Megan Hollasch

Patients with resectable (surgically unremovable) non-small cell lung cancer (NSCLC) undergoing treatment with perioperative Opdivo (nivolumab) demonstrated extended event-free survival (EFS; living without complications or disease worsening) versus placebo, according to findings from a phase 3 trial.

Updated data from the phase 3 CheckMate 77T trial presented during the 

demonstrated that, at a median follow-up of 33.3 months, 229 patients who received perioperative Opdivo achieved a median EFS of 40.1 months compared with 17 months among 232 patients who received placebo. The 12-month EFS rates were 73% versus 59%, and the 24-month rates were 65% versus 44%, respectively.

Patients with resectable non-small cell lung cancer (NSCLC) who received perioperative Opdivo (nivolumab) demonstrated significantly extended event-free survival (EFS) compared with placebo.

The improvement in EFS was observed in both patients who achieved a pathologic complete response (PCR) and those who did not, which suggested that Opdivo provides a benefit regardless of tumor response.

Patients in the Opdivo group had lower rates of circulating tumor DNA (ctDNA) recurrence, indicating a potential ability to prevent disease relapse.

In the trial, patients had resectable stage 2A to 3B NSCLC and had not previously received systemic anti-cancer treatment. Eligible patients also had an ECOG performance of 0 or 1, meaning they could perform daily tasks independently, and also did not have EGFR mutations or known ALK translocations.

Patients were randomly assigned to receive either Opdivo plus chemotherapy (229 patients) or placebo plus chemotherapy (232 patients). Both groups of patients received surgery and then adjuvant (postsurgical) Opdivo, according to the study.

The primary goal of the trial was EFS and secondary goals included pCR and major pathologic response rates, as well as overall survival (OS; time patients live, regardless of their disease status) and safety.

Among 58 patients who received Opdivo and experienced a pathologic complete response (pCR; disappearance of the tumor) also experienced a significant EFS benefit versus 11 patients who received placebo. Similarly, 98 patients without a pCR in the Opdivo group also experienced an EFS benefit compared with 148 patients who received placebo and did not achieve a pCR.

During the postoperative period, evaluable patients in the Opdivo group (48 patients) and the placebo group (44 patients) experienced circulating tumor DNA (ctDNA; remaining tumor cells present in the bloodstream) recurrence at rates of 8% versus 20%, respectively. Evaluable patients with a pCR in the Opdivo (26 patients) and placebo groups (5 patients) experienced ctDNA recurrence at rates of 4% versus 20%, respectively. Evaluable patients without a pCR in the Opdivo (22 patients) and placebo groups (39 patients) experienced ctDNA recurrence at rates of 14% versus 21%, respectively.

“[The EFS data] show an improvement that is both statistically and clinically significant with the addition of perioperative [Opdivo], with an increase in median EFS from 17 months to 40.1 months with the addition of perioperative [Opdivo],” Dr. Jonathan D. Spicer, said during the presentation. “The addition of perioperative [Opdivo] provided some benefit, both in the pCR and the non-pCR patients with HRs that are commensurate to the degree of pathological response. … These data support the use of perioperative [Opdivo] as an efficacious regimen for patients with resectable NSCLC.”

Spicer is the Dr. Ray Chiu Distinguished Scientist in Surgical Research, the Advanced Thoracic and Upper GI Surgical Oncology Fellowship program director, the Rossy Cancer Network Lung Cancer Disease Site Lead​, and an attending surgeon in the Division of Thoracic and Upper Gastrointestinal Surgery at McGill University Health Centre in Montreal, Canada.

Safety Outcomes for Patients With Unresectable NSCLC

In terms of safety, a total of 58 patients in the Opdivo and 11 patients in the placebo groups who achieved a pCR experienced an any-grade side effect. Patients in both groups also experienced grade 3 (severe) to 4 (life-threatening) side effects (48% versus 46%), any-grade treatment-related side effects (97% versus 82%), any-grade serious side effects (43% versus 36%) and grade 3 to 4 serious side effects (28% versus 36%).

In the Opdivo group, grade 3 to 4 treatment-related side effects (31%), any-grade side effects leading to treatment discontinuation (34%), grade 3 to 4 side effects leading to treatment discontinuation (17%), any-grade treatment-related side effects leading to discontinuation (29%), any-grade treatment-related serious side effects (24%) and grade 3 to 4 treatment-related serious side effects (14%) were also reported; no patients in the placebo group experienced these events.

