Keeping Track Of Oncology: US FDA Approves Herceptin Hylecta, Reviews Darolutamide And Pexidartinib

Oncology news and highlights from our US FDA Performance Tracker.

Convenience benefits for cancer patients took a leading role in the US FDA’s approvals for the week, thanks to a new subcutaneous injection formulation of Roche’s IV blockbuster Herceptin for breast cancer patients and a new, shorter IV push regimen to administer Heron Therapeutics Inc.’s IV anti-emetic Cinvanti.

Another aspect of patient experience, tolerability, will likely be a theme in FDA’s review of Bayer AG’s bid for darolutamide non-metastatic castration-resistant prostate cancer. Toxicity seen in Phase III could be an issue in the review of Daiichi Sankyo Co. Ltd.’s pexidartinib NDA for a rare type of non-malignant tumor, after the drug earned a breakthrough therapy designation with Phase I data.

Oncology news was rounded off by FDA approval of a new indication for Taiho Pharmaceutical Co. Ltd.’s Lonsurf and acceptance for priority review of a new indication for Celgene Corp.’s Revlimid.

Herceptin Hylecta Label Describes Patient Experience

FDA’s approval of Herceptin Hylecta (trastuzumab and hyaluronidase-oysk) with a “patient experience” section of labeling keeps Roche at the forefront of pharma companies incorporating patient-reported data in regulatory submissions.

The Herceptin Hylecta label is consistent with the model set by Roche and Genentech Inc. with Rituxan Hycela (rituximab/hyaluronidase), which broke new ground in June 2017 when it was approved with labeling including a “Patient Experience” subhead in the “Clinical Trials” section that described data from a dedicated randomized, cross-over study of patient preference. (Also see "Patient Experience Data May Require Separate Label, Genentech Suggests" - Pink Sheet, 25 Sep, 2017.)

Herceptin Hylecta, like Rituxan Hycela, uses recombinant hyaluronidase, an enzyme that increases dispersion and absorption of drugs, to enable subcutaneous administration of an oncologic agent that is otherwise given by IV. The subcutaneous administration offers a convenience benefit, but is not differentiated in efficacy or safety profile compared with the original IV formulation – a situation where documentation of the patient perspective is central to the company’s commercial strategy.

Herceptin Hylecta’s “patient experience” labeling summarizes the randomized cross-over PrefHER trial, which compared Hylecta with IV trastuzumab. Patients received four cycles of one formulation, then switched to four cycles of the other.

After cycle 8, 199 of 231 patients (86%) of patients reported preferring subcutaneous over IV therapy. “The most common reason cited was administration required less time (179/231) in the clinic,” the label states.

Labeling also points out that 13% of patients preferred IV trastuzumab over Herceptin Hylecta, with “fewer local injection reactions” as the most common reason. Only 1% of patients had no preference for route of administration.

FDA’s determination of Herceptin Hylecta’s safety and efficacy rested on two open-label studies, HannaH and SafeHER, in patients with HER2 overexpressing breast cancer. HannaH randomized patients to Hylecta or IV trastuzumab, while the nonrandomized SafeHER trial was a prospective, two-cohort study to assess overall safety and tolerability of Herceptin Hylecta.

“No new safety signals were identified for Herceptin Hylecta,” labeling reports. The label also cites clinical trials that underpinned approval of IV Herceptin to demonstrate the trastuzumab antibody’s safety and efficacy.

Taiho Lonsurf Rides TAGS Trial To Gastric Cancer Indication

Taiho’s Lonsurf (trifluridine and tipiracil) earned a second indication on Feb. 22 with FDA approval of the combination product for treatment of metastatic gastric or gastroesophageal junction adenocarcinoma previously treated with at least two prior lines of chemotherapy that included a fluoropyrimidine, a platinum, either a taxane or irinotecan, and if appropriate, HER2/neu-targeted therapy.

Lonsurf, which uses the thymidine phosphorylase inhibitor tipiracil to inhibit degradation of nucleoside metabolic inhibitor trifluridine, was first approved in 2015 to treat metastatic colorectal cancer patients previously treated with standard therapy.

FDA granted priority review to the new Lonsurf indication. The sNDA is based on the Phase III TAGS trial, which enrolled 507 patients treated with at least 2 prior regimens for advanced disease. The median overall survival (OS) of the Lonsurf patients was 5.7 months, compared with 3.6 months in the placebo arm.

