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Mar&iacute;a Varela, MD, PhD, discusses the findings from a real-life analysis to confirm the benefit of regorafenib as treatment of patients with hepatocellular carcinoma who have progressed on prior sorafenib. Regorafenib was approved by the FDA for second-line treatment in this patient population based on data from the phase III RESORCE trial.

Survival Benefit Confirmed in Real-Life Analysis of Second-Line Regorafenib in HCC

The biologics license application (BLA) of the subcutaneous formulation of nivolumab (Opdivo) coformulated with human hyaluronidase (rHuPH20) has been accepted by the FDA.

Findings from the CheckMate -67T (NCT04810078) support this BLA of subcutaneous nivolumab as the trial met its coprimary pharmacokinetic end points and key secondary end point of overall response rate (ORR) vs intravenous (IV) nivolumab in clear cell renal cell carcinoma.

The FDA has set a Prescription Drug User Fee Act (PDUFA) goal date for December 29, 2024.

The FDA has accepted the BLA of the subcutaneous formulation of nivolumab coformulated with rHuPH20, also known as subcutaneous nivolumab, for all previously approved adult solid tumor indications of nivolumab as a monotherapy, monotherapy maintenance following completion of the combination therapy with nivolumab plus ipilimumab (Yervoy), or in combination with chemotherapy or cabozantinib (Cabometyx).

Results from the phase 3 CheckMate -67T trial of subcutaneous nivolumab support this application. In the trial, experts sought to evaluate subcutaneous nivolumab vs its intravenous (IV) formulation.

 Here, the subcutaneous form demonstrated noninferior pharmacokinetics and efficacy, as well as consistent safety compared with the IV formulation of nivolumab among patients with advanced or metastatic clear cell renal cell carcinoma (ccRCC) who have received prior systemic therapy.

A PDUFA goal date has been set for December 29, 2024. With this, subcutaneous nivolumab shows promise to become the first and only subcutaneously administered PD-1 inhibitor.

“We believe subcutaneous nivolumab has the potential to make a significant difference in the lives of patients, which is reinforced by the FDA’s acceptance of our application,” said Gina Fusaro, PhD, vice president, global program lead, Bristol Myers Squibb, in a press release.

“[Nivolumab] is a foundational PD-1 inhibitor approved for many different types of cancer, and our continued investment in research that puts patients first remains a priority. If approved by the FDA, the subcutaneous administration of nivolumab would provide patients and their physicians with a new option that delivers the same well-known benefits as IV [nivolumab] but with the improved convenience of an injection administered in 3 to 5 minutes rather than a 30- to 60-minute infusion,” Fusaro continued.

The phase 3, randomized, open-label CheckMate -67T trial is exploring subcutaneous administration of nivolumab coformulated with rHuPH20 vs IV nivolumab for the treatment of patients with advanced or metastatic ccRCC who were previously treated with systemic therapy.

In the study, 495 patients were randomly assigned to receive either subcutaneous nivolumab or IV nivolumab. Enrollment was open to patients with a histological confirmation of ccRCC, advanced RCC not amenable to curative or radiation therapy, metastatic RCC, those who received no more than 2 prior systemic therapies, those with intolerance or progression after last treatment regimen within 6 months of randomization, and those with a Karnofsky performance score ≥ 70 at screening.

Experts assessed the coprimary end points of time-averaged serum concentration over 28 days and trough serum concentration at steady-state of subcutaneous nivolumab vs IV nivolumab. A key secondary end point of the trial was ORR.

The study met its coprimary pharmacokinetic end points and key secondary end point of ORR with subcutaneous nivolumab in this patient population.

 Subcutaneous nivolumab was noninferior in regard to time-averaged nivolumab serum concentration over 28 days and steady-state trough serum concentration vs treatment with IV nivolumab. Additionally, subcutaneous nivolumab also demonstrated a noninferior ORR compared with IV nivolumab.

