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FDA Actions & Updates

The latest approvals, designations, and new indications from the U.S. Food and Drug Administration for oncology drugs.

Friday, January 8, 2021

FDA Friday, January 8 Review - New Approvals This Week

Novel Anti-TIGIT Tiragolumab Granted FDA Breakthrough Therapy Designation in Combination With Atezolizumab for PD-L1-High Non-Small Cell Lung Cancer

Tiragolumab, a novel cancer immunotherapy designed to bind to TIGIT, has been granted Breakthrough Therapy Designation (BTD) by the FDA in combination with atezolizumab for the first-line treatment of people with metastatic non-small cell lung cancer (NSCLC) whose tumors have high PD-L1 expression with no EGFR or ALK genomic tumor aberrations. Tiragolumab is the first anti-TIGIT molecule to be granted BTD from the FDA, and the designation is based on randomized data from the Phase II CITYSCAPE trial. CITYSCAPE provides the first evidence that targeting both immune inhibitory receptors, TIGIT and PD-L1, may enhance anti-tumor activity by potentially amplifying the immune response.

BTD is designed to accelerate the development and review of medicines intended to treat serious or life-threatening conditions, with preliminary evidence that indicates they may demonstrate a substantial improvement over existing therapies. This marks the 37th BTD for Genentech's portfolio of medicines.

Tiragolumab in combination with atezolizumab has so far shown encouraging efficacy and safety in PD-L1-positive metastatic NSCLC based on data from the Phase II CITYSCAPE trial, the first randomized study in the anti-TIGIT field. Full results from CITYSCAPE, presented at the American Society of Clinical Oncology 2020 Virtual Scientific Program, showed that at an average of 10.9 months follow-up, the combination showed an improvement in the overall response rate (ORR; 37% vs. 21% with atezolizumab alone) and a 42 percent reduction in the risk of disease worsening or death (progression-free survival; PFS) compared with atezolizumab alone. An exploratory analysis in people with high levels of PD-L1 (tumor proportion score; TPS ≥ 50%) showed a clinically meaningful ORR vs. atezolizumab alone (66% vs. 24%) and median PFS was not reached (vs. 4.11 months with atezolizumab alone; HR=0.30, 95% CI: 0.15–0.61). The data suggest that tiragolumab plus atezolizumab was generally well-tolerated, showing similar rates of all Grade 3 or more all-cause adverse events when combining the two immunotherapies compared with atezolizumab alone (48% vs. 44%).

Researchers are investigating the potential of tiragolumab in a broad development program that builds on the benefit observed with atezolizumab while expanding into earlier stages of disease and new areas of unmet need. This includes randomized trials in metastatic NSCLC (SKYSCRAPER-01 and SKYSCRAPER-06) and small cell lung cancer (SKYSCRAPER-02), as well as exploration of tiragolumab in earlier stages, including stage III NSCLC (SKYSCRAPER-03) and locally advanced esophageal cancer (SKYSCRAPER-07). Tiragolumab is also being investigated in metastatic esophageal squamous cancer (SKYSCRAPER-08) and cervical cancer (SKYSCRAPER-04), with early trials in other tumor types.

Biomarker analyses from the CITYSCAPE study will be presented at the IASLC 2020 World Conference on Lung Cancer hosted by the International Association for the Study of Lung Cancer, taking place from January 28-31, 2021 (efficacy of tiragolumab + atezolizumab in PD-L1 IHC and TIGIT Subgroups in the Phase II CITYSCAPE Study in First-Line NSCLC).

 

Zenocutuzumab Granted FDA Fast Track Designation for the Treatment of Patients with Neuregulin 1

The FDA has granted Fast Track Designation to zenocutuzumab (zeno) for the treatment of patients with metastatic solid tumors harboring NRG1 gene fusions (NRG1+ cancers) that have progressed on standard of care therapy.

NRG1 gene fusions are a group of rare genomic alterations emerging as potential actionable drivers of tumorigenesis and growth across many types of solid tumors, including lung, breast, pancreatic, ovarian, and colorectal cancers. A Phase I/II  eNRGy trial is currently enrolling patients to evaluate zeno monotherapy in patients with NRG1+ cancers, in three cohorts: non-small cell lung cancer; pancreatic cancer; and other solid tumors.



Lorlatinib Snda In Previously Untreated Alk-Positive Lung Cancer Accepted For Priority Review

The FDA has accepted for Priority Review the supplemental New Drug Application (sNDA) for lorlatinib as a first-line treatment for people with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC). The sNDA is based on data from the pivotal CROWN study and is being reviewed by the FDA under its Real-Time Oncology Review (RTOR) pilot program. The Prescription Drug User Fee Act (PDUFA) goal date for a decision by the FDA is in April 2021.​​

Lorlatinib is a third-generation ALK inhibitor specifically developed to inhibit the most common tumor mutations that drive resistance to current medications and to address brain metastases. Up to 40 percent of people with ALK-positive lung cancer present with brain metastases.

The FDA also will conduct the review under Project ORBIS, an initiative introduced in 2019, which provides a framework for potential concurrent submissions and collaborative review with health authorities in Canada, Singapore, Switzerland, Australia, Brazil and the United Kingdom. Under Project ORBIS, collaboration among international regulators may allow patients with cancer to receive earlier access to products in other countries.

