The novel oral HIF2α inhibitor NKT2152 led to an objective response rate (ORR) of 20% in all-comers and 26.3% in the dose-escalation population of patients with previously treated advanced clear cell renal cell carcinoma (RCC), according to findings from a phase 1/2 study (NCT05119335) that were presented at the 

Among evaluable patients within the all-comer population (n = 100) best overall responses included complete response (CR; n = 1), partial response (PR; n = 19), stable disease (SD; n = 52), and progressive disease (PD; n = 28). Within the dose-escalation phase (n = 57) best overall responses included CR (1.75%; n = 1), PR (24.6%; n = 14), SD (49.1%; n = 28), and PD (24.6%; n = 14).

Further divided, responses were also observed irrespective of International Metastatic RCC Database Consortium (IMDC) risk category (favorable, 33.3%; intermediate, 23.7%; poor, 11.4%), ECOG performance status (0, 30.2%; >0, 12.5%), prior lines of therapy (≤3, 20.9%; >3, 18.2%), and being naive to prior mTOR inhibition (35.6%).

“NKT2152 demonstrated robust antitumor activity in heavily pretreated patients with high-risk advanced clear cell RCC,” Eric Jonasch, MD, lead study author and professor in the Department of Genitourinary Medical Oncology, Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center in Houston, said in a presentation of the data. “We can see a trend towards better ORRs in favorable- vs intermediate- and poor-risk [disease], ECOG 0 vs 1, and in the mTOR-naive population.”

HIF2α has been shown to be a driver of clear cell RCC with somatic Von Hippel-Lindau (VHL) deficiency and VHL diseases with germline VHL mutations. With restricted expression in normal tissue, HIF2α represents an ideal target for anticancer treatment development. In December 2023, the FDA approved the first HIF2α-directed therapy belzutifan (Welireg) for patients with advanced RCC following a PD-(L)1 inhibitor and a VEGF TKI.

NKT2152 is a potent, selective orally available HIF2α inhibitor optimized for enhanced pharmacokinetic exposure and sustained target inhibition, preventing transcription of HIF2α-regulated genes that are needed for angiogenesis, glycolysis, and tumorigenesis.

“[NKT2152] is another agent that will interact with HIF2α, prevent HIF2α and HIF1β heterodimerization, and will then prevent the downstream transcription of these various HIF dependent genes,” Jonasch said.

In part 1 dose escalation all 60 patients have been enrolled and in part 2 dose expansion 38 of 40 patients have been enrolled. Thirteen of the expected 17 patients have been enrolled in the clinical pharmacology cohorts and 2 of 10 have been enrolled in the post-belzutifan cohort in part 2.

Per the study design an initial 6 patients received NKT2152 at 200 mg daily, after which 3 patients each received the agent once daily at a dose of 50 mg, 100 mg, or 300 mg. A loading/maintenance regimen was added into the protocol, such that patients received either 200 mg of the agent once daily for 28 days followed by 50 mg once daily (n = 9); 200 mg once daily for 14 days followed by 50 mg once daily (n = 12); 200 mg once daily for 7 days followed by 200 mg weekly (n = 13); or 100 mg once daily for 7 days followed by 100 mg weekly (n = 11). In phase 2 expansion patients will be randomly assigned to 200 mg once daily for 14 days followed by 50 mg once daily or 100 mg once daily for 7 days followed by 100 mg weekly. 

“As it was apparent that there was significant accumulation of this agent due to long half-life loading and maintenance regimens were then investigated,” Jonasch said.

At the June 16, 2024, data cutoff, the median follow-up in part 1 was 20.8 months (range, 10.3-31.2) and was 13.5 months (range, 0.23-31.2) in the overall population.

Of the total 113 patients that have been enrolled to date 41% (n = 46) are ongoing treatment; the remainder have experienced disease or clinical progression (39%; n = 44), an adverse effect (AE; 12%; n = 14); withdrew consent (4%; n = 5), or gave another reason (4%; n = 4).

At baseline, most patients in the overall population had an ECOG performance status of 1 (55.4%; n = 62), IMDC intermediate risk (58.4%; n = 66), and had received either 2 (27.4%; n = 31) or 4 or more (33.6%; n = 38) prior lines of therapy. The median number of prior lines of therapy was 3 (range, 1-9), and most patients had received a prior VEGF TKI (93.8%; n = 106) and immuno-oncology agent (97.3%; n = 110), whereas only 28.3% (n = 32) had received a prior mTOR inhibitor.

Additional results indicated that the median time to response was 3.7 months (range, 1.6-9.1) and the median duration of response was not evaluable (NE; 95% CI, 8.31-NE). The disease control rate was 60% (95% CI, 50%-70%).

“The waterfall plot shows that in all the risk subcategories we see response and the majority of individuals had some degree of tumor shrinkage. The spider plot shows that there is a subset of individuals that had durable and fairly deep response,” Jonasch said.

The median progression-free survival (PFS) was 7.392 months (95% CI, 3.745-12.58) in the overall efficacy-evaluable population and the 12-month PFS rate was 41.8% (95% CI, 30.5%-52.6%). In the dose-escalation population the median PFS was 9.2 months and the 12-month PFS rate was 44%. The median PFS was 13.6 months, 9.4 months, and 3.7 months in the IMDC favorable-, intermediate-, and poor-risk populations, respectively. The median PFS in patients with an ECOG PS of 0 or 1 was 12.7 months and 5.5 months, respectively. Patients who had received 3 or fewer prior lines of therapy had a median PFS of 9.1 months vs 7.4 months in those who had received more than 3. Patients who had not received prior mTOR inhibition experienced a median PFS of 12.7 months.

