publication date: Apr. 24, 2020

Drugs & Targets

FDA approves Tukysa in breast cancer indication

FDA has approved Tukysa in combination with chemotherapy (trastuzumab and capecitabine) for the treatment of adult patients with advanced forms of HER2-positive breast cancer that can’t be removed with surgery, or has spread to other parts of the body, including the brain, and who have received one or more prior treatments.

Seattle Genetics sponsors Tukysa.

FDA collaborated with the Australian Therapeutic Goods Administration, Health Canada, Health Sciences Authority (HSA, Singapore) and Swissmedic (SMC, Switzerland) on this review.

This is the first Project Orbis partnership between the FDA, HSA and Swissmedic. While FDA approved Tukysa, the application is still under review at the other agencies.

Collaboration among international regulators may allow patients with cancer to receive earlier access to products in other countries where there may be significant delays in regulatory submissions, regardless of whether the product has received FDA approval. Early availability of new therapies and adoption as standard of care around the world may have an impact on the increasingly international conduct of cancer clinical trials, potentially accelerating the development of anticancer products.

“The FDA’s Project Orbis provides a framework for concurrent submission and review of oncology drug applications among the FDA’s international collaborators,” Richard Pazdur, director of the FDA Oncology Center of Excellence and acting director of the Office of Oncologic Diseases in the FDA Center for Drug Evaluation and Research, said in a statement.

“We are pleased to work with our Singapore and Switzerland colleagues for the first time, and to continue working alongside our Australian and Canadian colleagues as we facilitate new treatment options for patients—like today’s first new molecular entity under Project Orbis,” Pazdur said.

“The clinical trial supporting this approval enrolled and specifically studied patients with active brain metastases in addition to the overall population enrolled, which also demonstrated benefit in this subgroup,” Pazdur said.

More than 25% of women with metastatic HER2-positive breast cancer will develop brain metastases.

“We recognize that patients with cancer constitute a vulnerable population at risk of contracting the coronavirus disease,” said Pazdur. “In this critical time, we remain steadfast in our commitment to patients with cancer and doing everything we can to expedite oncology product development. Tukysa was approved four months prior to the FDA goal date, providing an example of this commitment and showing how our regular work in reviewing treatments for patients with cancer is moving forward without delay.”

Tukysa is a kinase inhibitor, and was approved for treatment after patients have taken one or more anti-HER2-based regimens in the metastatic setting. The FDA approved Tukysa based on the results of a clinical trial enrolling 612 patients who had HER2-positive advanced unresectable or metastatic breast cancer and had prior treatment with trastuzumab, pertuzumab and ado-trastuzumab emtansine (T-DM1).

Patients with previously treated and stable brain metastases, as well as those with previously treated and growing or untreated brain metastases, were eligible for the clinical trial, and 48% of enrolled patients had brain metastases at the start of the trial.

The primary endpoint was progression-free survival. The median PFS in patients who received Tukysa, trastuzumab, and capecitabine was 7.8 months compared to 5.6 months in those patients who received placebo, trastuzumab, and capecitabine.

Overall survival and PFS in patients with brain metastases at baseline were key secondary endpoints. The median overall survival in patients who received Tukysa, trastuzumab, and capecitabine was 21.9 months compared to 17.4 months in patients who received placebo, trastuzumab, and capecitabine. The median PFS in patients with brain metastases at baseline who received Tukysa, trastuzumab and capecitabine was 7.6 months compared to 5.4 months in patients who received placebo, trastuzumab and capecitabine.


FDA grants accelerated approval for Trodelvy in previously-treated metastatic TNBC

FDA has approved Trodelvy (sacituzumab govitecan-hziy) for the treatment of adult patients with metastatic triple-negative breast cancer who have received at least two prior therapies for metastatic disease.

Patients must have received at least two prior therapies before taking Trodelvy. Trodelvy is the first ADC approved by the FDA specifically for relapsed or refractory metastatic TNBC and is also the first FDA-approved anti-Trop-2 ADC.

Trodelvy, which was granted Breakthrough Therapy Designation and Priority Review, was approved under the FDA Accelerated Approval Program based on the objective response rate and duration of response observed in a single-arm, multicenter phase II study.

“Metastatic triple-negative breast cancer is an aggressive form of breast cancer with limited treatment options. Chemotherapy has been the mainstay of treatment for triple-negative breast cancer. The approval of Trodelvy today represents a new targeted therapy for patients living with this aggressive malignancy,” Richard Pazdur, director of the FDA Oncology Center of Excellence and acting director of the Office of Oncologic Diseases in the FDA Center for Drug Evaluation and Research, said in a statement. “There is intense interest in finding new medications to help treat metastatic triple-negative breast cancer. Today’s approval provides patients who’ve already tried two prior therapies with a new option.”

Continued approval may be contingent upon verification of clinical benefit in the confirmatory phase III ASCENT study, which was recently halted by the independent data safety monitoring Committee for compelling evidence of efficacy across multiple endpoints.

“In our trial, Trodelvy demonstrated clinically meaningful responses in patients with difficult-to-treat metastatic TNBC and moves the needle towards better outcomes for patients with metastatic breast cancer,” lead investigator Aditya Bardia, director of Precision Medicine at the Center for Breast Cancer, Massachusetts General Hospital Cancer Center, and assistant professor of Medicine at Harvard Medical School, said in a statement.

In the single-arm phase II study, Trodelvy demonstrated an ORR of 33.3% (95% CI: 24.6, 43.1) and a median DoR of 7.7 months (95% CI: 4.9, 10.8), as determined by local assessment, in 108 adult TNBC patients who had previously received a median of three prior systemic therapies in the metastatic setting (range: 2-10).