Patients without a pCR in the Opdivo (170 patients) and placebo (219 patients) groups experienced any-grade side effects (96% versus 98%), grade 3 to 4 side effects (46% versus 42%), any-grade treatment-related side effects (86% versus 87%), grade 3 to 4 treatment-related side effects (32% versus 26%), any-grade side effects leading to treatment discontinuation (22% versus 11%), grade 3 to 4 side effects leading to treatment discontinuation (13% versus 6%), any-grade treatment-related side effects leading to treatment discontinuation (16% versus 8%), and grade 3 to 4 treatment-related side effects leading to treatment discontinuation (10% versus 5%). Additionally, any-grade serious side effects (42% versus 31%), grade 3 to 4 serious side effects (29% versus 19%), any-grade treatment-related serious side effects (17% versus 10%) and grade 3 to 4 treatment-related serious side effects (14% versus 6%) also occurred.

Overall, two treatment-related deaths were reported in the Opdivo group, both because of pneumonitis (inflammation in the lung tissue).

“Low-grade [side effects] and [treatment-related side effects] are a bit more common in the pCR group versus the non-pCR group,” Spicer noted. “In total, these data are consistent with prior reports showing a significant improvement in EFS in the [Opdivo] cohort versus placebo. ... Exploratory ctDNA analyses indicate that ctDNA clearance is indicative of a higher likelihood of pCR and, perhaps more importantly, the lack of clearance is associated with residual disease.”

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Receiving perioperative Opdivo for non-small cell lung cancer showed event-free survival benefits compared with placebo. 

Perioperative Opdivo Extends Event-Free Survival in Lung Cancer 

Patients with metastatic renal cell carcinoma (RCC) — a type of kidney cancer — did not experience benefits after receiving a combination of Opdivo (nivolumab) and Fotivda (tivozanib). Patients previously experienced disease progression (worsening) on or after treatment with a PD-(L)1 inhibitor.

Findings were based on the phase 3 TiNivo-2 study and presented at the 

Patients with metastatic renal cell carcinoma (RCC) who received Opdivo and Fotivda after experiencing disease worsening on a PD-(L)1 inhibitor did not experience improved outcomes.

Fotivda alone was shown to be a more effective option for these patients compared to the combination therapy.

The study suggests that rechallenging patients with another immune checkpoint inhibitor (ICI) after progression on one is generally not recommended.

The optimal sequence of therapies for patients with RCC who progress on an ICI remains uncertain.

“TiNivo-2 was the first phase 3 trial to evaluate the efficacy and safety of a PD-1 inhibitor following progression on or after treatment with a PD-[L]1 therapy,” Dr. Toni Choueiri of Dana-Farber Cancer Institute in Boston, said in a presentation of the data at the meeting. “TiNivo-2 is a negative study, but I strongly believe it’s important. It is practice-changing, and it should make us think twice now. … These results support [Fotivda] monotherapy at 1.34 kilograms as a second-line therapy option in patients following progression on previous immune checkpoint inhibitor [ICI] therapy.”

At a median follow-up of 11.8 months in the Fotivda plus Opdivo group with 171 patients and 12.5 months in the Fotivda monotherapy group with 172 patients, the median progression-free survival (PFS; time patients live without their disease worsening or spreading) was not improved with the doublet versus monotherapy. Findings from the primary analysis of PFS, which was the study’s primary goal, revealed that the median PFS was 5.7 months for the combination versus 7.4 months for Fotivda alone in the intention-to-treat population.

“This trial confirms and expands key conclusions from the [phase 3] CONTACT-03 study. [TiNivo-2] is the second phase 3 trial in RCC and solid tumors that suggests that ICI rechallenge should be generally discouraged regardless of treatment sequence. We [also] believe that the reduced dose of [Fotivda] in the combination [group] may have impacted the efficacy, and that reflects in the lower median PFS [observed],” Choueiri said.

Patient Characteristics and Study Findings

Patients with locally advanced or metastatic clear cell RCC were enrolled following disease progression on one or two lines of therapy, one of which was an ICI they progressed on during or following at least six weeks of therapy.

