The combination of nivolumab (Opdivo) and cabozantinib (Cabometyx) produced prolonged progression-free survival (PFS) and higher response rates compared with sunitinib (Sutent) alone as frontline therapy in patients with advanced renal cell carcinoma (RCC), regardless of International Metastatic RCC Database Consortium risk status, according to 3-year follow-up from the phase 3 CheckMate 9ER trial (NCT03141177) presented at the 2023 Genitourinary Cancers Symposium.

With a median follow-up of 44.0 months (range, 36.5-56.5), median progression-free survival (PFS) in the intent-to-treat (ITT) population by blinded independent central review (BICR) was 16.6 months (95% CI, 12.8-19.8) with nivolumab plus cabozantinib vs 8.4 months (95% CI, 7.0-9.7) with sunitinib (HR, 0.58; 95% CI, 0.48-0.71). Additionally, PFS rate was 47.7% vs 27.0% at 18 months and 21.0% vs 11.6% at 36 months in each respective cohort.

In subgroups based on International Metastatic RCC Database Consortium (IMDC) risk scores, the median PFS in the intermediate-/poor-risk group was 16.4 months (95% CI, 11.2-19.3) with nivolumab plus cabozantinib vs 7.1 months (95% CI, 5.7-8.9) with sunitinib (HR, 0.55; 0.45-0.69). Additionally, PFS rate in this subgroup was 45.8% vs 23.8% at 18 months and 20.5% vs 10.0% at 36 months in each respective cohort.

Among patients with favorable-risk disease, the median PFS was 21.4 months (95% CI, 13.1-24.8) with nivolumab plus cabozantinib vs 13.9 months (95% CI, 9.6-18.5) with sunitinib (HR, 0.75; 0.50-1.13). PFS rate in this subgroup was 54.0% vs 38.6% at 18 months and 25.4% vs 16.1% at 36 months in each respective cohort.

Moreover, the median PFS in the poor-risk group was 9.9 months (5.9-17.7) vs 4.2 months (95% CI, 2.9-5.6) in the combination group and control group, respectively (HR, 0.38; 95% CI, 0.25-5.6). The 18-month and 36-month PFS rates were 37.8% vs 7.2% and 28.6% vs 2.4%, respectively.

Lastly, the intermediate-risk group had a median PFS of 17.5 months (95% CI, 12.3-20.3) and 8.5 months (95% CI, 7.0-10.4) in the combination and single-agent groups, respectively (HR, 0.61; 95% CI, 0.48-0.79). The 18-month and 36-month PFS rates were 48.5% vs 29.3% and 18.5% vs 12.1% in each respective group.

“These results continue to support nivolumab plus cabozantinib as first-line treatment for patients with advanced or metastatic RCC,” presenting author Mauricio Burotto, MD, a medical oncologist at Bradford Hill Clinical Research Center in Santiago, Chile, said in the presentation.

Investigators of the randomized, open-label, phase 3 CheckMate 9ER trial assessed nivolumab plus cabozantinib compared with sunitinib alone as treatment for clear cell, advanced, or metastatic RCC. Patients were randomly assigned 1:1 to receive 240 mg of nivolumab intravenously every 2 weeks plus 40 mg of cabozantinib orally once a day or 50 mg of sunitinib orally once a day using a 4 weeks on, 2 weeks off schedule.

The primary end point of the trial was PFS per blinded independent central review based on RECIST v1.1 criteria. Key secondary end points included overall survival (OS), overall response rate (ORR) per RECIST v1.1 criteria, and safety.

Patients who had previously untreated advanced or metastatic RCC, a clear cell component, or who were part of any IMDC risk group were eligible for enrollment on the trial.

Investigators included a total of 651 patients in the overall population. Baseline characteristics were generally consistent across IMDC risk subgroups, although notably fewer patients in the poor-risk group received a prior nephrectomy in the nivolumab plus cabozantinib (48%) and sunitinib (51%) cohorts, according to Burotto.

The median OS in the ITT population was 49.5 months (95% CI, 40.3-not evaluable [NE]) with nivolumab plus cabozantinib vs 35.5 months (95% CI, 29.2-42.3) with sunitinib (HR, 0.70; 95% CI, 0.56-0.87). Additionally, OS rate was 79.0% vs 68.8% at 18 months and 58.7% vs 49.5% at 36 months in each respective cohort.

In IMDC subgroups, the median OS in the combined intermediate-/poor-risk group was 49.5 months (95% CI, 34.9-NE) in the nivolumab plus cabozantinib cohort vs 29.2 months (95% CI, 23.7-36.0) in the sunitinib cohort (HR, 0.65; 95% CI, 0.51-0.83). Additionally, OS rate in this subgroup was 76.8% vs 63.6% at 18 months and 55.7% vs 43.6% at 36 months in each respective cohort.