“Once again we see that there’s a trend that is hypothesis generating of improved PFS with better [risk] status, ECOG performance status, as well as mTOR-naive status,” Jonasch said.

Jonasch stated that the pharmacokinetic and pharmacodynamic profiles support loading and maintenance dosing with NKT2152, evidenced by dose linear and time independent concentrations with an estimated median half-life of 38 days based on a 2-compartment population pharmacokinetic model. Additionally, significant and sustained suppression of the HIF2α client gene EPO was seen at all dose levels with a maximal fractional inhibition of EPO production of 72% and plasma NKT5152 concentration for 50% maximal inhibition of 16.4 ng/mL, which Jonasch stated was significantly exceeded with all doses.

Regarding safety, any-grade AEs experienced by at least 10% of patients occurred in approximately 92.0% of patients and included anemia, fatigue, hypoxia, nausea, dizziness, peripheral edema, and dyspnea. Dose-limiting toxicities included fatigue and hypoxia in 1 of 12 patients who received 200 mg of NKT2152 daily for 14 days followed by 50 mg once daily, and fatigue and hypoxia in 1 of 9 patients who received 200 mg of NKT2152 daily for 28 days followed by 50 mg once daily.

“The safety profile was consistent with this class of agent,” Jonasch said. “Two dose regimens with loading/maintenance dosing have been selected and are under evaluation in the dose expansion of this study,” Jonasch concluded.

Disclosures: Dr Jonasch reported research support from AbbVie, Arrowhead, Aveo, BMS, Vorvus, Merck, NiKang, ProFoundBio, and Telix; honoraria from Aveo, Clinical Care Options, DAVA, EBSCO, Eisai, Exelixis, GSK, IDEO Oncology, i3 Health, Ipsen, Kaplan, Merck, Novartis, NiKang, Petra Drugstore, and Plexus; and leadership positions in NCCN Guidelines (vice chair, Kidney Cancer Panel), member of the NCI RCC Steering Committee, and board member on the International Kidney Cancer Coalition.

Jonasch E, McGregor BA, Msaouel P, et al. NKT2152, a novel oral HIF-2a inhibitor, in participants with previously treated advanced clear cell renal cell carcinoma (accRCC): preliminary results of a phase 1/2 study. Presented at: 2024 ESMO Congress; September 13-17, 2024; Barcelona, Spain. Presentation 1690O.

FDA approves belzutifan for advanced renal cell carcinoma. FDA. December 14, 2023. Accessed September 19, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-belzutifan-advanced-renal-cell-carcinoma

Articles

The novel oral HIF2α inhibitor NKT2152 elicited encouraging responses in patients with previously treated advanced clear cell renal cell carcinoma.

NKT2152 Data Reinforce the Importance of HIF2α Inhibition in Advanced Clear Cell RCC 

A higher degree fucosylation and sialylation of serum proteins represent negative prognostic factors in advanced renal cell carcinoma (RCC) as they have been linked with worse clinical outcomes for nivolumab (Opdivo) plus cabozantinib (Cabometyx) and sunitinib (Sutent), according to findings from an exploratory post-hoc analysis of the phase 3 CheckMate-9ER study (NCT03141177).

, also suggested that serum glycoproteins involved in complement cascade and lipid metabolism could be predictive of response to the doublet vs sunitinib in this disease, according to David A. Braun, MD, PhD, assistant professor of medicine (Medical Oncology) and Louis Goodman and Alfred Gilman Yale Scholar at Yale School of Medicine, in New Haven, Connecticut. Specifically, high serum levels of CO3 glycopeptide are potentially predictive of favorable response to the nivolumab plus cabozantinib vs sunitinib, as are low serum levels of CFAH glycopeptide.

“We see that higher amounts of protein glycosylation, both sialylation and fucosylation, appear to be prognostic in this data set, and that specific protein glycosylation events related to lipid metabolism, but also related to the complement cascade, have the potential to [possibly] be predictive of response in anti–PD-1-based therapy, as opposed to sunitinib,” Braun said in a presentation of the data. “But I want to highlight this is really early exploratory work. I [believe] the main question is, is this an area for further investigation in biomarker development in RCC? And I [believe] the answer to that is, yes.” 

CheckMate-9ER enrolled patients with previously untreated advanced RCC with a clear cell component. They could have disease of any risk by International mRCC Database Consortium (IMDC) criteria, but they needed to have tumor tissue available for analysis.

Patients were randomly assigned 1:1 to receive 240 mg of intravenous (IV) nivolumab every 2 weeks paired with 40 mg of oral cabozantinib once daily vs 50 mg of oral sunitinib on a cycle of 4-weeks-on/2-weeks-off. Treatment continued until disease progression by RECIST v1.1 criteria or intolerable toxicity. Stratification factors included IMDC risk score, tumor PD-L1 expression, and geographic region.

The primary end point of the study was progression-free survival (PFS) by blinded independent review committee (BICR) and RECIST 1.1 criteria. Secondary end points included overall survival (OS), objective response rate (ORR) by BICR and RECIST 1.1 criteria, as well as safety. Health-related quality of life served as an important exploratory end point.

 for the first-line treatment of patients with advanced RCC based on earlier data from CheckMate-9ER.

