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James Stevenson, MD, Department of Hematology and Oncology, Cleveland Clinic, discusses the impact of a stage IV non-small cell lung cancer (NSCLC) care pathway on frontline and maintenance chemotherapy use.

Impact of a Stage IV NSCLC Care Pathway on Frontline and Maintenance Chemotherapy Use

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

According to data from an interim analysis of the phase 2 SunRISe-4 study (NCT04919512), neoadjuvant treatment with TAR-200 plus cetrelimab led to responses and a tolerable toxicity profile when used for the treatment of patients with muscle-invasive bladder cancer who are not eligible or refuse to receive neoadjuvant cisplatin-based chemotherapy. Findings were presented during the 2024 ESMO Congress.

TAR-200 plus cetrelimab (n = 53) led to a pathologic complete response (pCR) rate of 42% (95% CI, 28%-56%) and a pathologic overall response (pOR) rate of 60% (95% CI, 46%-74%) in the efficacy-evaluable population of patients with cT2 to CT4a disease. Cetrelimab monotherapy (n = 31), which was also evaluated, led to respective pCR and pOR rates of 23% (95% CI, 10%-41%) and 36% (95% CI, 19%-55%).

“SunRISe-4 demonstrates for the first time a benefit of the addition of TAR-200, an intravesical targeted releasing system, to checkpoint inhibition as neoadjuvant treatment in patients with MIBC,” Andrea Necchi, MD, of IRCCS San Raffaele Hospital, Vita-Salute San Raffaele University, in Milan, Italy, said in a late-breaking oral presentation of the data.

For patients with MIBC who have T2 to T4a N0M0 disease, the standard-of-care treatment approach is to undergo radical cystectomy with or without neoadjuvant cisplatin-based chemotherapy but up to half of patients are eligible for chemotherapy. Moreover, about 50% of patients who undergo radical cystectomy will recur within 2 years; after the procedure, 5-year survival rates are still low, at about 50%, Necchi said.

“Also, in patients with MIBC undergoing radical cystectomy, we know that pathological stage is prognostic for survival,” he added. With the procedure alone, pCR rates range from 10% to 15%; with neoadjuvant chemotherapy, pCR rate rises to approximately 30%; and with neoadjuvant checkpoint inhibition, pCR rates fall between 31% and 39%. Achievement of pCR in patients who have received neoadjuvant chemotherapy has been linked with a 55% lower risk of death and an 81% lower recurrence risk vs those who have residual disease. “There is a high unmet need for more tolerable treatment options for patients with MIBC who are candidates for radical cystectomy, but not candidates for or who refuse neoadjuvant chemotherapy,” he underscored.

A gemcitabine intravesical releasing system, TAR-200 was designed to deliver continued gemcitabine within the bladder; it is placed using a urinary placement catheter as part of an office procedure that takes under 5 minutes. Phase 1 data have demonstrated TAR-200’s clinical activity in patients with MIBC. “Cetrelimab is an anti–PD-1 agent that has been investigated also in bladder cancer with the SunRISe platform, Necchi said. “In particular, we have data in from SunRISe-1 [NCT04640623]

 with cetrelimab in patients with [Bacillus Calmette-Guérin–unresponsive, high risk] non–muscle-invasive disease and the clinical complete response rates are in the range of the rates provided by other checkpoint inhibitors.”

The ongoing, randomized, phase 2 SunRISe-4 trial was designed to understand the antitumor activity of TAR-200 plus cetrelimab and single-agent cetrelimab, as well as to show the contribution of components of the combination.

 Investigators hypothesized that a side-by-side descriptive summary of efficacy with the approaches will elucidate the contribution of TAR-200 to the efficacy of the combinatorial approach.

The trial enrolled patients with histologically confirmed MIBC who had cT2 to CT4a N0M0 disease and predominant urothelial carcinoma histology, who were scheduled for radical cystectomy and were ineligible for or refused neoadjuvant chemotherapy. Patients were required to be at least 18 years of age and have an ECOG performance status of 0 or 1.