According to Burotto, there was no difference in OS between the nivolumab plus cabozantinib and sunitinib arms for patients with favorable-risk disease. The median OS was not reached (95% CI, 40.7-NE) in the nivolumab plus cabozantinib arm and 47.6 months (95% CI, 43.6-NE) in the sunitinib arm (HR, 1.07; 95% CI, 0.63-1.79). OS rate at 18-months and 36-months was 86.3% vs 87.3% and 68.4% vs 70.1% for each respective cohort.

In the poor-risk group, the median OS was 34.8 months (95% CI, 21.4-NE) and 10.5 months (95% CI, 6.8-20.7) in the combination and monotherapy groups, respectively. Moreover, the 18-month and 36-month OS rates were 70.3% vs 43.3% and 46.8% vs 25.1% in each respective group.

Lastly, the median OS was 49.5 months (95% CI, 37.6-NE) compared with 36.2 months (95% CI, 25.7-46.0) in the nivolumab and sunitinib groups, respectively. The 18-month and 36-month OS rates were 78.9% vs 71.0% and 58.7% vs 50.4% in each respective group.

In the ITT population, ORR was 55.7% (95% CI, 50.1%-61.2%) in the nivolumab plus cabozantinib cohort vs 28.4% (95% CI, 23.5%-33.6%) in the sunitinib cohort (odds ratio [OR], 3.3; 95% CI, 2.4-4.6). This included a complete response rate of 12.4% and partial response rate of 43.3% in the combination group vs 5.2% and 23.2% in the sunitinib group, respectively.

Additionally, the median time to response was 2.8 months (range, 1.0-22.3) vs 4.2 months (range, 1.7-30.4), and the median duration of response was 23.1 months (95% CI, 20.2-27.9) vs 15.2 months (95% CI, 9.9-20.7) in each respective cohort.

Of note, the ORRs with nivolumab plus cabozantinib vs sunitinib in the favorable-, intermediate, poor-, and intermediate-/poor-risk subgroups were 66.2% vs 44.4%, 57.4% vs 28.7%, 37.7% vs 10.3%, and 52.6% vs 23.8%, respectively.

The median duration of therapy was 21.8 months (interquartile range [IQR], 8.8-34.0) in the nivolumab plus cabozantinib arm and 8.9 months (IQR, 2.9-20.7) in the sunitinib arm. The treatment discontinuation rate due to any-grade treatment-related adverse effects (TRAEs) was 27.5% and 10.6% in each respective arm and discontinuation due to disease progression occurred in 48.1% vs 62.8% of patients, respectively.

Thirty-six percent of patients receiving nivolumab plus cabozantinib and 45% of patients receiving sunitinib had any subsequent therapy in the ITT population. For patients who discontinued study treatment for any reason, 44% and 51% of patients in each respective arm received any subsequent therapy.

In a post hoc analysis, the baseline characteristics of those who completed 2 years of therapy with nivolumab were consistent with those observed in the ITT population, according to Burotto.

The median time to subsequent therapy 20.6 months (95% CI, 7.9-NE) for patients who completed 2 years of treatment with nivolumab plus cabozantinib.

“This prolonged period of time reflects the efficacy of nivolumab after treatment discontinuation,” Burotto said.

Investigators observed any-grade AEs in 97% of patients receiving nivolumab plus cabozantinib and 93% of those receiving sunitinib. Frequent any-grade AEs in each respective arm included diarrhea (59% vs 46%), palmar-plantar erythrodysesthesia (PPE; 39% vs 42%), and hypertension (33% vs 34%). Grade 3 or higher AEs were seen in 67% and 55% of each respective cohort, with the most frequent toxicities including hypertension (13% vs 13%), PPE (8% vs 8%), and diarrhea (7% vs 5%).

No new deaths associated with treatment have been reported since the last database lock.

Overall, 22% of patients receiving nivolumab plus cabozantinib had corticosteroid treatment with at least 40 mg of prednisone per day to manage any-grade immune-mediated AEs (IMAEs). Additionally, 13% and 5% of patients received corticosteroids continuously for at least 14 days and at least 30 days, respectively.

High-grade IMAEs in the experimental group included diarrhea (3%) and alanine transaminase increase (3%) compared with hypothyroidism (<1%) and hepatotoxicity (<1%) in the control arm.

Burotto M, Powles T, Escudier B, et al. Nivolumab plus cabozantinib vs sunitinib for first-line treatment of advanced renal cell carcinoma (aRCC): 3-year follow-up from the phase 3 CheckMate 9ER trial. 

