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Timothy Cloughesy, MD, is the director of the neuro-oncology program at the UCLA Brain Research Institute. 

Timothy F. Cloughesy, MD, director of UCLA’s neuro-oncology program and distinguished professor in neurology, discusses the mechanism of action of vorasidenib.


Understanding Vorasidenib’s Mechanism of Action

Timothy F. Cloughesy, MD, discusses the impact and significance of the FDA’s approval of vorasidenib, a first-in-class option for the treatment of patients with IDH-mutant gliomas.


Cloughesy’s Insights on the FDA Approval of Vorasidenib in IDH-Mutant Gliomas 

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

Results from the phase 3 KEYNOTE-522 trial (NCT03036488) in patients with early-stage triple-negative breast cancer (TNBC) showed that neoadjuvant pembrolizumab (Keytruda) plus chemotherapy, followed by adjuvant pembrolizumab, generated a statistically significant improvement in overall survival (OS) vs neoadjuvant chemotherapy plus placebo, followed by adjuvant placebo.

Findings presented at the 2024 ESMO Congress showed that the perioperative pembrolizumab regimen reduced the risk of death by 34% compared with the placebo regimen (HR, 0.66; 95% CI, 0.50-0.87; 

 = .00150). At a median follow-up of 75.1 months, patients treated in the pembrolizumab arm (n = 784) achieved a 5-year OS of rate of 86.6% (95% CI, 84.0%-88.8%) vs 81.7% (95% CI, 77.5%-85.2%) for those in the placebo arm (n = 390). The OS event rates were 14.7% and 21.8% for the pembrolizumab and placebo arms, respectively.

“[KEYNOTE-522] was a positive trial for its 2 primary end points—short-term pathological complete response [(pCR) rate] and event-free survival [EFS]—and most importantly, [data] demonstrated that [the pembrolizumab regimen] reduced the risk of death by 34%,” lead study author Peter Schmid, MD, PhD, of Barts Cancer Institute at Queen Mary University in London, United Kingdom, said in a press briefing at the ESMO Congress.

Previously reported data from the first interim analysis of KEYNOTE-522 at a median follow-up of 15.5 months showed that patients in the pembrolizumab arm achieved a pathological complete response (pCR) rate of 64.8% (95% CI, 59.9%-69.5%) compared with 51.2% (95% CI, 44.1%-58.3%) those in the placebo arm (estimated difference, 13.6%; 95% CI, 5.4%-21.8%; 

Additionally, prior data from the fourth interim analysis demonstrated that the pembrolizumab regimen led to a significant improvement in event-free survival (EFS) vs the placebo regimen (HR, 0.63; 95% CI, 0.48-0.82; 

 < .001). The 36-month EFS rate was 84.5% (95% CI, 81.7%-86.9%) in the pembrolizumab group vs 76.8% (95% CI, 72.2%-80.7%) in the placebo group.

In July 2021, the FDA approved pembrolizumab in combination with chemotherapy as neoadjuvant treatment, then continued as a single agent as adjuvant treatment after surgery, for the treatment of patients with high-risk, early-stage TNBC based on prior data from KEYNOTE-522.

The randomized, double-blind trial enrolled patients at least 18 years of age with centrally confirmed TNBC in all foci. Patients needed to have newly diagnosed, previously untreated, nonmetastatic disease, defined as tumor stage T1c, nodal stage N1-2, or tumor stage T2-4, nodal stage N0-2. An ECOG performance status of 0 or 1 and adequate organ function. Notably, those with bilateral or multifocal primary tumors and inflammatory breast cancers were allowed to participate.

Patients were randomly assigned 2:1 to the pembrolizumab vs placebo arms. In the neoadjuvant setting, patients received pembrolizumab at 200 mg or placebo once every 3 weeks for 4 cycles plus paclitaxel at 80 mg/m

 once weekly plus carboplatin at area under the curve of 5 mg/mL per minute once every 3 weeks or 1.5 mg/mL per minute once weekly in the first 12 weeks. The second neoadjuvant treatment cycle consisted of pembrolizumab or placebo for 4 additional cycles plus doxorubicin at 60 mg/m

 plus cyclophosphamide at 600 mg/m2 once every 3 weeks for 12 weeks.