 Data from the 55-month follow-up of the study shared during the 

 showed that nivolumab plus cabozantinib continues to provide a meaningful improvement over sunitinib in PFS, OS, and ORR.

 In the intention-to-treat population, the PFS by BICR was 16.4 months (95% CI, 12.5-19.3) with the doublet vs 8.4 months (95% CI, 7.0-9.7) with sunitinib (HR, 0.58; 95% CI, 0.49-0.70). The median OS with nivolumab plus cabozantinib was 46.5 months (95% CI, 40.6-53.4) vs 36.0 months (95% CI, 29.2-42.8) with sunitinib (HR, 0.77; 95% CI, 0.63-0.95). The ORR by BICR was 55.7% with the doublet vs 27.7% with sunitinib.

“[Although] anti–PD-1–based therapy is really the standard for first-line RCC, we still lack effective biomarkers to figure out which patients are likely to respond, and which tumors are likely to be resistant to therapy. Our group, and many others, have focused largely on the genomics and transcriptomics of the tumor itself, but we know that post-translational modifications of proteins themselves play an important role in those proteins’ function,” Braun said. “In fact, glycosylation of protein, altered glycosylation, is a hallmark of cancer and involved in many malignant processes. Hypersialylation in particular, engages sialic acid-binding immunoglobulin-like lectin receptors and is known to be immunomodulatory, potentially raising the idea that it could contribute to anti–PD-1 resistance.”

For the post-hoc analysis, Braun and colleagues evaluated the link between site-specific glycopeptide modifications with nivolumab plus cabozantinib/sunitinib response in patients with advanced RCC by leveraging pre-treatment serum samples. They used the InterVenn GlycoVision platform to conduct a glycoproteomic analysis, to understand if altered protein glycosylation is a possible avenue for biomarker studies in RCC. They identified 24 serum glycopeptides that were linked with PFS or OS with the doublet.

“The first question is, how are these regulated? Are they regulated in a coordinated fashion or not? We looked across patients for site-specific protein glycosylation, […and what] we can see is highly coordinated modules of altered protein glycosylation, [with] red piercing correlations across patients for these different site-specific glycosylations,” Braun said. “Now, in our initial study and our initial look at these particular proteins, we can see that these coordinated modules seem to be associated with altered PFS and OS with nivolumab plus cabozantinib, either positively or negatively. So, this gave us some initial insight for further study, that these are highly coordinated and potentially associated with clinical outcome.”

Braun added that the next question posed by the investigators was whether the total amount of glycosylation is important and if it plays a role in clinical outcomes. To that end, they examined the total amount of 2 forms of glycosylation: sialyation and fucosylation.

“We see basically an increasing amount of glycosylation, the number of amino acid residues that have a sialic acid or a fucose residue. As we can see, for both nivolumab [plus] cabozantinib and sunitinib, when you have more glycosylation, you have a higher hazard ratio, [which is] essentially worse PFS and OS with more protein glycosylation,” Braun explained. “This at least raises the potential that this could be prognostic and really reinforces prior studies seen in melanoma. So that’s a potential prognostic role.”

They then set out to evaluate whether this marker could be predictive for response to the doublet vs the monotherapy. When they look across several protein glycosylations, 2 patterns emerged, Braun noted. “One, proteins involved in lipid metabolism, and the second were members of the complement cascade,” he said. “One is CO3. And what we can see is that at low levels of protein glycosylation, there’s [essentially] no difference between nivolumab plus cabozantinib or sunitinib with respect to PFS, but at high levels of protein glycosylation, this is where we see tremendous benefit from nivolumab plus cabozantinib. This is hypothesis generating. This is a proinflammatory complement protein, so could this be mediating complement-induced antitumor activity?”

The opposite pattern was observed for CFAH glycopeptide. He noted that high levels of the checkpoint did not show benefit from the doublet whereas when the protein glycosylation was low, substantial benefit was observed with the combination. “The hypothesis is that this negative regulator of alternate complement activity, when it’s low, that’s when the immune therapy is able to act,” Braun said.

He concluded that the prognostic or predictive potential of glycopeptide biomarkers should be further examined in additional clinical trials.

Disclosures: Dr Braun shared that he has a non-CE consulting relationship with Cancer Expert Now, Adnovate Strategies, MDedge, CancerNetwork, Catenion, OncLive, Cello Health BioConsulting, PWW Consulting, Haymarket Medical Network, Aptitude Health, ASCO Post/Harborside, Targeted Oncology, Merck, Pfizer, MedScape, Accolade 2nd MD, DLA Piper, AbbVie, Compugen, Link Cell Therapies, Scholar Rock, and NeoMorph. He serves on the advisory board for Exelixis, AVEO, Eisai, and Elephas, and has equity in Elephas and Fortress Biotech (subsidiary). He received research grants from National Institutes of Health/National Cancer Institute, DOD, KCA, Akoya, Exelixis, and AstraZeneca. Support for the current study was provided by Bristol Myers Squibb.

Braun DA, Vemula SV, Wang Y, et al. Novel serum glycoproteomic biomarkers predict response to nivolumab plus cabozantinib (nivo+cabo) versus sunitinib (suni) in advanced RCC (aRCC): analysis from CheckMate 9ER. Presented at: 2024 ESMO Congress; September 13-17, 2024; Barcelona, Spain. Presentation 1694MO.

