first-in-class drugs were approved for the treatment of rare cancers: Polivy® (polatuzumab vedotin-piiq, Genentech), an ADC which was approved in combinationwith the chemotherapybendamustineand a rituximabproduct as the first chemo-immunotherapyregimenfor patientswith relapsed/refractory DLBCL, and Turalio® (pexidartinib, Daiichi-Sankyo), which has become the first treatment approved by the FDA for adult patients with symptomatic tenosynovialgiant cell tumor, a rare and non- malignant tumors that affects joints.

Other drug approvals in 2019 that made advances in patientcare across a broad range of cancers include: • Brukinsa® (zanubrutinib, BeiGene) capsules, for treatment of adult patients with relapsed/refractory MCL who have received at least one prior therapy, led to a reduction in tumor volume in 84% of patients for a median duration of 19.5 months; • Enhertu®(Fam-trastuzumab deruxtecan-nxki, Daiichi Sankyo) for patients with unresectable or metastatic HER2-positive breast cancer who received ≥2 prior anti- HER2-based regimens in the metastatic setting; • Inrebic®(fedratinib, Celgene), for treatment of patients with intermediate-2 or high- risk primary or secondary myelofibrosis. This is the first new treatment approved for primary or secondary myelofibrosis in nearly a decade; • Nubeqa® (darolutamide, Bayer), an androgenreceptor inhibitor, fortreatment of patientswith non-metastaticcastration-resistant prostatecancer; • Piqray® (alpelisib, Novartis) used in combination with fulvestrant for the treatment of men and postmenopausal women with HR+ HER2-negative, Phosphatidylinositol-4,5- Bisphosphate 3-Kinase (PI3K) Catalytic Subunit Alpha (PI3KCA)-mutated advanced or metastatic breast cancer as detected by an FDA-approved test following progression on or after an endocrine-based regimen. The compound is the first PI3K inhibitor to demonstrate a clinically meaningful benefit in treating patients with this type of breast cancer; • Rozlytrek® (entrectinib, Roche) and Vitrakvi® (larotrectinib, Loxo Oncology), both for treatment NTRKgene fusion-positive solid tumors. These treatments are both ‘tissue- agnostic’, targeting tumors based on genetic changes rather than the tissue of origin.

Conclusion 2019 saw a high number of positive recommendations/approvals for anti-cancer therapies, including numerous mAbs and ADCs, as well as a rise in small molecules. Many innovative treatments were developed for patients with metastatic, refractory or otherwise difficult-to-treat diseases, and are expected to benefit patients with generally few treatment options. Furthermore, treatments able to target multiple cancers (Keytruda®, Rozlytrek®, Vitrakvi®) suggest a potential for broad therapies. However, a lower numberof orphan drugs were approvedin 2019, despiteefforts for accelerated assessment. These numberscall for increasedinnovationfor patientswithorphan diseasesin the new decade.

References: 1.) https://www.ema.europa.eu/en/news/human-medicines-highlights-2019 2.) https://www.fda.gov/drugs/drug-and-biologic-approval-and-ind-activity-reports/nda-and-bla-approvals