Megan Hollasch

Scemblix outperformed standard tyrosine kinase inhibitors in treating chronic myeloid leukemia, with higher response rates and fewer side effects, according to data from the phase 3 ASC4FIRST trial.

Scemblix (asciminib) further solidified its role in treating chronic myeloid leukemia (CML) as 96-week data showed it outperformed standard-of-care investigator-selected tyrosine kinase inhibitors (TKIs) and met key secondary goals of the phase 3 ASC4FIRST trial.

Data presented at the 2024 ASH Annual Meeting showed that the major molecular response (MMR) rate at week 96 continued to be superior among patients who received Scemblix (201 patients) versus all IS-TKIs (204 patients), meeting a key secondary end point of the trial; rates were 74.1% versus 52%, respectively with investigators noting the difference was 22.4%. This represented an increase in MMR as the 48-week MMR rates were 67.7% and 49%, respectively, which originally met the primary end point of the trial.

“The 96-week data that I am showing you today for the first time [reveal that] all of these comparisons against all TKIs, [Gleevec] and second generation TKIs, favor [Scemblix]. The ones that are powered [for it] are statistically significant [as well],” Dr. Jorge E. Cortes said in a presentation of the data. Cortes is director for the Georgia Cancer Center and the Cecil F. Whitaker Jr, GRA Eminent Scholar Chair in Cancer in Augusta.

The 96-week MMR rates were also consistently higher with Scemblix across the trial strata. In the Gleevec (imatinib) stratum, patients who received Scemblix (101 patients) experienced a 96-week MMR rate of 76.2% versus 47.1% among those in the IS-TKI group (102 patients), for a difference of 29.7%. In the second-generation TKI stratum, the 96-week MMR rates were 72% in the Scemblix group (100 patients) and 56.9% in the IS-TKI group (102 patients) for a difference of 15.1%.

Major molecular responses (MMR): MR4 and MR4.5, measure the reduction of cancer cells in the blood, with lower values indicating deeper responses and better long-term outcomes for CML patients.

Tyrosine kinase inhibitors (TKIs): a type of targeted therapy that blocks specific proteins involved in cancer cell growth.

Arterial occlusive events: blockage of blood flow in an artery.

EUTOS long-term survival score (ELTS): a scoring system used to predict the long-term survival of patients with chronic myeloid leukemia.

The FDA Approval of Scemblix and ASC4FIRST Trial Enrollment

The Oct. 29, 2024 FDA accelerated approval of Scemblix for the treatment of adults with newly diagnosed Philadelphia chromosome-positive CML in chronic phase (CP) was based on the 48-week MMR data from ASC4FIRST. Findings supporting the approval showed that the 48-week MMR rate was 68% in the Scemblix group versus 49% in the IS-TKIs group, for a difference of 19%, meeting one of the trial’s primary end points. The other primary end point, 48-week MMR rate with Scemblix versus IS-TKIs in the Gleevec stratum, was also met in the primary analysis of ASC4FIRST with high statistical significance. The MMR rate was 69% versus 40%, respectively, for a difference of 30%.

ASC4FIRST enrolled adults newly diagnosed Philadelphia chromosome-positive CML-CP who had not been previously treated with a TKI. Patients received Scemblix at 80 milligrams once daily or IS-TKIs at label doses. Physicians and patients consulted to select a TKI should the patient be randomly assigned to the IS-TKI group of the trial and stratification occurred by prerandomization TKI selection and EUTOS long-term survival score (ELTS) risk category. Secondary end points of the trial included 96-week MMR with Scemblix versus all IS-TKIs and 96-week MMR with Scemblix versus IS-TKIs in the Gleevec stratum.

“The patient characteristics were very well balanced,” Cortes said. “When you look at the individual strata, however, it becomes obvious that the patients in the Gleevec strata were somewhat older and had a higher Framingham [risk] score, whereas the patients in the second-generation TKI strata tended to have more patients in the high-risk ELTS risk classification.”

Scemblix’s Safety Profile Continues to Best Gleevec and Second-Generation TKIs

By the 96-week data cutoff, safety and tolerability data continued to be more favorable with Scemblix compared with Gleevec and second-generation TKIs. The risk of treatment discontinuation due to side effects was 54% lower with Scemblix versus second-generation TKIs.

“[Scemblix’s] safety and tolerability profile continued to be better than that of Gleevec and second-generation TKIs after longer follow-up and [data were] consistent with its known safety profile,” Cortes said.

