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Barbara O’Brien, MD, is an associate professor of neuro-oncology at MD Anderson Cancer Center. 

Barbara O'Brien, MD, discusses the goals and results of a study investigating tucatinib, trastuzumab, and capecitabine for the treatment of leptomeningeal metastases in patients with HER2-positive breast cancer. 

Study Shows First Evidence of Effective Systemic Therapy for HER2+ Breast Cancer With LM

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

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.

Hamid presented updated results from these cohorts with a total of 40 patients in each cohort, plus 18 in an additional cohort of first-line patients with metastatic disease who had received prior adjuvant/neoadjuvant therapy. They received 1600 mg fianlimab plus 350 mg cemiplimab every 3 weeks for 12 months, with an additional 12 months if clinically indicated.1 Tumors were measured every 6 weeks for 24 weeks, then every 9 weeks thereafter.

The median age of patients was 68.0 years. Two percent of patients had received prior treatment for metastatic disease, 23.5% had received adjuvant or neoadjuvant systemic treatment with a disease-free interval of at least 6 months. The 13 patients who received adjuvant/neoadjuvant PD-1/PD-L1 therapy had been treated with nivolumab (Opdivo) or pembrolizumab (Keytruda). Thirty patients across the 3 cohorts had a 

At the data cut-off of November 1, 2022, the median follow-up was 12.6 months and the median duration of treatment was 32.9 weeks. Three patients (8%) in the initial cohort, 14 (35%) in the confirmatory cohort, and 5 (28%) in the prior adjuvant cohort were ongoing treatment; others had completed or discontinued therapy.

The RECIST 1.1-based investigator-assessed ORR of 61.2% included 12 complete responses (CR) and 48 partial responses (PR). The disease control rate was 78%. The median duration of response (DOR) was not reached (95% CI: 23-not estimated [NE]). The Kaplan-Meier estimated median progression-free survival (PFS) was 15.3 months (95% CI, 9.4-NE).

“Tumor responses in these cohorts together compared favorably with historical controls in relation to follow-up, overall response, disease control rate, and estimated median [PFS],” Hamid said.

When looking at the patients who had prior adjuvant therapy of any type, including 5 in the initial cohort, 14 out of 23 responded to the fianlimab/cemiplimab combination, with a median DOR that was not reached and a median PFS of 13.3 months. Adjuvant/neoadjuvant therapies included PD-1 agents, interferon, and BRAK/MEK-targeted treatments. For those who had received prior adjuvant nivolumab or pembrolizumab, 8 out of 13 responded to the combination, including 1 complete response. They had a median DOR that was not reached and a median PFS of 11.8 months.

A subgroup analysis was conducted for patients with poor prognosis melanoma including 21 with liver metastases, 32 with high baseline lactate dehydrogenase (LDH), and 17 M1c stage plus LDH greater than the upper limit of normal. These subgroups had an ORR of 43%, 53%, and 35%, respectively, and this analysis was also presented in detail by Inderjit Mehmi, MD, in a poster at the conference.

Fifty-five patients had LAG-3 expression of at least 1% and 26 had PD-L1 expression of at least 1%. According to Hamid, “In this cohort, efficacy was observed regardless of LAG-3 or PD-L1 tumor expression.”

In terms of safety, 43.9% had grade 3 or higher treatment-emergent adverse events (TEAEs) and 32.7% had serious TEAEs. Immune-related adverse events (irAEs) occurred in 65.3%, with 12% being grade 3 or higher. Patients required treatment discontinuation in 16.3% due to TEAEs. Rates of irAEs were similar to PD-1 monotherapy in general.

“Overall, the safety overview of this combination was generally consistent with the safety profile that we are familiar with of single-agent cemiplimab and other anti–PD-1 agents,” Hamid said. “Only adrenal insufficiency, at a rate of 11%, appeared to be higher in this cohort, most grade 1 or 2, and all cases successfully managed with steroid replacement.” One case of adrenal insufficiency was associated with treatment discontinuation.

A phase 3 trial (NCT05352672) of fianlimab plus cemiplimab in treatment-naive advanced melanoma is currently underway with a targeted enrollment approximately of 1590 patients. It includes 4 arms including 1 using the dose level of the phase 1 trial, 1 with a lower dose of fianlimab, and 2 comparator arms of pembrolizumab plus placebo and cemiplimab plus placebo. Another phase 3 trial (NCT05608291) is taking place in the adjuvant setting in comparison to pembrolizumab plus placebo.

These data support the efficacy and safety of the anti–PD-1/LAG-3 combination even in patients who have received prior adjuvant immunotherapy, as well as those with poor prognostic features.

1. Hamid O, Lewis KD, Weise AM, et al. Significant durable response with fianlimab (anti–LAG-3) and cemiplimab (anti–PD-1) in advanced melanoma: Post adjuvant PD-1 analysis. 

. 2023;41(suppl_16):9501. doi:10.1200/JCO.2023.41.16_suppl.9501

2. Hamid O, Weise AM, Kim TM, et al. Phase I study of fianlimab, a human lymphocyte activation gene-3 (LAG-3) monoclonal antibody, in combination with cemiplimab in advanced melanoma (mel). 

 2022;33(suppl_7):S356-S409. doi:10.1016/annonc/annonc1059

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.

Conference News

Fianlimab Plus Cemiplimab Shows Efficacy in PD-1–Pretreated Metastatic Melanoma

The FDA has granted an orphan drug designation (ODD) for elraglusib (9-ING-41) for treatment of patients with pancreatic cancer, according to Actuate Therapeutics, Inc.

Data from a phase 2 study (NCT03678883) investigating the combination of elraglusib with gemcitabine and nab-paclitaxel in patients with advanced pancreatic cancer support this ODD as treatment with elraglusib generated encouraging clinical activity.

Among the 21 patients in the study evaluable for response, the disease control rate (DCR) was 62% and the overall response rate (ORR) was 43%, respectively, with 2 confirmed complete responses, 6 confirmed and 1 unconfirmed partial response, 4 patients with stable disease, and 8 with disease progression. However, adverse events (AEs) related to chemotherapy were significant.

“Based on the promising final data from our completed single arm phase 2 study, we have initiated an open label, randomized phase 2 study of elraglusib in combination with gemcitabine/nab-paclitaxel for the frontline treatment of patients with metastatic pancreatic cancer” said Andrew Mazar, MD, Actuate’s chief operating officer, in a press release.

Elraglusib is a small molecule GSK-3β inhibitor currently under investigation for the treatment of adults and children with advanced refractory cancers.

In a phase 1/2 study (NCT03678883), investigators are evaluating the combination of elraglusib with gemcitabine and nab-paclitaxel in patients with advanced pancreatic cancer. The first 2 parts of the trial have been completed with part 1 evaluating elraglusib as a monotherapy and part 2 assessing elraglusib with standard anticancer agents.

Participation in each portion of the study is open to patients with an ECOG performance status of 0-2, no prior therapy in the metastatic setting, and no systemic therapy in the prior 6 months. Patients must also have adequate bone marrow function, liver function, renal function, and blood coagulation.

The primary end point of the study is DCR with secondary end points of safety and ORR.

A total of 42 patients were enrolled in the study with a median age of 67. Twenty-four patients were females, 18 were males, 38 patients had metastatic disease, and 4 had locally advanced disease.

A promising disease control rate and overall response rate was seen with elraglusib when given with chemotherapy for patients with pancreatic cancer, according to phase 2 study findings.

Barbara O'Brien, MD

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