Those who completed or discontinued the first neoadjuvant cycle were allowed to start the second neoadjuvant cycle or undergo surgery. In the adjuvant setting, patients received pembrolizumab or placebo once every 3 weeks for up to 9 cycles. Radiation was also permitted in the adjuvant setting.

The trial’s dual primary end points were pCR rate and EFS in the intention-to-treat population. Secondary end points included pCR and EFS in patients with PD-L1–positive tumors, and OS among all patients and those with PD-L1–positive tumors.

Additional Efficacy Data Presented at ESMO

Updated efficacy analysis showed that the pembrolizumab regimen maintained a significant improvement in EFS vs the placebo regimen in the overall population (HR, 0.65; 95% CI, 0.51-0.83). The 5-year EFS rates were 81.2% for the pembrolizumab arm vs 72.2% for the placebo arm. EFS events were reported in 20.3% of patients in the experimental arm vs 29.2% of patients in the control arm.

Patients who achieved a pCR on the study also experienced an OS benefit, irrespective of treatment arm. For responders, the 5-year OS rate was 95.1% for the pembrolizumab arm (n = 495) vs 94.4% for the placebo arm (n = 217; HR, 0.69; 95% CI, 0.38-1.26). In non-responders, the 5-year OS rate was 71.8% for the pembrolizumab arm (n = 289) vs 65.7% for the placebo arm (n = 173; HR, 0.76; 95% CI, 0.56-1.05).

1. Schmid P, Cortes J, Dent R, et al. Neoadjuvant pembrolizumab or placebo plus chemotherapy followed by adjuvant pembrolizumab or placebo for high-risk early-stage TNBC: overall survival results from the phase III KEYNOTE-522 study. Presented at: 2024 ESMO Congress; September 13-17, 2024; Barcelona, Spain. Abstract LBA4.

2. Schmid P, Cortes J, Pusztai L, et al. Pembrolizumab for early triple-negative breast cancer. 

. 2020;382(9):810-821. doi:10.1056/NEJMoa1910549

3. Schmid P, Cortes J, Dent R, et al. Event-free survival with pembrolizumab in early triple-negative breast cancer. 

. 2022;386(6):556-567. doi:10.1056/NEJMoa2112651

4. FDA approves pembrolizumab for high-risk early-stage triple-negative breast cancer. FDA. July 26, 2021. Accessed September 15, 2024. 

In KEYNOTE-522, treatment with neoadjuvant pembrolizumab and chemotherapy, followed by adjuvant pembrolizumab, led to improvements in overall survival among patients with triple-negative breast cancer.

Conference News

Neoadjuvant and Adjuvant Pembrolizumab Extends Survival in Early-Stage TNBC

The FDA granted an accelerated approval to dostarlimab-gxly (Jemperli), a programmed cell death receptor-1 (PD-1) blocking antibody, for the treatment of adult patients with mismatch repair-deficient (dMMR) recurrent or advanced solid tumors that have progressed on or following prior treatment and who have no satisfactory alternative treatment options, according to a press release by GlaxoSmithKline (GSK).

Dostarlimab-gxly works by blocking interaction with PD-L1 and PD-L2 ligands. It is being studied as both a monotherapy and in combination with advanced endometrial cancer, epithelial ovarian cancer, and advanced solid tumors. 

“For patients with tumors expressing the dMMR biomarker, there continues to be a significant need for new and effective treatments. I’m excited about GSK’s second oncology FDA approval this year, and the new treatment option it provides for these patients,” said Hal Barron, MD, chief scientific officer and president of research and development at GSK, in a press release.

Approval is based on results of the GARNET trial (NCT02715284).

 The phase 1 non-randomized trial had an actual enrollment of 740 participants and an estimated completion date of April 2024. Primary end points of part 1 and 2 include the number of treatment-emergent adverse events (TEAEs), overall response rate (ORR), and duration of response. Secondary end points include immune-related ORR, progression-free survival (PFS), and disease control rate.