In the safety populations of patients who received Scemblix (200 patients), Gleevec (99 patients), and second-generation TKIs (102 patients), grade 3 (severe) or worse side effects (44.5% versus 49.5% versus 59.8%, respectively), side effects leading to treatment discontinuation (5% versus 13.1% versus 12.7%) and side effects leading to dose adjustment/interruption (33% versus 41.4% versus 57.8%) occurred.

Additionally, arterial occlusive events (AOEs) did not occur frequently with any agents in the trial. Four patients experienced at least one AOE in the Scemblix group (200 patients), and three patients experienced at least one event in the second-generation TKI group (102 patients); one patient in each of the aforementioned groups experienced a grade 3 or worse event and no patients in the Gleevec group (99 patients) experienced an AOE.

“[Scemblix’s] favorable risk-benefit profile compared with all IS-TKIs, Gleevec, and second-generation TKIs in patients with newly diagnosed CML-CP reinforces the use of Scemblix as a SOC for this patient population,” Cortes concluded.

At the Oct. 22, 2024, data cutoff, more patients were ongoing treatment with Scemblix (81.6%) than all IS-TKIs (60.3%). Patients in the Scemblix group versus all IS-TKIs group discontinued treatment (17.9% versus 38.2%, respectively) due to unsatisfactory therapeutic effect (9.5% versus 20.6%), adverse effect (AE; 6% versus 12.7%), progressive disease (1% versus 2%), physician decision (0.5% versus 0%), protocol deviation (0.5% versus 1%), patient decision (0.5% versus 1.5%), or pregnancy (0% versus 0.5%).

“The discontinuation rate was twice as high with all IS-TKIs compared with [Scemblix],” Cortes noted.

Furthermore, the cumulative incidence of MMR was higher with Scemblix (80.5%) versus all IS-TKIs (62.1%) at 96-weeks. Across strata, this was also true; in the Gleevec stratum rates were 80% in the Scemblix group and 56.5% in the IS-TKI group, and in the second-generation TKI stratum rates were 81% in the Scemblix group and 67.6% in the IS-TKI group.

At week 96, data on deep molecular responses revealed that 48.8% of patients who received Scemblix achieved an MR4 and 30.9% achieved an MR4.5; these respective rates were 27.5% and 17.7% in the all IS-TKIs group. In the Gleevec stratum 52.5% of patients treated with Scemblix experienced an MR4 and 35.6% experienced an MR4.5; respective rates were 23.5% and 11.8% in the IS-TKI group. Additionally, in the second-generation TKI stratum, 45% of patients treated with Scemblix experienced an MR4 and 26% experienced an MR4.5; respective rates were 31.4% and 23.5% in the IS-TKI group.

“There is a continued and increasing difference in favor of [Scemblix] [versus IS-TKI] for both MR4 and MR4.5,” Cortes explained. “One important analysis is to look at the difference in subsets of patients. These are small subsets [and the study was] not powered for any one of them, but it is very good to see that in any individual subgroup — whether it’s by ELTS, sex, race and ethnicity, age category [or] Framingham score — all of them favor the treatment of [Scemblix] in terms of the rate of MMR at [week] 96. There’s really no subset of patients where we don’t see at least a trend in benefit for [Scemblix] compared with the investigator selected control [group].”

Investigators also examined postbaseline treatment-emergent BCR::ABL1 gene mutations by next-generation sequencing. “In summary, all the mutations that emerged in this study with the treatment [of] [Scemblix] have been myristoyl pocket mutations,” Cortes noted.

“Scemblix (ASC) demonstrates favorable safety and tolerability compared with each investigator-selected tyrosine kinase inhibitor (IS TKI) in newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP) in the pivotal phase 3 ASC4FIRST study” by Dr. Jorge E. Cortes et al., 

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Articles

Scemblix (asciminib) has demonstrated superior efficacy and safety in treating chronic myeloid leukemia (CML) compared to standard tyrosine kinase inhibitors (TKIs) in the phase 3 ASC4FIRST trial. At 96 weeks, Scemblix showed a higher major molecular response (MMR) rate than all investigator-selected TKIs, including Gleevec and second-generation TKIs. The FDA granted accelerated approval based on earlier 48-week data. Scemblix also exhibited a favorable safety profile, with lower rates of severe side effects and treatment discontinuation. The trial highlighted Scemblix's potential as a standard of care for newly diagnosed CML patients.