They were randomly assigned 5:3 to cohort 1 (n = 79), where they received TAR-200 plus 225 mg of gemcitabine every 3 weeks (indwelling) 12 weeks plus intravenous (IV) cetrelimab for 12 weeks; or cohort 2 (n = 41), where they received IV cetrelimab alone for 12 weeks. Patients were stratified by visible residual disease at transurethral resection of bladder tumor (TURBT; complete vs incomplete or ≤3 cm) and tumor stage at time of MIBC diagnosis (cT2 vs cT3 to cT4a).

Treatment was given for 4 total cycles and then they went on to radical cystectomy. Follow-up was done every 4 weeks after surgery until week 12 and then every 12 weeks until week 108 after surgery. The primary end point was pCR (ypT0N0), and secondary end points included recurrence-free survival and safety. Exploratory end points included pOR (≤ypT1N0), overall survival, time to symptomatic progression, quality of life per FACT-BI, pharmacokinetics, and biomarker analysis.

The interim analysis 2, which was slated to be performed after approximately 80 patients completed radical cystectomy, was shared at the congress. The data cutoff date for the analysis was May 31, 2024.

A total of 122 patients were randomized; 80 patients comprised cohort 1 and 42 comprised cohort 2; 98.8% and 97.6% of patients, respectively, received treatment. A total of 53 patients in cohort 1 and 31 patients in cohort 2 were determined evaluable for efficacy.

Necchi said that the main baseline characteristics between the arms were “pretty well balanced.” Regarding neoadjuvant chemotherapy, 39.2% of those in the combination arm were ineligible and 60.8% refused it; in the monotherapy arm, these respective rates were 36.6% and 63.4%. Moreover, 20.3% of patients in cohort 1 had visible residual disease before starting therapy; this was also true for 14.6% of those in cohort 2. With regard to tumor stage in cohort 1, 78.5% had cT2 disease and 21.5% had cT3-cT4a disease; these rates were 85.4% and 14.6%, respectively, in cohort 2. Further, 20.3% and 26.8% of patients had urothelial carcinoma with variant histology. “There are [also] a few patients with a history of intravesical therapy, in general meaning, a history of previous non–muscle-invasive disease progressing to muscle-invasive disease,” Necchi said.

Investigators also evaluated efficacy by clinical stage and completeness of TURBT in cohorts 1 and 2. In cohort 1, those with cT2 disease (n = 40) experienced a pCR rate of 48% (95% CI, 32%-64%) with the combination; the pOR rate was 68% (95% CI, 51%-81%). In those with cT3 to cT4a disease (n = 13), the pCR rate was 23% (95% CI, 5%-54%) with TAR-200 plus cetrelimab and the pOR rate was 39% (95% CI, 14%-68%. Moreover, in those with incomplete TURBT (n = 9), the pCR rate with the combination was 56% (95% CI, 21%-86%) and the pOR rate was 67% (95% CI, 30%-93%); in those with complete TURBT (n = 44), these respective rates were 39% (95% CI, 24%-55%) and 59% (95% CI, 43%-74%).

“Results seem to be consistent, regardless of the radicality of the completeness of the TURBT, although we should acknowledge that that proportion and sample size in patients with incomplete TURBT is still preliminary,” Necchi said.

In cohort 2, those with cT2 disease (n = 26), experienced a pCR rate of 23% (95% CI, 9%-44%) with cetrelimab alone and a pOR rate of 31% (95% CI, 14%-52%). In those with cT3 to cT4a disease (n = 5), these rates were 20% (95% CI, 1%-72%) and 60% (95% CI, 15%-95%), respectively. In those with incomplete TURBT (n = 4), no pCRs were experienced. In those with complete TURBT (n = 27), the pCR rate with the monotherapy was 26% (95% CI, 11%-46%) and the pOR rate was 41% (95% CI, 22%-61%).

Necchi and colleagues also examined efficacy by TAR-200 dose exposure in the efficacy-evaluable population. In the subset of patients who received 1 to 2 doses (n = 11), the pCR was 27% (95% CI, 6%-61%) and the pOR was 46% (95% CI, 17%-77%). In those who received 3 doses (n = 10), pCR and pOR rates climbed to 30% (95% CI, 7%-65%) and 50% (95% CI, 19%-81%), respectively. Those who received 4 doses (n = 32), experienced the highest pCR and pOR rates, at 50% (95% CI, 32%-68%) and 69% (95% CI, 50%-84%), respectively.