 2023;41(suppl 6):603. doi:10.1200/JCO.2023.41.6_suppl.603

Articles

The combination of nivolumab and cabozantinib produced prolonged progression-free survival and higher response rates compared with sunitinib alone as frontline therapy in patients with advanced renal cell carcinoma, regardless of International Metastatic RCC Database Consortium risk status.

Nivolumab Plus Cabozantinib Shows Sustained Survival Advantage in Advanced RCC

Neoadjuvant treatment with the combination of tremelimumab (Imjudo) and durvalumab (Imfinzi) produced responses and was well tolerated in patients with mismatch repair–deficient (dMMR) and microsatellite instability–high (MSI-H), Epstein-Barr virus (EBV)–negative gastric or gastroesophageal junction (GEJ) adenocarcinoma, according to findings from the phase 2 INFINITY trial (NCT04817826) presented at the 2023 Gastrointestinal Cancers Symposium.

In the efficacy evaluable population, tremelimumab plus durvalumab elicited a  pathological complete response (pCR) rate of 60%, and the rate of major to complete pathological response in those with less than 10% of viable cells was 80%.

“One [patient] had heterogenous proficient and dMMR status at surgery, thus highlighting the importance of adequate initial sampling,” presenting author Filippo Pietrantonio, MD, Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy, said in the presentation.

With a median follow-up of 13.4 months (interquartile range [IQR], 9.7-14.2) months, investigators observed progression-free survival (PFS) events in 2 patients and 4 deaths, which were attributed to progressive disease (n = 1), late surgical complications (n =2), and secondary brain tumor (n = 1).

Investigators of the INFINITY trial evaluated tremelimumab plus durvalumab combination therapy among patients resectable gastric or GEJ cancer. Patients received 300 mg of tremelimumab for 12 weeks with 1500 mg of durvalumab every 4 weeks for 3 cycles followed by surgery.

The primary end point for cohort 1 was pCR and negative circulating tumor DNA status following neoadjuvant therapy. Key secondary end points included health-related quality of life during neoadjuvant treatment, disease-free survival, OS, safety and surgical morbidity, and exploratory and translational analyses.

From May 2021 to February 2022, 18 patients enrolled and began study treatment. Of these patients, 1 withdrew consent after 1 cycle and 2 refused surgery. Fifteen patients were evaluable for the primary end point, 14 of whom underwent radical surgery. One patient had progressive disease and did not receive radical surgery.

Of the total population, the median age was 71.5 years (IQR, 65-80). Additionally, most patients were male (67%), had an ECOG performance status of 0 (67%), and had gastric cancer (78%). Most patients had T3 disease (56%), N2 disease (50%), and no bulky tumors (78%).

In an analysis of exploratory end points, the pCR rate was 17% (n = 1/6) for those with T4 disease and 89% (n = 8/9) for those with stage T2 or T3 tumors (

 = .011). Investigators also reported no correlation between pCR and N status. Moreover, PD-1 combined positive score was not associated with outcomes, and tumor mutational burden demonstrated a non-significant trend towards correlation with pCR.

The most common any-grade immune-related adverse effects (AEs) included pruritus (22%), thyroiditis (22%), hepatitis (17%), and skin rash (17%). Investigators observed several events of grade 3 or higher AEs including hepatitis (n = 1), colitis (n = 1), and pneumonitis (n = 1).

“The global quality of life was preserved during the neoadjuvant phase [of treatment],” Petrantonio said regarding findings from the quality-of-life end point.

Pietrantonio F, Raimondi A, Lonardi S, et al. INFINITY: a multicentre, single-arm, multi-cohort, phase II trial of tremelimumab and durvalumab as neoadjuvant treatment of patients with microsatellite instability-high (MSI) resectable gastric or gastroesophageal junction adenocarcinoma (GAC/GEJAC). 

2023;41(suppl 4):358. doi:10.1200/JCO.2023.41.3_suppl.358

Neoadjuvant treatment with the combination of tremelimumab and durvalumab produced responses and was well tolerated in patients with mismatch repair–deficient and microsatellite instability–high, Epstein-Barr virus–negative gastric or gastroesophageal junction adenocarcinoma.