FDA approves nivolumab plus cabozantinib for advanced renal cell carcinoma. FDA. January 22, 2021. Accessed September 17, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-nivolumab-plus-cabozantinib-advanced-renal-cell-carcinoma?utm_medium=email&utm_source=govdelivery

Bourlon MT, Escudier B, Burotto M, et al. Nivolumab plus cabozantinib versus sunitinib for previously untreated advanced renal cell carcinoma: results from 55-month follow-up of the CheckMate 9ER trial. 

. 2024;42 (suppl 4):362. doi:10.1200/JCO.2024.42.4_suppl.362

Elevated fucosylation and sialylation of serum proteins were negative prognostic factors in RCC after treatment with nivolumab plus cabozantinib or sunitinib.

CheckMate-9ER Post-Hoc Analysis Seeks to Identify Efficacy Biomarkers for Nivolumab/Cabozantinib in RCC

Ipilimumab (Yervoy) plus nivolumab (Opdivo) significantly improved the 12-month overall survival (OS) rate vs standard-of-care (SOC) therapies in patients with non-clear cell renal cell carcinoma (nccRCC), meeting the primary end point of the phase 2 SUNNIFORECAST trial (NCT03075423), according to data presented during the 

At a median follow-up of 24.3 months (range, 0.5-70.2), the 12-month OS rate was 86.9% (95% CI, 80.24%-91.46) among patients who received ipilimumab in combination with nivolumab (n = 157) vs 76.8% (95% CI, 68.62%-83.09%) among those treated with SOC (n = 152; 

 = .0141). The 6-month OS rates were 94.7% (95% CI, 89.72%-97.32%) vs 90.0% (95% CI, 83.75%-93.98%), respectively (

 = .067) and the 18-month rates were 76.6% (95% CI, 68.69%-82.79%) vs 69.1% (95% CI, 60.25%-76.34%), respectively (

 = .084). The median OS was 42.4 months (95% CI, 35.24-55.54) in the doublet arm compared with 33.9 months (95% CI, 25.52-not estimable) in the SOC arm (

“A significant difference [in 12-month OS rate was observed] in favor of the combination arm,” Lothar Bergmann, MD, the deputy medical director in the Department of Internal Medicine at J.W. Goethe University in Frankfurt, Germany, said during the presentation. “The SOC for most patients [in the study] was TKI monotherapy and only 17% of patients received a TKI/IO combination in this group.”

SUNNIFORECAST enrolled patients with metastatic or locally advanced nccRCC, including those with papillary, chromophobe, collecting duct carcinoma, renal medullary carcinoma, sarcomatoid, or unclassified disease subtypes. To be eligible for the study, patients could not have received prior systemic therapy for RCC or have active central nervous system metastases. Patients must have had measurable disease per RECIST 1.1 criteria and a Karnofsky performance status of at least 70%. Stratification was done by histology (papillary vs non-papillary) and IMDC score.

Patients were randomly assigned 1:1 to receive SOC agents or intravenous nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for 4 cycles followed by nivolumab 240 mg flat every 2 weeks or 480 mg flat every 4 weeks. Treatment in both arms continued until disease progression, unacceptable toxicity, or patient withdrawal. Treatment beyond disease progression was permitted under protocol-defined circumstances.

The primary end point was 12-month OS rate. Key secondary end points included OS, 6- and 12-month OS rates, progression-free survival, objective response rate, time to progression, safety, and quality of life.

The baseline characteristics were generally well balanced between the combination and SOC arms; the median patient ages were 61.4 years (range, 18.8-81.8) vs 64.0 years (range, 19.4-86.2), respectively. In total, patients (n = 309) in the study were male (70.9%), had a Karnofsky performance score of 100% (52.4%), had IMDC intermediate risk disease (51.8%), and underwent prior surgery (76.7%). Patients had sites of metastasis including the lungs (22.0%), liver (10.1%), bone (5.1%), lymph nodes (30.8%), and other (20.3%). The median time since initial diagnosis among all patients enrolled was 30.9 months (range, 1.3-1416.6).

Histological subtypes in the combination and SOC arms consisted of papillary RCC (56.7% vs 58.6%), chromophobe RCC (17.8% vs 21.2%), renal medullary carcinoma (0.0% vs 2.0%), translocation RCC (7.6% vs 3.3%), tubulocystic RCC (1.9% vs 0.0%), mucinous tubular and spindle cell carcinoma (0.6% vs 0.0%), sarcomatoid (5.1% vs 3.9%), Ductus Bellini carcinoma (0.0% vs 2.0%), and others (7.0% vs 6.6%).

In terms of PFS, the median value in the combination arm was 5.52 months (range, 4.30-8.23) vs 5.65 months (range, 5.49-8.46) in the SOC arm (HR, 0.99; 95% CI, 0.76-1.18). The respective ORRs were 32.8%, with an 8.0% complete response (CR) rate, vs 19.6%, with a 1.6% CR rate, (

 = .001). The ORR was higher with the combination vs SOC in patients with papillary (29.2% vs 21.0%), non-papillary (37.7% vs 18.2%), and chromophobe (25.9% vs 11.1%) histologies, respectively.