With regard to safety, at least 1 any-grade treatment-related adverse effect (TRAE) was experienced by 72.2% of those in cohort 1 and 43.9% of those in cohort 2. The most common TRAEs in these respective arms were dysuria (27.8%; 18.3%), pollakiuria (27.8%; 18.3%), micturition urgency (15.2%; 10.0%), and hematuria (13.9%; 9.2%). TRAEs that were grade 3 or higher were reported in 11.4% of those in cohort 1 and 4.9% of those in cohort 2. Serious TRAEs occurred in 11.4% of those in the combination arm and 2.4% of those in the monotherapy arm. TRAEs led to discontinuation of TAR-200 in 8.9% of patients and cetrelimab discontinuation in 7.6% of patients—all in cohort 1. One patient in cohort 2 experienced a TRAE that proved fatal.

Grade 3 or higher immune-related toxicities were experienced by 6.3% of those in cohort 1 and 4.9% of those in cohort 2. The median time to radical cystectomy in the respective cohorts was 13.7 weeks and 12.6 weeks.

Disclosures: Dr Necchi disclosed having received grants or research funding (institutional) from AstraZeneca, Bristol Myers Squibb, Gilead, Ipsen, and Merck; and receipt of consulting or advisory fees from Astellas, AstraZeneca, Bristol Myers Squibb, Catalym, Gilead, Johnson & Johnson, Samsung Bioepis, Bicycle Therapeutics, and Merck. He also serves in a leadership role for the Global Society of Rare Genitourinary Tumors and serves as associate editor for the 

1. Necchi A, Guerrero-Ramos F, Crispen PL, et al. TAR-200 plus cetrelimab or cetrelimab alone as neoadjuvant therapy in patients with muscle-invasive bladder cancer who are ineligible for or refuse neoadjuvant cisplatin-based chemotherapy: interim analysis of SunRISe-4. Presented at: 2024 ESMO Congress; September 13-17, 2024; Barcelona, Spain. Presentation LBA84.

2. van der Heijden MS, Simone G, Bögemann M, et al. TAR-200 +/- cetrelimab and cetrelimab alone in patients with Bacillus Calmette-Guérin–unresponsive high-risk non–muscle-invasive bladder cancer: Updated results from SunRISe-1. Presented at: 2024 ESMO Congress; September 13-17, 2024; Barcelona, Spain. Presentation LBA85.

Given as neoadjuvant treatment, TAR-200 plus cetrelimab generated responses in patients with muscle-invasive bladder cancer.

Conference News

Canonical

Neoadjuvant Treatment With TAR-200 Plus Cetrelimab Elicits Responses in MIBC

Ribociclib (Kisqali) plus nonsteroidal aromatase inhibitor (NSAI) therapy led to sustained improvements in invasive disease-free survival (iDFS) and distant disease-free survival (DDFS) vs NSAI alone in patients with hormone receptor (HR)-positive, HER2-negative early breast cancer, according to 4-year landmark analysis results from the phase 3 NATALEE trial (NCT03701334) presented at the 

2024 European Society for Medical Oncology (ESMO) Congress.

With a median follow-up of 44.2 months across the intent-to-treat (ITT) population, the 3-year iDFS rates were 90.8% with ribociclib plus NSAI vs 88.1% with NSAI alone, representing a difference of 2.7%. At 4 years, the respective iDFS rates were 88.5% vs 83.6%; a difference of 4.9% (HR, 0.715; 95% CI, 0.609-0.840; 

Of note, most iDFS events in each arm were associated with distant recurrence (6.9% vs 9.6%). The iDFS benefit with the ribociclib-based combination also extended across all key prespecified subgroups based on characteristics such as menopausal status, prior chemotherapy, region, and prior endocrine therapy.