Patients needed to have an ECOG performance status of 0 or 1, meaning they were able to perform daily tasks independently; measurable disease; and a time from the immediate prior line of therapy received to their random assignment of six months or less.

“What remains unknown, in large part, is the optimal sequence [of therapies in RCC] in patients whose disease has progressed after treatment with an ICI. If we rechallenge with the same or a different ICI, does this improve clinical outcomes?” Choueiri asked. He noted that following the encouraging efficacy seen in the phase 1/2 TiNivo study with [Fotivda] plus nivolumab, TiNivo-2 was initiated.

Choueiri noted that the reduced dose was agreed upon with regulatory authorities due to the potential risk of increased rates of grade 3/4 (severe to life-threatening) hypertension (high blood pressure) in the combination treatment group.

The trial’s main goal was PFS and secondary goals were overall survival (OS; time patients live, regardless of disease status), objective response rate (ORR; percentage of patients whose tumors shrunk or disappeared), duration of response and safety/tolerability.

The median age of patients in the Fotivda plus Opdivo group was 64 years compared with 63 years in the Fotivda monotherapy group. Most patients were male (73% for the combination versus 78% for Fotivda monotherapy), White (65% versus 62%), had an ECOG performance score of 1 (55% versus 51%), received one prior line of therapy (65% versus 61%) and received an ICI as their most recent therapy (71% versus 71%). Additionally, patients had favorable- (18% versus 18%), intermediate- (67% versus 66%) and poor- (16% versus 16%) risk disease and approximately one-third of patients did not receive a prior VEGFR-TKI (31% versus 31%).

More Survival Findings for Patients With Metastatic Kidney Cancer

When examining PFS by line of therapy, higher PFS rates were observed in the second-line setting, although Fotivda monotherapy outdid Fotivda plus Opdivo. The median PFS among patients who received Fotivda plus Opdivo (111 patients) in the second-line setting was 7.3 months versus 9.2 months among patients treated with the monotherapy in this setting.

Those who received treatment in TiNivo-2 as third-line therapy experienced a median PFS of 4.8 months in the doublet group of 60 patients versus 5.5 months in the monotherapy group with 67 patients.

“I believe [these data] debunk the theory that break and rechallenge is better,” Choueiri added.

Data revealed that the median OS was 17.7 months in the Fotivda plus Opdivo group compared with 22.1 months in the Fotivda monotherapy group. However, Choueiri noted that OS data were not mature because at the data cutoff, only 32% of events had occurred in patients.

Additionally, the ORR was 19.3% in the doublet group versus 19.8% in the singlet group. One patient in each group achieved a complete response, meaning they no longer showed signs of cancer. Patients also experienced stable disease (43.3% versus 47.1%), progressive disease (28.7% versus 25%) or were not evaluable (8.8% versus 8.1%). The median duration of response was 15.77 months with the doublet compared with 9.66 months with monotherapy.

Safety Outcomes in Patients With Metastatic Kidney Cancer

Side effects leading to death occurred in seven patients in the doublet group and five patients in the Fotivda monotherapy group. Patients experienced grade 2 (serious) or greater side effects (61% for the doublet versus 60% for the singlet), serious side effects (32% versus 37%) and treatment-emergent side effects leading to discontinuation (16% versus 19%), dose interruption (49% versus 54%) and dose reduction of Fotivda (11% versus 22%). The median duration of treatment was 6.3 months and 7.4 months, respectively.

The most common any-grade side effects observed were hypertension (37% versus 40%), fatigue (29% versus 40%), diarrhea (30% versus 36%) and nausea (16% versus 28%), in the doublet and monotherapy groups, respectively.

Fotivda monotherapy may show better outcomes in second-line therapy than the combination of Opdivo and Fotivda in metastatic kidney cancer. 

Fotivda Shows Better Outcomes Than Combo in Metastatic Kidney Cancer

Anti–PD-L1 monoclonal antibody benmelstobart plus anlotinib for the frontline treatment of advanced renal cell carcinoma (RCC), a type of kidney cancer, demonstrated improved clinical outcomes compared with Sutent (sunitinib), according to findings from the phase 3 ETER100 trial presented during the 2024 ESMO Congress.