Notably, the HR for OS favored the combination arm among patients with a PD-L1 combined positive score (CPS) of at least 1% (HR, 0.56; 95% CI, 0.33-0.95; 

 = .031) but did not favor this arm among patients with patients who had a PD-L1 CPS of less than 1% (HR, 1.40; 95% CI, 0.79-2.46; 

Regarding safety, the most common any-grade adverse effects (AEs) in the combination and SOC arms included skin reactions (48.4% vs 74.2%), fatigue (42.9% vs 63.7%), diarrhea (21.0% vs 45.1%), pruritus (25.0% vs 2.8%), and nausea (20.6% vs 31.5%). The most common grade 3 or 4 AEs included increased alanine aminotransferase levels (5.7% vs 0.0%), fatigue (3.8% vs 8.4%), and diarrhea (3.2% vs 4.9%). Rates of any-grade AEs were generally higher in the SOC arm vs combination arm.

Patients in the nivolumab plus ipilimumab arm went on to receive subsequent second (63.7%), third (28.7%), and fourth (11.5%) lines of therapy. Patients went on to receive these lines of therapy at rates of 55.9%, 13.2%, and 9.2%, respectively, in the SOC arm.

“This is the first prospective randomized trial which compared dual checkpoint inhibitor combination therapy with the actual SOC in nccRCC,” Bergmann noted in conclusion. “The randomized SUNNIFORECAST trial underlines a relevant clinical benefit of the combination [of ipilimumab and nivolumab] in nccRCC and may be a new standard in these entities. Further data in the study of these rare diseases are needed in the future.”

Bergmann L, Ahrens M, Albiges L, et al. Prospective randomised phase-II trial of ipilimumab/nivolumab versus standard of care in non-clear cell renal cell cancer: Results of the SUNNIFORECAST trial. Presented at: 2024 ESMO Congress; September 13-17, 2024; Barcelona, Spain. Abstract LBA75.

Ipilimumab given in combination with nivolumab met the primary end point of 12-month OS rate vs SOC in patients with nccRCC in the SUNNIFORECAST trial.

Ipilimumab Plus Nivolumab Increases 12-Month OS Rate vs SOC in nccRCC

Frontline treatment with the anti–PD-L1 monoclonal antibody benmelstobart (TQB2450) plus anlotinib (AL3818) displayed superior clinical outcomes vs sunitinib (Sutent) in patients with advanced renal cell carcinoma (RCC), according to findings from the phase 3 ETER100 trial (NCT04523272) presented during the 

Patients in the combination arm (n = 264) achieved a median progression-free survival (PFS) by blinded independent central review (BICR) of 18.96 months (95% CI, 15.34-22.83) vs 9.76 months (95% CI, 8.38-12.42) in the sunitinib arm (n = 263; HR, 0.53; 95% CI, 0.42-0.67; 

 < .0001). The median overall survival (OS) was not estimable (NE; 95% CI, 38.18-NE) compared with NE (95% CI, 30.49-NE), respectively (HR, 0.66; 95% CI, 0.48-0.92; 

 = .0673). The respective overall response rates (ORRs) by BICR were 71.6% vs 25.1%; 1.1% of patients in the combination arm 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,” Xinan Sheng, MD, 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 arm over the sunitinib arm. The combination treatment reduced the risk of progression or death by 47% compared with sunitinib.”

ETER100 was a positive parallel controlled, 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, and have at least 1 measurable lesion per RECIST 1.1 criteria. Patients with prior exposure to any VEGFR-directed TKIs or immune checkpoint inhibitors were excluded.

Patients were randomly assigned 1:1 to receive anlotinib 12 mg daily on days 1 to 14 every 3 weeks plus benmelstobart 1200 mg on day 1 every 3 weeks or sunitinib 50 mg daily on days 1 through 28 every 6 weeks. Patients were stratified by IMDC risk group (favorable vs intermediate vs poor). Treatment in both arms continued until disease progression or intolerable toxicity.

The primary end point was PFS by BICR per RECIST 1.1 criteria. Secondary end points included investigator-assessed PFS, OS, ORR, disease control rate, duration of response, and safety.

The baseline characteristics were well balanced between the 2 arms; the median age in the combination arm was 60.5 years (range, 54.0-67.0) vs 59.0 years (range, 54.0-67.0) in the sunitinib arm. Most patients in both arms were less than 65 years old (64.02% vs 69.20%), male (77.27% vs 74.52%), had an ECOG performance status of 1 (72.73% vs 73.76%), had IMDC intermediate risk disease (71.21% vs 71.86%), and underwent a prior nephrectomy (66.67% vs 66.16%). Sites of disease metastasis included the lung (62.50% vs 60.84%), bone (21.59% vs 20.53%), and liver (13.26% vs 10.27%), in the combination vs sunitinib arm, respectively.

Findings from a subgroup analysis showed that the PFS benefit observed with anlotinib plus benmelstobart vs sunitinib was sustained across all subgroups. The most pronounced benefit reported was among patients with sarcomatoid differentiation (HR, 0.33; 95% CI, 0.08-1.26) and those with liver metastasis (HR, 0.44; 95% CI, 0.23-0.85).

In terms of safety, patients in the investigational and control arms both experienced any-grade treatment-emergent adverse effects (TEAEs) at rates of 99.24%. Patients in both arms also had grade 3 or higher TEAEs (75.00% vs 74.62%), any-grade treatment-related adverse effects (TRAEs; 98.11% vs 98.11%), grade 3 or higher TRAEs (67.42% vs 65.91%), and serious AEs (38.64% vs 28.03%), respectively. Additionally, patients in the combination arm experienced immune-related AEs (33.33%), grade 3 or higher immune-related AEs (9.47%), and immune-related reactions (4.92%).