Scemblix resulted in better outcomes and fewer side effects compared to standard tyrosine kinase inhibitor therapies in patients with chronic myeloid leukemia.

Scemblix May Outperform Standard Treatments for Chronic Myeloid Leukemia

Tecartus demonstrated similar effectiveness across age groups of patients with relapsed or refractory B-cell acute lymphoblastic leukemia, according to a real-world study presented at the 2024 ASH Annual Meeting.

Tecartus (brexucabtagene autoleucel) produced similar treatment outcomes in patients aged 60 to 69 with relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL) compared to patients of other ages, according to findings from a real-world study presented at the 2024 ASH Annual Meeting.

Patients who were less than 60 years of age (220 patients) achieved a complete remission (CR)/CR with incomplete count recovery (CRi) rate of 89%, including a minimal residual disease (MRD)-negativity rate of 74%. Patients who were 60 to 69 years of age (57 patients) also experienced a CR/CRi rate of 89%, with an MRD-negativity rate of 59%. These respective rates were 94% and 67% among patients who were 70 years of age or older (19 patients).

“The rates of CR were similar across the groups at approximately 90% and no statistically significant difference was detected between the groups,” Dr. Ibrahim Muhsen of Baylor College of Medicine in Houston, Texas, said during the presentation. “MRD-negativity rates were numerically lower among patients aged 60 to 69 compared with other groups.”

Moreover, there were no significant differences in overall survival (OS) between the less than 60, 60 to 69 and 70-plus years age groups. The respective median OS values were 695 days, not yet reached and 673 days. The six-month OS rates were 81%, 81% and 73%, respectively, and the 12-month OS rates were 68%, 63% and 61%, respectively.

Complete remission (CR): complete disappearance of cancer.

Incomplete count recovery (CRI): blood counts have not fully returned to normal after treatment.

Minimal residual disease (MRD): small amount of cancer cells remaining after treatment.

MRD negativity: no detectable cancer cells remaining after treatment.

MRD positivity: detectable cancer cells remaining after treatment.

Overall survival (OS): length of time a patient lives after being diagnosed with cancer.

Progression-free survival (PFS): length of time a patient lives without disease worsening.

ECOG performance status of 0, 1, 2 or more: a scale used to measure a person's functional ability and how well they can perform daily activities.

There was also no difference in progression-free survival (PFS) by age and the median PFS values in the less than 60, 60 to 69 and 70-plus years age groups were 397 days, 393 days and 259 days. The six-month PFS rates were 64%, 58% and 56%, respectively, and the 12-month PFS rates were 51%, 52% and 38%.

“It should be noted that the 12-months PFS [rate] and median PFS were lower in patients aged 70 and above. However, the number of patients in that group was small, which makes it very hard to draw any conclusions. Although we can see a plateau towards the end, a longer follow-up period is needed to better estimate how many patients are cured by this approach,” Muhsen commented.

In October 2021, Tecartus was the first CAR T-cell therapy approved by the FDA for the treatment of adult patients with relapsed or refractory B-cell precursor ALL; the regulatory decision was supported by findings from the phase 1/2 ZUMA-3 trial. Among the 55 patients enrolled in the study, only eight were at least 65 years old and all of these patients achieved a CR/CRi.

“Although multiple studies have demonstrated the safety and efficacy of CAR T-cell therapies in older patients with lymphoma, data on the efficacy and safety of [Tecartus] in older patients with ALL remain very limited,” Muhsen noted.

To conduct their study, investigators identified adult patients with B-ALL who received Tecartus from October 2021 to June 2024 across 40 US-based academic and community institutions using the Real-World Outcomes Collaborative of CAR-T in Adult ALL (ROCCA) consortium database. The dataset included 318 patients who underwent apheresis to receive Tecartus, 22 of whom were not infused and thus not included in the analysis.

At baseline, the median age in the under 60 group was 36 years. Sixty-two percent of patients were male, and patients were non-Hispanic White (44%), Hispanic (39%), or Black (7%). Patients had an ECOG performance status of 0 (27%), 1 (52%) or 2 or more (12%). ALL subtypes were comprised of Philadelphia chromosome (Ph)-negative (47%), Ph-positive (29%), or Ph-like (22%) disease. The median follow-up was 309 days. Patients received a median of four prior lines of therapy, including Blincyto (blinatumomab; 57%), Besponsa (inotuzumab; 45%) and/or allogeneic hematopoietic cell transplantation (HCT; 42%). Patients received bridging therapy with chemotherapy (42%), immunotherapy (17%) or targeted therapy (14%), and most (51%) had active disease pre-apheresis whereas 28% had an MRD-positive CR and 12% had an MRD-negative CR.

