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FDA Pipeline: Two Reviews in NSCLC, Plus Prescribing Information Update for Darolutamide


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Recently, the U.S. Food and Drug Administration (FDA) granted Priority Review to lorlatinib in ALK-positive non–small cell lung cancer (NSCLC) and Breakthrough Therapy designation to the combination of tiragolumab plus atezolizumab in NSCLC with high PD-L1 expression. The FDA also updated the prescribing information for darolutamide in patients with prostate cancer.

Priority Review for Lorlatinib in Previously Untreated ALK-Positive NSCLC

The FDA accepted for Priority Review a supplemental new drug application for lorlatinib as a first-line treatment for people with anaplastic lymphoma kinase (ALK)-positive metastatic non–small cell lung cancer (NSCLC). The application is based on data from the pivotal CROWN study and is being reviewed by the FDA under its Real-Time Oncology Review pilot program. The Prescription Drug User Fee Act 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% 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, which met the primary endpoint of improved progression-free survival vs crizotinib in people with previously untreated advanced ALK-positive NSCLC. Detailed results were published in The New England Journal of Medicine and previously presented at the European Society for Medical Oncology Virtual Congress 2020 (Abstract LBA2).

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.

About the CROWN Study

CROWN is a phase III, randomized, open-label, parallel two-arm trial in which 296 people with previously untreated advanced ALK-positive NSCLC were randomly assigned 1:1 to receive lorlatinib monotherapy (n = 149) or crizotinib monotherapy (n = 147). The primary endpoint of the CROWN trial is progression-free survival based on blinded independent central review; secondary endpoints include progression-free survival based on investigator’s assessment, overall survival, objective response rate, intracranial objective response, and safety.

Tiragolumab/Atezolizumab Granted Breakthrough Therapy Designation for PD-L1–High NSCLC

Tiragolumab, a novel cancer immunotherapy designed to bind to TIGIT, has been granted Breakthrough Therapy designation by the FDA in combination with atezolizumab for the first-line treatment of people with metastatic NSCLC whose tumors have high PD-L1 expression and no EGFR or ALK genomic tumor aberrations. Tiragolumab is the first anti-TIGIT molecule to be granted Breakthrough Therapy designation 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 antitumor activity by potentially amplifying the immune response.

Tiragolumab is a monoclonal antibody designed to bind with TIGIT, a protein receptor on immune cells. Atezolizumab is a monoclonal antibody designed to bind with the protein PD-L1, which is expressed on tumor cells and tumor-infiltrating immune cells, blocking its interactions with both PD-1 and B7.1 receptors.

Tiragolumab in combination with atezolizumab has so far shown efficacy and good 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 ASCCO20 Virtual Scientific Program (Abstract 9503), demonstrated that at an average of 10.9 months follow-up, the combination showed an improvement in the overall response rate (37% vs 21% with atezolizumab alone) and a 42% reduction in the risk of disease worsening or death (progression-free survival) compared with atezolizumab alone.

An exploratory analysis in people with high levels of PD-L1 (tumor proportion score ≥ 50%) showed a clinically meaningful overall response rate vs atezolizumab alone (66% vs 24%), and median progression-free survival was not reached (vs 4.11 months with atezolizumab alone). 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%).

Biomarker analyses from the CITYSCAPE study will be presented at the 2020 World Conference on Lung Cancer, hosted by the International Association for the Study of Lung Cancer (IASLC) and taking place from January 28 to 31, 2021.

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

The FDA approved a supplemental new drug application to add overall survival and other secondary endpoint data from the phase III ARAMIS trial to the darolutamide prescribing information. Darolutamide reduced the risk of death by 31% in men with nonmetastatic castration-resistant prostate cancer. 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 (median = 29 months) for the overall study population.

The updated prescribing information follows the presentation of these data at the ASCO20 Virtual Scientific Program (Abstract 5514) and subsequent publication in The New England Journal of Medicine.

Darolutamide is an androgen-receptor inhibitor with a distinct chemical structure that competitively inhibits androgen binding, androgen receptor nuclear translocation, and androgen receptor–mediated transcription.

Previously published results on 1,509 patients from the phase III ARAMIS trial demonstrated a highly significant improvement in the primary efficacy endpoint of metastasis-free survival, with a median of 40.4 months (n = 955) with darolutamide plus androgen-deprivation therapy compared to 18.4 months (n = 554) for placebo plus androgen-deprivation therapy (P < .001). Metastasis-free survival is defined as the time from random assignment to the time of first evidence of blinded independent central review–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% vs 11%), pain in extremity (6% vs 3%), and rash (3% vs 1%).

In the ARAMIS trial, men with nonmetastatic castration-resistant prostate cancer receiving darolutamide plus androgen-deprivation therapy showed a statistically significant improvement in overall survival compared to placebo plus androgen-deprivation therapy, with a 31% reduction in risk of death. Overall survival was statistically significant despite 31% (n = 170) of patients in the androgen-deprivation therapy arm crossing over to darolutamide. In total, 55% (n = 307) of patients in the androgen-deprivation therapy 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 and time to initiation of cytotoxic chemotherapy. Time to pain progression was defined as at least a two-point worsening from baseline of the pain score on Brief Pain Inventory–Short Form or initiation of opioids and reported in 28% of all patients on study.

There was no safety update of the prescribing information, reflecting no new safety signals discovered at the final analysis. However, the prescribing information was updated to include additional drug interactions.

Fast Track Designation of Zenocutuzumab for the Treatment of Patients With NRG1 Fusion–Positive Cancers

The FDA granted Fast Track designation to zenocutuzumab for the treatment of patients with metastatic solid tumors harboring NRG1 gene fusions 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. Patients are currently being enrolled in the phase I/II eNRGy trial evaluating zenocutuzumab monotherapy in patients with NRG1 gene fusion–positive cancers, in three cohorts: NSCLC, pancreatic cancer, and other solid tumors.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
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