One-hundred and thirty-eight patients in the combination arm discontinued treatment due to disease progression (n = 84), AEs (n = 12), patient withdrawal (n = 6), death (n = 17), lost to follow-up (n = 3), and other reasons (n = 16). Among patients in the sunitinib arm, 209 discontinued treatment due to disease progression (n = 142), AEs (n = 12), patient withdrawal (n = 21), death (n = 8), lost to follow-up (n = 1) and other reasons (n = 25).

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

Disclosures: Dr Sheng has consulting or advisory roles with Pfizer, Novartis, Astellas, AstraZeneca, Bayer, MSD, RemeGen, and Junshi Biosciences.

Sheng X, Shen P, Qu W, et al. Anlotinib in combination with anti–PD-L1 antibody benmelstobart (TQB2450) versus sunitinib in first-line treatment of advanced renal cell carcinoma (RCC). Presented at: 2024 ESMO Congress; September 13-17, 2024; Barcelona, Spain. Abstract LBA76.

A study of TQB2450 injection combined with anlotinib hydrochloride capsule versus sunitinib in subjects with advanced renal cancer. ClinicalTrials.gov. Updated September 10, 2020. Accessed September 15, 2024. https://clinicaltrials.gov/study/NCT04523272

Benmelstobart plus anlotinib improved PFS, OS, and ORR vs sunitinib in first-line advanced renal cell carcinoma.

Benmelstobart Plus Anlotinib Demonstrates Efficacy in Frontline Advanced RCC

The addition of nivolumab (Opdivo) to tivozanib (Fotivda) did not improve clinical outcomes for patients with metastatic renal cell carcinoma (RCC) who experienced disease progression on or after therapy with a PD-(L)1 inhibitor, according to findings from the phase 3 TiNivo-2 study (NCT04987203).

“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,” Toni Choueiri, MD, of Dana-Farber Cancer Institute in Boston Massachusetts, said in a presentation of the data at the 

. “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 tivozanib monotherapy at 1.34 kg 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 tivozanib plus nivolumab arm (n = 171) and 12.5 months in the tivozanib monotherapy arm (n = 172), the median progression-free survival (PFS) was not improved with the doublet vs monotherapy (stratified HR, 1.10; 95% CI, 0.84-1.43; 

 = .49). Findings from the primary analysis of centrally reviewed PFS, which was the study’s primary end point, revealed that the median PFS was 5.7 months (95% CI, 4.0-7.4) for the combination vs 7.4 months (95% CI, 5.6-9.2) for tivozanib alone in the intention-to-treat population.

When examining centrally reviewed PFS by subgroups, no group appeared to benefit from the doublet vs monotherapy, according to Choueiri. The lowest HR was 0.92 (95% CI, 0.61-1.37) in patients 65 years of age or older, and the highest HR was 1.37 (95% CI, 0.69-2.73) in patients with International Metastatic RCC Database Consortium (IMDC) favorable-risk disease.

“This trial confirms and expands key conclusions from the [phase 3] CONTACT-03 study [NCT04338269]. [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 tivozanib in the combination arm may have impacted the efficacy, and that reflects in the lower median PFS [observed],” Choueiri said.

Diving Into TiNivo-2’s Design and Difference in Dosing Between Arms

Patients with locally advanced or metastatic clear cell RCC were enrolled following disease progression on 1 or 2 lines of therapy, 1 of which was an ICI they progressed on during or following at least 6 weeks of therapy. Patients needed to have an ECOG performance status of 0 or 1, measurable disease per RECIST 1.1 criteria, and a time from immediate prior line of therapy received to random assignment of 6 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? Could outcomes be impacted if we use a non-ICI drug before ICI rechallenge and an ICI break? What about using a PD-1 vs PD-L1 inhibitor, does that matter?” Choueiri asked. He noted that following encouraging efficacy seen in the phase 1/2 TiNivo study (NCT03136627) with tivozanib plus nivolumab, TiNivo-2 was initiated.

Random assignment for TiNivo-2 was done in a 1:1 fashion, and stratification factors included IMDC risk category and prior therapy received (ICI as most recent therapy vs not). Patients in the tivozanib monotherapy arm received the agent orally at 1.34 mg on days 1 to 21 of each 28-day cycle. Those in the doublet arm received a reduced dose of 0.89 mg on the same schedule plus 480 mg of intravenous nivolumab given on day 1 of each cycle.

Choueiri noted that the reduced dose was agreed upon with regulatory authorities due to the potential risk of increased rates of grade 3/4 hypertension in the combination arm.

PFS by independent radiology review served as the trial’s primary end point, and secondary end points were overall survival (OS), PFS by investigator assessment, objective response rate (ORR), duration of response (DOR), and safety/tolerability.

Baseline patient characteristics were also well balanced between the two arms. The median age of patients in the tivozanib plus nivolumab arm was 64 years (range, 37-87) compared with 63 years (range, 33-82) in the tivozanib monotherapy arm. Most patients were male (73% for the combination vs 78% for tivozanib monotherapy), White (65% vs 62%), had an ECOG performance score of 1 (55% vs 51%), received 1 prior line of therapy (65% vs 61%), and received an ICI as their most recent therapy (71% vs 71%). Additionally, patients had favorable- (18% vs 18%), intermediate- (67% vs 66%), and poor- (16% vs 16%) risk disease by IMDC, and approximately one-third of patients did not receive a prior VEGFR-TKI (31% vs 31%).