The submission is supported by positive results from the Phase III CROWN trial, CROWN is a randomized, open-label, parallel 2-arm trial in which 296 people with previously untreated advanced ALK-positive NSCLC were randomized 1:1 to receive lorlatinib monotherapy (n=149) or crizotinib monotherapy (n=147). The primary endpoint of the CROWN trial is progression-free survival (PFS) based on blinded independent central review (BICR). Secondary endpoints include PFS based on investigator's assessment, overall survival (OS), objective response rate (ORR), intracranial objective response, and safety. The trial met the primary endpoint of improved progression-free survival (PFS) versus crizotinib.  Detailed results were published in the New England Journal of Medicine and previously presented at the European Society for Medical Oncology (ESMO) Virtual Congress 2020.

In 2018, the FDA approved lorlatinib for the treatment of patients with ALK-positive metastatic NSCLC whose disease has progressed on crizotinib and at least one other ALK inhibitor for metastatic disease; or whose disease has progressed on alectinib or ceritinib as the first ALK inhibitor therapy for metastatic disease. This indication was approved under accelerated approval based on tumor response rate and duration of response. Data from the CROWN study will also support the conversion to a full approval for the use of lorlatinib for this indication.



FDA Grants ARX788 Fast Track Designation for HER2-positive Metastatic Breast Cancer

The FDA granted ARX788 Fast Track Designation as monotherapy for the treatment of advanced or metastatic HER2-positive breast cancer patients who have received one or more prior anti-HER2 based regimens in the metastatic setting.

ARX788 is a homogeneous and highly stable antibody drug conjugate (ADC) targeting the HER2 receptor. ARX788 is a Precision Biologic ADC that consists of two cytotoxic payloads site-specifically conjugated to a trastuzumab based antibody. ARX788 was designed for maximum performance in the preclinical setting by optimizing the number, position and chemical bonds that conjugate the cytotoxic AS269 payload to the antibody. AS269 is a proprietary tubulin inhibitor specifically designed to form a highly stable covalent bond with our synthetic amino acids, a fundamental step in the creation of a Precision ADC.

 

FDA Approves Addition of Overall Survival and Other Secondary Endpoint Data to Darolutamide Prescribing Information

The FDA approved a supplemental New Drug Application (sNDA) to add overall survival (OS) and other secondary endpoint data from the Phase III ARAMIS trial to the darolutamide Prescribing Information. darolutamide significantly reduced the risk of death by 31 percent, offering men with non-metastatic castration-resistant prostate cancer (nmCRPC) extended survival for a greater chance of living longer. Additional data include time to pain progression and time to initiation of cytotoxic chemotherapy. The Prescribing Information was also updated to include additional guidance on drug interactions. The final analysis reinforced darolutamide 's safety profile with an extended follow-up of median 29 months for the overall study population.

The updated Prescribing Information follows the presentation of these data at the American Society of Clinical Oncology (ASCO) 2020 Virtual Scientific Program and subsequent September 10 publication in The New England Journal of Medicine (2020; DOI: 10.1056/NEJMoa2001342).

Data from Primary and Final Analyses of Phase III ARAMIS Trial

Previously published results in 1,509 patients from the Phase III ARAMIS trial demonstrated a highly significant improvement in the primary efficacy endpoint of metastasis-free survival (MFS), with a median of 40.4 months (n=955) with darolutamide plus androgen deprivation therapy (ADT), compared to 18.4 months (n=554) for placebo plus ADT (p<0.001). MFS is defined as the time from randomization to the time of first evidence of blinded independent central review (BICR)-confirmed distant metastasis or death from any cause within 33 weeks after the last evaluable scan, whichever occurred first.

The proven tolerability of darolutamide was supported by the three adverse reactions occurring more frequently in the darolutamide arm (≥2% over placebo): fatigue (16% versus 11%), pain in extremity (6% versus 3%) and rash (3% versus 1%). Darolutamide was not studied in women and there is a warning and precaution for embryo-fetal toxicity.

 

Secondary Endpoint Data from Phase III ARAMIS Trial Now Included in Prescribing Information

In the Phase III ARAMIS trial, men with nmCRPC receiving darolutamide plus ADT showed a statistically significant improvement in OS compared to placebo plus ADT, with a 31% reduction in risk of death (HR=0.69, 95% CI 0.53-0.88; p=0.003). OS was statistically significant despite 31% (n=170) of patients in the ADT arm crossing over to darolutamide. In total, 55% (n=307) of patients in the ADT arm crossed over to darolutamide or received another life-prolonging therapy prior to this analysis.

Other secondary endpoints incorporated in the Prescribing Information for darolutamide also showed statistical significance, including delaying time to pain progression (HR=0.65, 95% CI 0.53-0.79; p<0.0001) and time to initiation of cytotoxic chemotherapy (HR=0.58, 95% CI 0.44-0.76; p<0.0001).1

Time to pain progression was defined as at least a 2-point worsening from baseline of the pain score on Brief Pain Inventory-Short Form or initiation of opioids and reported in 28 percent of all patients on study.​

There was no safety update of the Prescribing Information, reflecting no new safety signals discovered at the final analysis. The Prescribing Information was updated to include additional drug interactions. darolutamide inhibits OATP1B1 and OATP1B3 transporters. Concomitant use may increase plasma concentrations of OATP1B1 or OATP1B3 substrates. Monitor more frequently for adverse reactions and consider dose reduction of these substrates.