1. U.S. Food and Drug Administration accepts Bristol Myers Squibb’s application for subcutaneous nivolumab (nivolumab and hyaluronidase). News release. Bristol Myers Squibb. May 6, 2024. Accessed May 6, 2024. 

2. Phase 3 Check-Mate -67T trial of subcutaneous nivolumab (nivolumab and hyaluranisade) meets co-primary end points in advanced or metastatic clear cell renal cell carcinoma. News release. Bristol Myers Squibb. October 19, 2024. Accessed May 6, 2024. 

3. A study of subcutaneous nivolumab versus intravenous nivolumab in participants with previously treated clear cell renal cell carcinoma that is advanced or has spread (CheckMate-67T). ClinicalTrials.gov. Updated October 12, 2023. Accessed May 6, 2024. 

https://www.clinicaltrials.gov/study/NCT04810078

The FDA is considering a subcutaneous nivolumab formulation for various solid tumors based on promising data from the phase 3 CheckMate -67T trial. A target action date has been set for December 29, 2024.

News

Clinical

FDA Accepts BLA for Subcutaneous Nivolumab Across Various Solid Tumors

Talazoparib is the first PARP inhibitor to be granted approval with an approved standard-of-care therapy, enzalutamide for the treatment of adult patients with homologous recombination repair (HRR) gene-mutated metastatic castration resistant prostate cancer (mCRPC).

In addition to the United States approval, a marketing authorization application has been accepted for review by the European Medicines Agency.

The agent has approval in over 70 countries for the treatment of 

-mutated, HER2-negative locally advanced or metastatic breast cancer.

The FDA has granted approval to the combination of talazoparib (Talzenna) plus enzalutamide (Xtandi) for the treatment of patients with HRR gene–mutated mCRPC.

Findings from the phase 3 TALAPRO-2 trial (NCT03395197) support the approval. According to data recently presented at the American Society of Clinical Oncology (ASCO) Annual Meeting, the combination achieved statistically significant and clinically meaning progression free survival (PFS) improvement as a first-line therapy for patients with mCRPC that have HRR gene-altered disease.

“Despite treatment advancement in metastatic castration-resistant prostate cancer, the disease can progress quickly, and many patients may only receive one line of therapy. Therefore, new first-line treatment options are needed to reduce the risk of disease progression or death. For patients with mCRPC harboring HRR genetic alterations, outcomes are even worse,” said Neeraj Agarwal, MD, FASCO, professor and presidential endowed chair of Cancer Research at Huntsman Cancer Institute, University of Utah, in a press release.

“The FDA’s approval of the talazoparib and enzalutamide combination is based on the findings from the pivotal TALAPRO-2 study, which demonstrated statistically significant and clinically meaningful reductions in the risk of progression or death among HRR gene-mutated tumors in patients with metastatic castration-resistant prostate cancer. It represents a treatment option deserving of excitement and attention.”

The primary endpoint of radiographic PFS (rPFS) with a 55% reduced risk of progression of death in patients on the combination arm (n = 200) was achieved in the TALAPRO-2 study, despite median rPFS was not being reached (NR) in the talazoparib arm (95% CI, 21.9-NR) compared with 13.8 months (95% CI, 11.0-16.7) in the placebo arm (HR, 0.45; 95% CI, 0.33-0.61, 

 < 0.0001). Further, the combination showed in a 37% lower risk of rPFS in the talazoparib plus enzalutamide arm compared with the placebo plus enzalutamide arm (HR, 0.63; 95% CI 0.51–0.78; 

In the HRR gene-altered subgroup, there was also an rPFS benefit demonstrated with talazoparib plus enzalutamide (HR, 0.44; 95% CI, 0.32-0.60, 

 < 0.0001), and this benefit was extended to the 

-mutated population (HR, 0.20; 95% CI, 0.11-0.36, 

population (HR, 0.68; 95% CI, 0.46-1.02; 