When examining PFS by line of therapy, higher PFS rates were observed in the second-line setting, although tivozanib monotherapy bested tivozanib plus nivolumab. The median PFS among patients who received tivozanib plus nivolumab (n = 111) in the second-line setting was 7.3 months (95% CI, 5.4-9.3) vs 9.2 months (95% CI, 7.4-10.0) among patients treated with the monotherapy in this setting (n = 105; HR, 1.15; 95% CI, 0.82-1.62; 

Those who received treatment in TiNivo-2 as third-line therapy experienced a median PFS of 4.8 months (95% CI, 3.2-7.5) in the doublet arm (n = 60) vs 5.5 months (95% CI, 2.9-7.4) in the monotherapy arm (n = 67; HR, 0.97; 95% CI, 0.65-1.45; 

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

Furthermore, data revealed that the median OS was 17.7 months (95% CI, 15.1–not reached [NR]) in the tivozanib plus nivolumab arm compared with 22.1 months (95% CI, 15.2-NR) in the tivozanib monotherapy arm (HR, 1.00; 95% CI, 0.68-1.46; 

 = .9868). However, Choueiri noted that OS data were not mature; at data cutoff, 32% of events had occurred.

Additionally, the ORR was 19.3% (95% CI, 13.7%-26.0%) in the doublet arm vs 19.8% (95% CI, 14.1%-26.5%) in the singlet arm. One patient in each arm achieved a complete response. Patients also experienced stable disease (43.3% vs 47.1%), progressive disease (28.7% vs 25.0%), or were not evaluable (8.8% vs 8.1%). The median DOR was 15.77 months (95% CI, 5.65-NR) with the doublet compared with 9.66 months (95% CI, 3.71-NR) with monotherapy.

Safety Findings Are Comparable Between Arms

Adverse effects (AEs) leading to death occurred in 7 patients in the doublet arm and 5 patients in the tivozanib monotherapy arm. Patients experienced grade 2 or greater AEs (61% for the doublet vs 60% for the singlet), serious AEs (32% vs 37%), and treatment-emergent AEs leading to discontinuation (16% vs 19%), dose interruption (49% vs 54%), and dose reduction of tivozanib (11% vs 22%). The median duration of treatment was 6.3 months (range, 0.0-20.7) and 7.4 months (range, 0.1-17.9), respectively.

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

Disclosures: Dr Choueiri cited receiving institutional and/or personal, paid and/or unpaid support for research, advisory boards, consultancy, and/or Honoria in the past 5 years, ongoing or not, from: Alkermes; Arcus Biosciences; AstraZeneca; Aravive; Aveo; Bayer; Bristol-Myers Squibb; Calithera; Circle Pharma; Deciphera Therapeutrics; Eisai; EMD Serono; Exelixis; GSK; Gilead; HiberCell; IQVIA; Infinity; Ipsen; Janssen Oncology; Kanaph Therapeutics; Lilly; Merck; NiKang Therapeutics; Neomorph; Neucon/Precede Biosciences; Novartis; OncoHost; Pfizer; Roche; Sanofi-Aventis; Scholar Rock; Surface Oncology; Takeda; Tempest Therapeutics; UpToDate; and CME events. He also cited having institutional patents filed on molecular alterations and immunotherapy response/toxicity and ctDNA. Choueiri also has equity in Tempest; Pionyr, Osel; Precede Biosciences; Curesponse; InnDura Therapeutics; and Premium. He is on committees for the NCCN; GU Steering Committee; ASCO; ESMO; ACCRU; and KidneyCAN.

Choueiri TK, Motzer RJ, Beckermann K, et al. Tivozanib–nivolumab vs tivozanib monotherapy in patients with renal cell carcinoma (RCC) following 1 or 2 prior therapies including an immune checkpoint inhibitor (ICI): Results of the phase III TiNivo-2 study. Presented at: 2024 ESMO Congress; September 13-17, 2024; Barcelona, Spain. Abstract LBA73.

The addition of nivolumab to tivozanib did not improve outcomes in metastatic RCC and 1.34 mg of tivozanib monotherapy may be considered as a second-line therapy. 

Tivozanib Monotherapy Bests Lower-Dose Tivozanib Plus Nivolumab in Metastatic RCC 

Belzutifan (Welireg) retained a statistically significant improvement in progression-free survival (PFS) and objective response rate (ORR) vs everolimus (Afinitor) in previously treated patients with advanced clear cell renal cell carcinoma (RCC); however, the agent fell short in terms of an overall survival (OS) advantage, according to findings from the final analysis of the phase 3 LITESPARK-005 trial (NCT04195750) presented at the 

At a median follow-up of 35.8 months (range, 26.9-49.2), the median PFS was 5.6 months (95% CI, 3.8-6.5) with belzutifan (n = 374) vs 5.6 months (95% CI, 4.8-5.8) with everolimus (n = 372; HR, 0.75; 95% CI, 0.63-0.88). The 12- and 24-month PFS rates with belzutifan were 33.7% and 17.5%, respectively, vs 17.6% and 4.1% with everolimus. The median OS was 21.4 months (95% CI, 18.2-24.3) with belzutifan vs 18.2 months (95% CI, 15.8-21.8) with everolimus (HR, 0.92; 95% CI, 0.77-1.10; 

 =.18). The 12- and 24-month OS rates with belzutifan were 67.9% and 45.2%, respectively, vs 65.8% and 41.2% with everolimus.