Lonsurf’s success in the TAGS study came after several notable Phase III failures in gastric cancer, including Lilly’s Cyramza in first-line patients, Merck’s Keytruda in second-line PD-L1+ patients, and Merck KGaA and Pfizer’s Bavencio in a third-line setting.  (Also see "Lonsurf Hits Phase III OS Target In Gastric Cancer Study" - Scrip, 10 May, 2018.)

FDA Clears Faster Injection Of Heron’s Cinvanti

Heron’s Cinvanti is only NK1 receptor antagonist anti-emetic that can be administered with a two-minute IV push, the company announced after FDA approved the new administration regimen on Feb. 26. Cinvanti is an IV formulation of the NK1 RA aprepitant (Merck & Co. Inc.’s Emend and generics) that is free of the surfactant polysorbate 80, which can cause hypersensitivity and infusion site reactions.

FDA approved Cinvanti in November 2017 as a 30-minute IV infusion for prevention of acute and delayed nausea and vomiting associated with highly emetogenic cancer chemotherapy (HEC) and nausea and vomiting associated with moderately emetogenic chemotherapy (MEC).

“Data now show that the 2-minute IV push has comparable safety to the 30-minute IV infusion,” Heron said. The sNDA for the new method of administration was supported by a study demonstrating bioequivalence and a comparable safety profile for CINVANTI given as a 30-minute IV infusion and as a 2-minute IV injection, or push.

"Administration of Cinvanti by 2-minute IV push is an important advantage for our customers compared to Emend IV, which requires reconstitution and an IV bag for infusion,” the company observed.

Bayer’s Darolutamide Plans Rely On Tolerability Advantage

The rolling NDA submission for darolutamide to treat non-metastatic castration-resistant prostate cancer (nmCRPC), which started in December 2018, has been completed, Bayer announced Feb. 27. Bayer licensed the androgen receptor antagonist from Orion in 2014.

While nmCRPC – patients with no discernable metastases who have rising PSA levels while on androgen deprivation therapy – is a relatively new indication for drug therapy, darolutamide is in line to be the third androgen receptor in the space. FDA cleared Pfizer Inc./Astellas Pharma Inc.'s Xtandi (enzalutamide) and Johnson & Johnson's Erleada (apalutamide) in 2018 for nmCRPC.

In an interview at the recent American Society of Clinical Oncology Genitourinary Cancers Symposium, Bayer Head of Oncology Robert LaCaze emphasized importance of safety in the nmCRPC population, who are largely asymptomatic.

"A lot of these men may be on this drug for three or four years, and even low-grade toxicities like Grade 1 and 2 become problematic over a long period of time," LaCaze said. "We feel there is still unmet need in this space." (Also see "Bayer Sees Room For Third-To-Market Darolutamide In Prostate Cancer" - Scrip, 14 Feb, 2019.)

The pivotal study for the NDA is the Phase III ARAMIS trial in 1,509 men treated with standard of care ADT therapy who are at high risk for developing metastatic disease. The primary endpoint measured metastasis-free survival, which reached a median of 40.4 months in patients who received darolutamide and 18.4 months in the placebo arm – a 59% reduction in risk.

A New England Journal of Medicine article published the same day as the ASCO GU presentation described similar efficacy for darolutamide, Xtandi and Erleada, but highlighted the potential for fewer and less severe toxicity with darolutamide, partly stemming from its chemical structure and low penetration of the blood/brain barrier in animal studies.

In contrast to Xtandi and Erleada trials, fatigue effects associated with darolutamide were not associated with higher rates of falls or fractures in ARAMIS, the NEJM article pointed out. "The incidences of rash and hypothyroidism, which were higher among patients receiving apalutamide than among those receiving placebo, were low and similar in the darolutamide and placebo groups, as were the incidences of hypertension and central nervous system (CNS)-related adverse events. In the PROSPER and SPARTAN trials, hypertension and CNS-related adverse effects, such as mental-impairment disorders and dizziness, were more common among patients receiving enzalutamide or apalutamide than among those receiving placebo," the article adds.