In terms of specific subgroup data, the iDFS rates among patients with stage II disease were 94.4% vs 92.7% at 3 years with a change of 1.7% and 93.9% vs 89.6% at 4 years with ribociclib/NSAI vs NSAI alone with a change of 4.3%, respectively (HR, 0.644; 95% CI, 0.468-0.887). Among those with stage III disease, the respective 3-year iDFS rates were 88.3% vs 84.8% with a change of 3.5%, and the 4-year rates were 84.3% vs 78.4% with a change of 5.9% (HR, 0.737; 95% CI, 0.611-0.888).

Regarding nodal status, the 3-year iDFS rates among patients with N0 disease were 93.4% vs 90.8% with a change of 2.6% with ribociclib/NSAI vs NSAI alone, respectively; the 4-year rates were 92.1% vs 87.0% with a change of 5.1% (HR, 0.666; 95% CI, 0.397-1.118). For those with N1 to N3 disease, the 3-year iDFS rates were 90.4% vs 87.7% with a change of 2.7%, and the 4-year rates were 88.0% vs 83.0% with a change of 5.0% (HR, 0.731; 95% CI, 0.617-0.866).

“The results continue to support the benefit of adding 3 years of ribociclib to adjuvant [NSAI] in this broad population of 

HR-positive, HER2-negative early breast cancer

 at risk of recurrence,” study author Peter A. Fasching, MD, an associate professor of Gynecology and Obstetrics Translational Medicine at the University Hospital Erlangen and Comprehensive Cancer Center Erlangen-EMN in Germany, said in a presentation on these data.

In the NATALEE trial, 5101 patients were randomly assigned to receive ribociclib at 400 mg daily as part of a 3-weeks-on, 1-week-off schedule for 3 years plus NSAI (n = 2549) or NSAI alone (n = 2552). Treatment with NSAI consisted of letrozole (Femara) or anastrozole (Arimidex) for at least 5 years plus goserelin (Zoladex) for male patients and female patients who are premenopausal.

The trial’s primary end point was iDFS based on Standardized Definitions for Efficacy End Points in Adjuvant Breast Cancer Trials criteria. Secondary end points included DDFS, recurrence-free survival, overall survival (OS), and safety and tolerability.

Adult patients with HR-positive, HER2-negative early breast cancer were eligible for enrollment on the trial. Those with prior endocrine therapy at 12 months or earlier prior to randomization were able to enroll. Investigators stratified patients based on anatomical stage, menopausal status, receipt of previous chemotherapy, and geographic location.

As of the data cutoff, 62.8% of patients in the experimental arm completed 3 years of treatment with ribociclib. Of note, 36.2% of patients discontinued treatment with ribociclib early, with 20.0% discontinuing due to adverse effects (AEs). The median duration of exposure to study therapy was 45.1 months in the ribociclib/NSAI arm compared with 45.0 months in the NSAI alone arm.

Data showed that treatment with ribociclib/NSAI produced enduring DDFS improvements compared with NSAI alone (HR, 0.715; 95% CI, 0.604-0.847; 

 <.0001) as well as a positive trend associated with OS (HR, 0.827; 95% CI, 0.636-1.074; 

 = .0766). Fasching noted that follow-up for OS is still ongoing.

Any-grade AEs of special interest (AESIs) in the ribociclib/NSAI arm and NSAI alone arm included neutropenia (62.8% vs 4.5%), arthralgia (38.8% vs 44.4%), liver-related toxicity (26.7% vs 11.4%), and nausea (23.5% vs 7.9%). The most common grade 3 or higher AESI in the ribociclib arm was neutropenia (44.4%). AEs associated with the liver generally consisted elevated alanine aminotransferase or aspartate aminotransferase without accompanying increases in bilirubin.

Fasching PA, Stroyakovskiy D, Yardley DA, et al. Adjuvant ribociclib plus nonsteroidal aromatase inhibitor in patients with HR+/HER2– early breast cancer: 4-year outcomes from the NATALEE trial. Presented at the 2024 European Society for Medical Oncology Congress (ESMO); September 13-17, 2024; Barcelona, Spain. LBA13.

Ribociclib-Based Therapy Extends Survival in HR+/HER2– Breast Cancer

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.

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.

James Stevenson, MD

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