Patients in the combination group (benmelstobart plus anlotinib; 264 patients) achieved a median progression-free survival (PFS; how long a person lives without their disease getting worse) of 18.96 months versus 9.76 months in the Sutent group (263 patients). The median overall survival (OS; the time from the start of treatment when a patient with cancer is still alive) was not estimable compared with NE, respectively. Of note, when median OS is not estimable in a clinical trial, it means that there was insufficient data for researchers to calculate this.

Benmelstobart plus anlotinib significantly outperformed Sutent in terms of progression-free survival for patients with advanced renal cell carcinoma (RCC).

The combination therapy led to a much higher overall response rate compared to Sutent, with more patients experiencing disease shrinkage or disappearance.

Patients treated with benmelstobart plus anlotinib had a 47% lower risk of disease progression or death compared to those receiving Sutent.

The findings suggest that this drug combination could become a new standard first-line treatment for advanced RCC.

The respective overall response rates (ORRs; the percentage of people whose disease shrinks or disappears after treatment) were 71.6% versus 25.1%; 1.1% of patients in the combination group achieved a complete response.

“Based on our findings, we believe that benmelstobart in combination with anlotinib has the potential to become a new standard first-line treatment for advanced RCC,” Dr. Xinan Sheng, of Peking University Cancer Hospital and Institute in Beijing, China, said during the presentation. “At the [data cutoff] date, [findings from] the analysis showed a significant improvement in the combination group over the [Sutent] group. The combination treatment reduced the risk of progression [of disease] or death by 47% compared with [Sutent].”

ETER100 was a multicenter study that enrolled patients with locally advanced or metastatic clear cell RCC who did not undergo prior systemic antitumor therapy. To be eligible for the study, patients needed to be 18 to 80 years of age, have an ECOG performance status of 1 or less (1 being lightly active, 0 being fully active) and have at least 1 measurable lesion. Patients with prior exposure to any VEGFR-directed TKIs or immune checkpoint inhibitors were excluded.

Patients were randomly assigned to receive anlotinib plus benmelstobart or Sutent. Treatment in both groups continued until disease progression or intolerable toxicity.

The primary focus was PFS. The secondary focus included investigator (healthcare professional)-assessed PFS, OS, ORR, disease control rate, duration of response (the length of time a person's disease remains in remission after treatment) and safety.

Findings from a subgroup analysis showed that the PFS benefit observed with anlotinib plus benmelstobart versus Sutent was sustained across all subgroups. Patients with sarcomatoid differentiation (highly aggressive form of RCC) and those with liver metastasis experienced the greatest positive effects from the treatment.

In terms of safety, patients in the investigational and control groups both experienced any-grade treatment-emergent side effects at rates of 99.24%. Patients in both groups also had grade 3 (severe) or higher (life-threatening or death) treatment-emergent side effects (75% versus 74.62%), any-grade treatment-related side effects (98.11% versus 98.11%), grade 3 or higher treatment-related side effects (67.42% versus 65.91%) and serious side effects (38.64% versus 28.03%), respectively. Additionally, patients in the combination group experienced immune-related side effects (33.33%), grade 3 or higher immune-related side effects (9.47%) and immune-related reactions (4.92%).

One-hundred and thirty-eight patients in the combination group discontinued treatment due to disease progression (84 patients), side effects (12 patients), patient withdrawal (six patients), death (17 patients), lost to follow-up (three patients) and other reasons (16 patients). Among patients in the Sutent group, 209 discontinued treatments due to disease progression (142 patients), side effects (12 patients), patient withdrawal (21 patients), death (eight patients), lost to follow-up (one patient) and other reasons (25 patients).

“The addition of benmelstobart to anlotinib as a first-line treatment for [patients with] advanced RCC provided superior [results] compared with [Sutent],” Sheng said in conclusion. “The combination [of drugs] was generally well-tolerated, with a safety profile consistent with each agent.”

Benmelstobart plus anlotinib significantly improved survival versus Sutent in the first-line treatment of advanced renal cell carcinoma.

Anti-PD-L1 Antibody Drug Combo May Improve Outcomes in Advanced Kidney Cancer

A treatment combination with Yervoy (ipilimumab) plus Opdivo (nivolumab), compared with standard-of-care therapies, significantly improved 12-month survival in patients with non-clear cell renal cell carcinoma (nccRCC; a type of kidney cancer), according to data presented during the 

The presentation at ESMO highlighted findings from the phase 2 SUNNIFORECAST trial, which included a total of 309 patients. The Yervoy-Opdivo combination group included 157 patients and the standard-of-care group included 152 patients. The median ages were 61.4 and 64 years in the respective groups. Among the total amount of patients in the study, 70.9% were male, 52.4% had a full Karnofsky performance score (meaning they were able to independently complete daily tasks) and 76.7% had undergone prior surgery. The median time since initial diagnosis among all patients enrolled was 30.9 months.