During the study, patients received 500 mg of the agent intravenously once every 3 weeks for 4 doses followed by 1000 mg once every 6 weeks or until disease progression or unacceptable toxicity.

The ORR in all dMMR solid tumors was 41.6% with a complete response of 9.1% and a partial response rate of 32.5%. The median duration of response was 34.7 months with 95.4% of patients maintaining the response for at least 6 months. For patients in the dMMR solid tumor non-endometrial cancer cohort, the ORR was 38.7%.

In total, 267 patients with recurrent or advanced dMMR solid tumors were evaluated for safety. The most common reported AEs were fatigue/asthenia (42%), anemia (30%), diarrhea (25%) and nausea (22%). Common grade 3 or 4 adverse reactions (≥2%) were anemia, fatigue/asthenia, increased transaminases, sepsis, and acute kidney injury. Reported grade 3 or 4 laboratory abnormalities (≥2%) included decreased lymphocytes, decreased sodium, increased alkaline phosphatase and decreased albumin.

“Dostarlimab is an important new treatment option for patients with mismatch repair-deficient recurrent or advanced solid cancers who have progressed and have no alternative options. As we saw in the GARNET trial, of those patients who respond to treatment with dostarlimab, nearly all continued to respond for six months or longer,” said Jubilee Brown, MD, professor and division director of Gynecologic Oncology at Atrium Health Levine Cancer Institute, and investigator on the GARNET study in the release.

1. GSK receives FDA accelerated approval for JEMPERLI (dostarlimab-gxly) for adult patients with mismatch repair-deficient (dMMR) recurrent or advanced solid tumours. News release. GlaxoSmithKline. August 17, 2021. Accessed August 17, 2021. 

2. Study of TSR-042, an Anti-programmed Cell Death-1 Receptor (PD-1) Monoclonal Antibody, in Participants With Advanced Solid Tumors (GARNET). ClincialTrials.gov. Accessed August 17, 2021. 

The FDA granted an accelerated approval to dostarlimab-gxly (Jemperli), a programmed cell death receptor-1 blocking antibody, for the treatment of adult patients with mismatch repair-deficient recurrent or advanced solid tumors that have progressed on or following prior treatment and who have no satisfactory alternative treatment options.

FDA Grants Accelerated Approval to Dostarlimab for Solid Tumors

The FDA has granted breakthrough therapy designation (BTD) to trastuzumab deruxtecan (Enhertu; T-DXd) for the treatment of adult patients with unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH-negative) breast cancer who have received prior systemic therapy in the metastatic setting or who have developed disease recurrence during or within 6 months of completing adjuvant chemotherapy, according to AstraZeneca.

Results of the phase 3 DESTINY-Breast04 trial (NCT03734029) serve as basis for the BTD. In the study, 

T-DXd demonstrated significant improvement in progression-free survival (PFS) and overall survival (OS)

“Historically, only patients with HER2-positive metastatic breast cancer were shown to benefit from HER2-directed therapy. DESTINY-Breast04, in which Enhertu showed a clinically meaningful survival benefit in patients with HER2-low metastatic breast cancer, is the first trial to demonstrate that selecting patients for treatment based on low expression of HER2 has the potential to change the diagnostic and treatment paradigms for these patients,” stated Ken Takeshita, global head, R&D of Daiichi Sankyo, in the press release. “This Breakthrough Therapy Designation acknowledges the potential of Enhertu to fulfill an unmet medical need and we look forward to working closely with the FDA to bring the first HER2-directed therapy to patients with metastatic breast cancer whose tumors have lower levels of HER2 expression.”

The multicenter, global, open label DESTINY-Breast04 study enrolled a total of 557 patients with HER2-low, unresectable and/or metastatic breast cancer to determine the safety and efficacy of T-DXd in this patient population.