FDA Review Of Daiichi Sankyo Pexidartinib To Weigh Hepatic Toxicity, Unmet Need In TGCT

Daiichi Sankyo could see FDA approval of two breakthrough-designated novel targeted therapies in the coming year, propelling the company towards its goal of delivering seven new molecular entities from 2018 to 2025.

FDA assigned an Aug. 3, 2019 priority review user fee goal to the colony stimulating factor 1 receptor (CSF1R) inhibitor pexidartinib for treatment of adult patients with symptomatic tenosynovial giant cell tumor (TGCT) that is associated with severe morbidity or functional limitations, and is not amenable to improvement with surgery.

The agency is already reviewing Daiichi Sankyo’s elective FLT3 inhibitor quizartinib for relapsed or refractory FLT3-ITD acute myeloid leukemia (AML), which has a May 29 priority review goal date.

Pexidartinib could be the first systemic therapy approved for TGCT, which is also known as pigmented villonodular synovitis (PVNS) or giant cell tumor of the tendon sheath (GCT-TS). The pivotal trial supporting the NDA, the Phase III ENLIVEN study, is the first systemic TGCT therapy trial with a placebo control, the company said.

ENLIVEN met its primary endpoint, showing a greater percentage of pexidartinib than placebo patients who achieved complete or partial response after 24 weeks of treatment.

Hepatic toxicity could be a concern for the pexidartinib review. Enrollment in ENLIVEN was stopped at 120, just short of its target, and the protocol was revised in 2016 after two cases of serious but non-fatal liver toxicity. (Also see "Daiichi Presses On With Lead Pexidartinib Trial Despite Liver Toxicity" - Scrip, 25 Oct, 2016.)

In February 2019, Daiichi Sankyo noted that hepatic adverse events were more frequent on the pexidartinib arm in ENLIVEN; eight patients discontinued the drug due to hepatic AEs, including four serious nonfatal AEs with increased bilirubin, one lasting approximately seven months.

“In non-TGCT development studies using pexidartinib, two severe liver toxicity cases (one required liver transplant, one was associated with death) were observed,” Daiichi Sankyo added.

Pexidartinib moved directly into Phase III after a Phase I trial showed reduced tumor burden in TGCT patients. Data from an extension cohort of the single-arm Phase I earned pexidartinib a breakthrough therapy designation in 2015. (Also see "Keeping Track: Nucala, Genvoya Approved; New Breakthrough Claims For Daiichi Sankyo, Merck Oncologics" - Pink Sheet, 9 Nov, 2015.)

TGCT is non-malignant, but can be locally aggressive and debilitating; repeat surgery to remove tumors can lead to significant joint damage, functional impairments, reduced quality of life and amputation, the company said.

Oncology is central to the Japanese pharma’s ambitions. (Also see "Daiichi Sankyo Hauls Back Mid-Term Profit Outlook As It Builds Oncology" - Scrip, 2 Nov, 2018.)

Celgene Looks AUGMENT Revlimid With Marginal Zone Lymphoma Claim

FDA set a June 27 priority review user fee goal date for Celgene’s application to add the R² regimen of Revlimid (lenalidomide) plus rituximab for treatment of patients with previously treated follicular and marginal zone lymphoma, Celgene reported in a Feb. 26.

Celgene is working to expand use of Revlimid, a blockbuster tentpole of the company’s oncology business, in advance of generic competition expected in 2022. While Celgene submitted the sNDA, Bristol-Myers Squibb Co. might eventually be making the marketing decisions. BMS announced an agreement to buy the smaller firm in early January 2019, but some big investors have doubts about the wisdom of the offer. (Also see "Celgene/Bristol: Happy Union Or Runaway Bride?" - Scrip, 28 Feb, 2019.)

Revlimid's sNDA is based on the Phase III AUGMENT trial comparing the R² combination against rituximab plus placebo in relapsed or refractory indolent lymphomas. The trial enrolled 295 patients with follicular lymphoma and 63 with marginal zone lymphoma.

The Revlimid/rituximab arm showed a median progression-free survival (PFS, the primary endpoint) of 39.4 months compared with 14.1 months for placebo/rituximab, Celgene reported in December 2018 at the American Society of Hematology annual meeting. Celgene noted a positive trend for improvement on overall survival, a secondary endpoint, with a two-year OS rate of 93% for R² patients and 87% for the placebo arm.