FDA approves first targeted treatment for patients with cholangiocarcinoma

FDA has granted accelerated approval to Pemazyre (pemigatinib), the first treatment approved for adults with certain types of previously treated, advanced cholangiocarcinoma.

FDA also approved the FoundationOne CDX (Foundation Medicine Inc.)  as a companion diagnostic for patient selection.

Incyte Corp. sponsors the drug.

“This approval demonstrates that while we continue to focus our efforts on addressing the COVID-19 pandemic, the FDA remains committed to the important work of reviewing treatments for patients with cancer and other serious conditions,” said Richard Pazdur, director of the FDA Oncology Center of Excellence and acting director of the Office of Oncologic Diseases in the FDA’s Center for Drug Evaluation and Research, said in a statement.

“With Pemazyre, we considered the observed efficacy results to be clinically meaningful and the overall risk to benefit assessment for patients with tumors harboring FGFR2 gene fusions and other rearrangements to be favorable, particularly when we considered that these patients have no other good options following first line treatment with chemotherapy,” Pazdur said.

The approval is for locally advanced or metastatic cholangiocarcinoma in patients who have tumors that have a fusion or other rearrangement of the FGFR2 gene.

At diagnosis, a majority of patients with cholangiocarcinoma have advanced disease. Prior to the April 17 approval, there were no FDA-approved therapies for the disease. FGFR2 fusions have been found in the tumors of approximately 9% to 14% of patients with cholangiocarcinoma. Pemazyre is a tablet that works by blocking FGFR2 in tumor cells.

Efficacy was investigated in FIGHT-202 (NCT02924376), a multicenter open-label single-arm trial, in 107 patients with locally advanced unresectable or metastatic cholangiocarcinoma whose disease had progressed on or after at least one prior therapy and had an FGFR2 gene fusion or rearrangement. Patients received pemigatinib, 13.5 mg orally, once daily for 14 consecutive days, followed by 7 days off therapy.

The major efficacy outcome measures were overall response rate and duration of response determined by an independent review committee using RECIST 1.1. Among the 107 patients, the ORR was 36% (95% CI: 27%, 45%), including three complete responses. The median DOR was 9.1 months with responses lasting ≥ 6 months in 24 of the 38 (63%) responding patients and ≥ 12 months in 7 (18%) patients.


FDA approves Imbruvica in CLL/SLL indication

FDA has approved Imbruvica (ibrutinib) in combination with rituximab for the treatment of previously untreated patients with chronic lymphocytic leukemia or small lymphocytic lymphoma.

AbbVie sponsors Imbruvica.

“The FDA approval of ibrutinib and rituximab regimen is welcome news for these previously untreated patients who have been looking forward to a non-chemotherapy treatment option. The results from ECOG-ACRIN’s E1912 clinical trial in previously untreated, younger adult patients and today’s milestone represent a paradigm shift in how physicians can treat patients with CLL and may enable many to choose a non-chemotherapy treatment option,” Brian Koffman, chief medical officer and executive vice president of CLL Society, said in a statement.

Approval was based on the E1912 trial (NCT02048813), a 2:1 randomized, multicenter, open-label, actively controlled trial of ibrutinib with rituximab compared to fludarabine, cyclophosphamide, and rituximab (FCR) in 529 adult patients 70 years or younger with previously untreated CLL or SLL requiring systemic therapy. Patients with 17p deletion were excluded. Ibrutinib was administered at 420 mg daily until disease progression or unacceptable toxicity.

The main efficacy outcome measure was progression-free survival (PFS). The trial demonstrated a statistically significant improvement in PFS for patients receiving ibrutinib plus rituximab compared with those receiving FCR (HR 0.34; 95% CI: 0.22, 0.52; p<0.0001). Median PFS was not reached in either arm after a median follow-up duration of 37 months.

In addition to the Real-Time Oncology Review pilot program and priority review, the approval was granted under the FDA’s recently established Project Orbis, an initiative of the FDA Oncology Center of Excellence, which provides a framework for submission and review of oncology medicine applications among multiple regulatory agencies worldwide.

For this application, a modified Project Orbis was undertaken because of the timing of submission to other regulatory agencies. FDA is collaborating with the Australian Therapeutic Goods Administration, Health Canada, and Swissmedic as they review the application.

“Imbruvica enables long-term disease management and now has demonstrated superior progression-free survival compared to a standard chemoimmunotherapy regimen. Today, many patients who were previously considered appropriate for chemotherapy now have an alternative treatment option,” Danelle James, Imbruvica Clinical Development Lead, Pharmacyclics LLC, an AbbVie company, said in a statement.

The E1912 study demonstrated that previously untreated patients (ages 70 or younger) with CLL have superior progression free survival Imbruvica plus rituximab compared to those treated with fludarabine, cyclophosphamide and rituximab (FCR).

At a median follow-up of 37 months, Imbruvica plus rituximab significantly improved PFS compared to FCR (hazard ratio [HR] 0.34; 95% confidence interval [CI]: 0.22-0.52; p<0.0001). With a median follow-up time of 49 months, median overall survival was not reached with a total of 23 deaths: 11 (3%) in the IMBRUVICA plus rituximab and 12 (7%) in the FCR treatment arms.


FDA approves Keytruda companion diagnostic

FDA has approved PD-L1 IHC 22C3 pharmDx as a companion diagnostic to identify patients with non-small cell lung cancer who are appropriate for first-line monotherapy with Keytruda on the Dako Omnis platform.

Agilent Technologies Inc. sponsors PD-L1 IHC 22C3 pharmDx. Dako Omnis is Agilent’s fully automated, walk-away solution for staining tumor samples that provides a flexible, high-throughput diagnostic service integrated into the core of the laboratory workflow.

Copyright (c) 2020 The Cancer Letter Inc.