Inclusion in the study was open to patients with pathologically confirmed disease who were aged 18 and older or who reached the age of maturity in their country. Other requirements included documented radiographic progression, at least 1 protocol-defined measurable lesion, adequate archival tumor samples available or the ability to provide fresh tissue, and protocol-defined adequate cardiac, bone marrow, renal, hepatic and blood clotting functions.

The primary end point of the study, which was met, was PFS with secondary end points including OS, objective response rate (ORR), and duration of response (DOR) among the study subjects.

Participants were randomized 2:1 and received either T-DXd at 5.4mg/kg or physician’s choice of chemotherapy which included capecitabine, eribulin, gemcitabine, paclitaxel or nab-paclitaxel. Of those enrolled in the study, 480 were patients with HR-positive disease and 60 had HR-negative HER2-low unresectable and/or metastatic breast cancer previously treated with one or two prior lines of chemotherapy.

The safety profile of T-DXd was consistent with previous clinical trials and no new safety concerns were identified.

The agent has now been granted a total of 5 BTD’s including 3 in breast cancer, 1 in lung cancer, and 1 in gastric cancer.

“Today’s news is a significant validation of the potential we see for the historic DESTINY-Breast04 trial to enable a paradigm shift in how breast cancer is classified by targeting the full spectrum of HER2 expression. Enhertu continues to show transformative potential, and this milestone represents an important advance for patients with HER2-low metastatic breast cancer who are in urgent need of new treatment options and better outcomes,” added Susan Galbraith, executive vice president, oncology R&D, in the press release.

1. Enhertu granted breakthrough therapy designation in the US for patients with HER2-low metastatic breast cancer. News release. April 27, 2022. Accessed April 27, 2022. 

2. Trastuzumab deruxtecan (DS-8201a) versus investigator's choice for HER2-low breast cancer that has spread or cannot be surgically removed [DESTINY-Breast04]. Clinicaltrials.gov. Accessed April 27, 2022. 

Breakthrough therapy designation has been granted to trastuzumab deruxtecan by the FDA for patients with unresectable or metastatic HER2-low breast cancer.

FDA Grants Breakthrough Therapy Designation to T-DXd for HER2-Low Breast Cancer

The combination of fianlimab and cemiplimab (Libtayo) demonstrated efficacy and safety in patients with advanced melanoma including some who had previously received adjuvant immunotherapy for advanced melanoma, according to results of a study presented at the 2023 American Society of Clinical Oncology Annual Meeting.

The phase 1 study (NCT03005782) enrolled 98 patients, 13.3% of whom had received PD-1/PD-L1 inhibitors as adjuvant or neoadjuvant therapy. The objective response rate (ORR) for fianlimab/cemiplimab was 61.2% in all patients, 60.9% in patients with any adjuvant treatment, and 61.5% in those who had received adjuvant PD-1 therapy.

“In the combination of fianlimab and cemiplimab, we showed a consistent and reproducible high clinical activity in 3 independent cohorts of patients who were naive to anti–PD-1 in the advanced melanoma setting,” Omid Hamid, MD, chief of translational research and immunotherapy and director of melanoma therapeutics at The Angeles Clinic and Research Institute in Los Angeles, California, stated in his presentation. “Similar clinical activity was observed in patients treated with prior adjuvant therapies including anti–PD-1.”

Patients with unresectable or metastatic melanoma who had not received prior anti–PD-1/PD-L1 therapy for advanced disease were enrolled in 3 expansion cohorts of the study. Two of these cohorts had previously been reported on at an earlier data cut-off of July 1, 2022; in those results, the combination of the LAG-3 inhibitor fianlimab with the PD-1 inhibitor cemiplimab had an ORR of 62.5% in patients in an initial first or second-line cohort and a confirmatory first-line cohort which had both received no prior anti–PD-1/PD-L1 therapy.

In the combination of fianlimab and cemiplimab, we showed a consistent and reproducible high clinical activity in 3 independent cohorts of patients who were naive to anti–PD-1 in the advanced melanoma setting, says Omid Hamid, MD.

Timothy F. Cloughesy, MD

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