Neoadjuvant Tremelimumab/Durvalumab Elicits Responses in Gastric/GEJ Adenocarcinoma

Administration of Teclistamab (Tecvayli) in combination with daratumumab (Darzalex) and lenalidomide (Revlimid) demonstrated promising overall response rates (ORR) and tolerability in patients with relapsed/refractory multiple myeloma who had prior lenalidomide exposure, according to initial data from the phase 1b MajesTEC-2 trial (NCT04722146). The regimen’s safety profile was consistent with that of teclistamab or daratumumab alone, and no new safety signals were identified. Findings were presented during the 

2022 American Society of Hematology (ASH) Annual Meeting

In terms of the hematologic safety profile of the combination therapy, the most common grade 3/4 hematologic adverse effects (AE) were neutropenia, which occurred among 78.1% of patients, 15.6% had thrombocytopenia, and12.5% had febrile neutropenia. The majority of non-hematologic AEs were low-grade, with any-grade cytokine release syndrome occurring most frequently among 81.3% (n = 26) of patients and lasted on average for 2 days.

The majority of infections among patients during treatment were low-grade. The most common grade 3/4 infections included pneumonia (15.6%) COVID-19 (12.5%), and sepsis (9.4%). Two fatal AEs occurred among patients, including 1 related to COVID-19 77 days following the last treatment dose, and another involving multiorgan failure due to sepsis.

“The safety profile of [the combination regimen] was consistent with what is known about the individual agents, with no new safety signals identified,” Emma Searle, MD, MRCP, FRCPath, presenting author of the MajesTEC-2 trial and honorary senior lecturer at the University of Manchester, said.

In the ongoing, multicohort, phase 1b MajesTEC-2 study, patients received teclistamab at 0.72 mg/kg or 1.5 mg/kg subcutaneously once a week, and may transition to 3 mg/kg of teclistamab taken subcutaneously once every 2 weeks starting on the third cycle. Patients also received 1800 mg of subcutaneous daratumumab once every week during cycles 1 to 2, once every 2 weeks during cycles 3 to 6, and once every 4 weeks during cycles 7 and beyond. Lenalidomide was given at 25 mg by mouth daily for 21 days of a 28-day cycle starting with cycle 2. Additionally, 40 mg of dexamethasone was taken by mouth once every week during cycles 2 to 4.

The primary end points of the study included safety regarding AEs, as well as dose-limiting toxicities of teclistamab, daratumumab, and lenalidomide. Important secondary end points included overall response rate (ORR), very good partial responses (VGPRs) or better, complete responses (CRs) or better, duration of response (DOR), and time to response.

Patients with measurable multiple myeloma following 1 to 3 prior lines of therapy, including a proteasome inhibitor and immunomodulatory drug were eligible to enroll in the study.

A total of 32 patients were treated with the triplet regimen in the study; 13 received 0.72 mg/kg of teclistamab, and 19 received 1.5 mg/kg of teclistamab. The median age of patients was 65 years in the 0.72 mg/kg group and 60 years in the 1.5 mg/kg group. According to Searle, over one-third of patients had high-risk cytogenetics defined as having at least 1 of the following aberrations: del17p, t(4;14), or t(14;16). Six patients (46.2%) in the 0.72 mg/kg group and 3 patients (15.8%) in the 1.5 mg/kg group were refractory to lenalidomide. Three patients (23.1%) in the 0.72 mg/kg group and 3 (15.8%) in the 1.5 mg/kg group were refractory to an anti-CD38 antibody.

At a median follow-up of 8.4 months, the ORR was 93.5%. The median time to first response among patients was 1 month, and the median time to CR or better was 3 months.

“At data cutoff, [CR] or better was achieved in over 55% of patients in both dosing groups, and VGPR or better was achieved in 90% [of both dosing groups],” Searle said.

In total, 80.6% of patients remained progression-free and were on treatment at the time of data cutoff. Patient responses deepened over time, and the median DOR had not been reached.

According to Searle, the triplet regimen will be prospectively compared vs daratumumab with lenalidomide and dexamethasone in patients with newly-diagnosed multiple myeloma who are transplant-ineligible or in the randomized, open-label phase 3 MajesTEC-7 trial (NCT05552222). This study will be presented as a trial-in-progress in a later poster session during ASH 2022.

Searle E, Quach H, Wong SW, et al. Teclistamab in combination with subcutaneous daratumumab and lenalidomide in patients with multiple myeloma: results from one cohort of MajesTEC-2, a phase 1b, multicohort study. Presented at: 64th American Society of Hematology Annual Meeting and Exposition;

Administration of teclistamab in combination with daratumumab and lenalidomide demonstrated promising overall response rates and tolerability in patients with relapsed/refractory multiple myeloma who had prior lenalidomide exposure, according to initial data from the phase 1b MajesTEC-2 trial.

Russ Conroy

Articles

Nivolumab Plus Cabozantinib Shows Sustained Survival Advantage in Advanced RCC

Neoadjuvant Tremelimumab/Durvalumab Elicits Responses in Gastric/GEJ Adenocarcinoma

Teclistamab Triplet Shows Encouraging Responses and Safety in Relapsed/Refractory Multiple Myeloma