A treatment combination of Yervoy and Opdivo significantly improved survival rates in patients with non-clear cell renal cell carcinoma (nccRCC) compared to standard-of-care therapies.

Patients receiving the combination therapy had a higher 12-month overall survival rate (86.9%) than those receiving standard of care (76.8%).

The combination therapy was generally well-tolerated, with manageable side effects, with most of the side effects of any severity occurring in the standard-of-care group.

“This is the first prospective randomized trial which compared dual checkpoint inhibitor combination therapy with the actual SOC in nccRCC,” Dr. Lothar Bergmann, deputy medical director in the Department of Internal Medicine at J.W. Goethe University in Frankfurt, Germany, said during the presentation.

Survival Outcomes Among Patients With nccRCC

At a median follow-up of 24.3 months, the 12-month overall survival (OS; time patients live, regardless of their disease status) rate was 86.9% among the 157 patients who received the Yervoy-Opdivo combination. The 12-month OS was 76.8% among the 152 patients treated with standard of care. The six-month OS rates were 94.7% versus 90%, respectively and the 18-month rates were 76.6% versus 69.1%, respectively. The median OS was 42.4 months in the combination group compared with 33.9 months in the standard-of-care group.

“A significant difference [in 12-month OS rate was observed] in favor of the combination arm,” Bergmann said. “The standard of care for most patients [in the study] was [tyrosine kinase inhibitor (TKI)] monotherapy and only 17% of patients received a TKI/IO combination in this group.”

The primary goal of the study was the 12-month OS rate. Key secondary goals included OS, six- and 12-month OS rates, progression-free survival (PFS; time patients live without their disease worsening or spreading), objective response rate (ORR; percentage of patients whose tumors shrunk or disappeared), time to progression, safety and quality of life.

In terms of PFS, the median value in the combination arm was 5.52 months versus 5.65 months in the standard-of-care group. The respective ORRs were 32.8%, with an 8% complete response (CR; complete tumor disappearance) rate, versus 19.6%, with a 1.6% CR rate. The ORR was higher with the combination versus standard of care in patients with papillary (29.2% versus 21%), non-papillary (37.7% versus 18.2%) and chromophobe (25.9% versus 11.1%) histologies, respectively.

Side Effects Experienced Within the Study

Regarding safety, the most common side effects of any severity in the combination and standard of care groups included skin reactions (48.4% versus 74.2%), fatigue (42.9% versus 63.7%), diarrhea (21% versus 45.1%), pruritus (itching; 25% versus 2.8%) and nausea (20.6% versus 31.5%). The most common grade 3 (severe) or 4 (life-threatening) side effects included increased alanine aminotransferase levels (high liver enzyme levels; 5.7% versus 0%), fatigue (3.8% versus 8.4%) and diarrhea (3.2% versus 4.9%). Rates of side effects of any severity were generally higher in the standard of care group versus the combination group.

Patients in the combination group went on to receive subsequent second (63.7%), third (28.7%) and fourth (11.5%) lines of therapy. Patients in the standard-of-care group went on to receive these lines of therapy at rates of 55.9%, 13.2% and 9.2%, respectively.

“The randomized SUNNIFORECAST trial underlines a relevant clinical benefit of the combination [of Yervoy and Opdivo] in nccRCC and may be a new standard in these entities,” Bergmann said. “Further data in the study of these rare diseases are needed in the future.”

The 12-month survival rates in patients with non-clear cell renal cell carcinoma showed improvements after treatment with Yervoy plus Opdivo.

Megan Hollasch

Perioperative Opdivo Extends Event-Free Survival in Lung Cancer

Fotivda Shows Better Outcomes Than Combo in Metastatic Kidney Cancer

Anti-PD-L1 Antibody Drug Combo May Improve Outcomes in Advanced Kidney Cancer

Survival Rate Increased With Yervoy-Opdivo Combo in Kidney Cancer

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