Additional results showed that talzoparib with first-line enzalutamide also prolonged the time to PSA progression for these mCRPC patients, resulting in an approximately 40% reduction of risk between both arms. A median of 28.6 months (95% CI, 26.7-NR) time to PSA progression in the treatment arm was seen compared with 11.1 months (95% CI, 9.3-13.9) in the placebo and enzalutamide arm (HR, 0.41; 95% CI, 0.30-0.57, 

Time to cytotoxic chemotherapy was improved with the combination at 38 events vs 65 in the placebo arm (HR, 0.46; 95% CI, 0.31-0.79, 

 = 0.0001). Moreover, there was a median PFS2 of 36.4 months (95 CI, 364.4-NR) and 28.1 months (95% CI, 24.5-NR), respectively (HR, 0.57; 95% CI, 0.39-0.85, 

The combination arm had an objective response rate (ORR) of 67.1, which included complete responses in 38.4% of patients and stable disease rate of 26% was observed, while 5.6% of remaining patients on the combination arm had progressive disease. Comparatively, the ORR was 40% in the placebo arm with 18.5% of those responses being complete, 32.3% had stable disease and 20% had progressive disease.

There were no new safety signals observed with talazoparib when combined with enzalutamide in the study. Investigators reported grade 3-4 treatment emergent adverse effects (TEAEs) in 66.2% of patients in the combination therapy vs 37.2% of those in the placebo and enzalutamide treatment. Of those treated with the combination, 67.2% of patients had a dose interruption of talazoparib due to an AE compared with 19.6% of those on the placebo arm and 55.6% of patients in the combination arm had to dose reduce their talazoparib. Overall, treatment discontinuation rates were low in both arms.

“Pfizer has a legacy of bringing medicines to patients with genitourinary cancers and helping improve outcomes for patients suffering from advanced prostate cancer,” said Angela Hwang, chief commercial officer, president, Global Biopharmaceuticals Business, Pfizer, in the press release.

 “As a global standard of care, Xtandi has shown efficacy in three types of prostate cancer, and the addition of Talzenna demonstrated significant improvements in delaying or preventing radiographic progression-free survival or death in patients with this type of advanced prostate cancer. With today’s FDA approval of Talzenna plus Xtandi, we are proud to be able to offer this potentially practice-changing treatment to patients and add to their options in managing this aggressive disease.”

1. Pfizer’s TALZENNA® in combination with XTANDI® receives U.S. FDA approval. News release. Pfizer. June 20, 2023. Accessed June 20, 2023. 

2. Fizazi K, Azad A, Matsubara N, et al. TALAPRO-2: Phase 3 study of talazoparib (TALA) + enzalutamide (ENZA) versus placebo (PBO) + ENZA as first-line (1L) treatment for patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) harboring homologous recombination repair (HRR) gene alterations. 

. 2023;5004(suppl 16). doi: 10.1200/JCO.2023.41.16_suppl.5004

On the heels of an ASCO presentation of data from the phase 3 TALAPRO-2 trial, the FDA has granted approval to the study combination for the treatment of a metastatic castration-resistant prostate cancer subgroup.

FDA Grants Approval to Talazoparib Plus Enzalutamide for HRR-Gene Altered mCRPC

Considerations for Durvalumab Treatment Approach

Panelists discuss how considerations for treatment approach encompass patient-specific factors, treatment modalities, and the integration of emerging therapies to optimize outcomes in clinical practice.

Surgical Perspectives on Durvalumab

Panelists discuss how surgical perspectives on durvalumab emphasize its role in enhancing patient outcomes, informing surgical decision-making, and integrating immunotherapy into comprehensive treatment plans.

Final Thoughts 

Panelists discuss how final thoughts emphasize the importance of ongoing research, collaborative care, and adapting treatment strategies to improve patient outcomes in the evolving therapy landscape.

Results and Outcome of the AEGEAN Trial

Panelists discuss how the results and outcomes of the AEGEAN trial reveal significant findings regarding the treatment’s effectiveness and safety, shaping future approaches in patient care and management.

Maria Varela, MD, PhD

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