In the 60 to 69 aged group, the median age was 64 years and 54% of patients were male. The group included patients who were non-Hispanic White (67%), Hispanic (18%), or Black (9%). Patients had an ECOG performance status of 0 (12%), 1 (68%) or 2 or more (11%). ALL subtypes included Ph-negative (53%), Ph-positive (37%), or Ph-like (11%) disease. The median follow-up time was 296 days. Patients received a median of three prior lines of therapy, including Blincyto (60%), Besponsa (44%), and/or allogeneic HCT (46%) and received bridging therapy with chemotherapy (32%), immunotherapy (18%) or targeted therapy (23%). Forty-six percent of patients had active disease, 25% had an MRD-positive CR and 24% had an MRD-negative CR pre-apheresis.

Furthermore, patients in the 70-plus group were a median age of 73 years and most patients were male (53%). The group included patients who were non-Hispanic White (74%), Hispanic (21%) or Black (5%). Patients had an ECOG performance status of 0 (11%), 1 (53%) or 2 or more (32%). ALL subtypes included Ph-negative (63%), Ph-positive (26%) or Ph-like (11%) disease. The median follow-up time was 395 days. Patients received a median of three prior lines of therapy, including Blincyto (68%), Besponsa (26%) and/or allogeneic HCT (16%), and received bridging therapy with chemotherapy (42%), immunotherapy (26%) or targeted therapy (11%). Forty-two percent of patients had active disease, 42% had an MRD-positive CR and 11% had an MRD-negative CR pre-apheresis.

Safety Findings Are Largely Consistent Across Age Groups

Patients in the under 60, 60 to 69 and 70-plus age groups experienced any-grade cytokine release syndrome (CRS) at respective rates of 84%, 86% and 89%. Grade 3 (severe) to 4 (life-threatening) CRS occurred at rates of 11%, 4% and 11%, respectively. Any-grade immune effector cell-associated neurotoxicity syndrome (ICANS) was reported in 48%, 56% and 79% of patients, respectively, and grade 3 to 4 ICANS occurred in 29%, 30% and 32% of patients, respectively.

In terms of hematotoxicity, the median time to absolute neutrophil (white blood cell) count recovery was 16 days, 15 days and 15 days in the under 60, 60 to 69 and 70-plus years old groups. The respective median times to platelet recovery were 27 days, 31 days and 51 days. Patients in all three groups required intravenous immunoglobulin infusion within 90 days (28% versus 18% versus 17%), granulocyte colony-stimulating factor (GCSF) use within 30 days (43% versus 33% versus 33%), GCSF use within 30 to 90 days (37% versus 30% versus 33%), thrombopoietin mimetics use on days 30 to 90 (6% versus 6% versus 6%) and red blood cell transfusion from days 30 to 90 (14% versus 22% versus 6%). Eighteen percent of patients in the under 60 group and 26% in the age 60 to 69 group required platelet transfusion from days 30 to 90. Patients in each group also experienced at least one any-grade infection (30% versus 30% versus 26%) and at least one grade 3 or higher infection (14% versus 4% versus 11%), respectively.

“The rates of a growth factor transfusion support and infections were not higher in older patients,” Muhsen said. “Our data support and confirm that treating patients with B-ALL age 60 and older with Tecartus is feasible. Longer follow-up and a larger sample size, particularly in the 70-plus age group, are needed.”

“Efficacy and safety of brexucabtagene autoleucel for relapsed/refractory B-cell acute lymphoblastic leukemia in patients aged 60 and above.” By Dr. Ibrahim Muhsen, et al., 

Tecartus demonstrated similar effectiveness across age groups of patients with relapsed or refractory B-cell acute lymphoblastic leukemia.

Tecartus Shows Similar Efficacy Across Age Groups in Leukemia

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.”

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. 

Megan Hollasch

Scemblix May Outperform Standard Treatments for Chronic Myeloid Leukemia

Tecartus Shows Similar Efficacy Across Age Groups in Leukemia

Perioperative Opdivo Extends Event-Free Survival in Lung Cancer

Fotivda Shows Better Outcomes Than Combo in Metastatic Kidney Cancer

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