“At the final analysis of the phase 3 LITESPARK-005 study, belzutifan continued to show PFS and ORR benefits vs everolimus, including durable responses lasting over 2 years,” Brian Rini, MD, lead study author and chief of clinical trials at Vanderbilt-Ingram Cancer Center in Nashville, Tennessee, said in a presentation of the data. “With over 2 years of minimum follow-up, more participants remained on treatment with belzutifan vs everolimus, [but] significant improvement in OS was not observed.”

Belzutifan is a first-in-class oral HIF-2a inhibitor that impedes heterodimerization with HIF-1b and downstream oncogenic pathways.

FDA approved belzutifan for patients with advanced RCC

 following a PD-(L)1 inhibitor and a VEGF TKI, based on earlier findings from LITESPARK-005 that demonstrated a statistically significant improvement in PFS with belzutifan vs everolimus (HR, 0.75; 95% CI, 0.63-0.90; 1-sided 

 =.0008). The agent also led to an improved ORR of 22% (95% CI, 18%-27%) vs 4% (95% CI, 2%-6%) with everolimus. OS results were immature at the time of the analysis with 59% of deaths reported, but no detrimental trend was observed.

To be eligible for enrollment patients had to have unresectable, locally advanced or metastatic clear cell RCC with disease progression after 1 to 3 prior lines of systemic therapy, including at least 1 anti–PD-(L)1 monoclonal antibody and at least 1 VEGFR TKI. A Karnofsky performance status (KPS) of at least 70% was also required.

Patients were randomly assigned 1:1 to 120 mg of oral belzutifan once daily or 10 mg of oral everolimus once daily. The dual primary end points were PFS per RECIST 1.1 criteria by blinded independent central review (BICR) and OS. The study would be deemed positive if either primary end point was met. Secondary end points included ORR and duration of response (DOR) per RECIST 1.1 criteria by BICR, and safety.

Patients were stratified by the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) prognostic score (0 vs 1-2 vs 3-6) and the number of prior VEGFR TKIs (1 vs 2-3).

Between March 10, 2020, and January 19, 2022, 746 patients were randomly assigned; 374 and 372 were ultimately treated with belzutifan and everolimus, respectively. Fifty-four (14.5%) and 5 (1.4%) patients remained on treatment with belzutifan and everolimus, respectively. In the belzutifan arm, reasons for treatment discontinuation were progressive disease (68.5%), adverse effects (AEs; 6.2%), clinical progression (5.9%), patient withdrawal (3.0%), receipt of non-study anticancer therapy (1.3%), physician decision (0.3%), and parent/guardian withdrawal (0.3%). In the everolimus arm, reasons for discontinuation were progressive disease (68.9%), AEs (15.3%), clinical progression (7.2%), patient withdrawal (3.9%), receipt of non-study anticancer therapy (2.8%), and physician decision (0.6%).

Baseline characteristics were well matched in both arms. In the belzutifan arm, the median age was 62 years (range, 22-90), and most patients were male (79.4%). Most patients had a KPS of 90% or 100% (63.6%) as opposed to 70% or 80% (36.1%); 0.3% of patients in each arm had a missing KPS score. Patients with all IMDC risk categories were represented: favorable (21.7%), intermediate (66.3%), and poor (12.0%), and 11.2% had sarcomatoid features. Prior nephrectomy had been performed in 69.8% of patients. The number of prior lines of VEGFR TKI therapy was evenly split between 1 (49.7%) and 2 or 3 (50.3%). Regarding overall prior lines of therapy, 12.0% of patients had received 1, 42.2% had received 2, and 45.2% had received 3.

Among the patients still on belzutifan at the time of the analysis (n = 54), most had a KPS of 90% or 100% (81.5%), IMDC intermediate risk (59.3%), prior nephrectomy (83.3%), and 2 or 3 prior VEGFR TKIs (53.7%).

Additional efficacy findings demonstrated that belzutifan led to a substantially higher ORR than everolimus at 22.7% (95% CI, 18.6%-27.3%) vs 3.5% (95% CI, 1.9%-5.9%), reflecting an estimated difference of 19.2% (95% CI, 14.8%-24.1%). In the belzutifan arm, confirmed best objective responses included complete response (CR; 3.5%), partial response (PR; 19.3%), stable disease (SD; 38.2%), and progressive disease (PD; 34.0%); 5.0% of patients were not evaluable or had no assessment because of insufficient data or lack of an available post-baseline evaluation. In the everolimus arm, confirmed best objective responses included PR (3.5%), SD (65.9%), and PD (21.5%); 9.1% of patients were not evaluable or had no assessment for the same reason.

In the belzutifan arm, the median time to response (TTR) among responders (n = 85) was 3.8 months (range, 1.7-22.0) and the median DOR was 19.3 months (range, 1.9+ to 40.1+). The rate of belzutifan-treated patients in ongoing response at 12 and 24 months was 71.1% and 43.7%, respectively. In the everolimus arm, the median TTR among responders (n = 13) was 3.7 months (range, 1.8-5.7) and the median DOR was 13.7 months (range, 3.8 to 29.5+). The rate of everolimus-treated patients in ongoing response at 12 and 24 months was 61.5% and 23.1%, respectively. 

Survival follow-up in patients who did not receive subsequent therapy in the belzutifan (n = 173; alive at follow-up, n = 61) and everolimus (n = 121; alive at follow-up, n = 12) arms was also presented.

“The point [here is that] there are many more [patients alive without need of subsequent therapy] in the belzutifan arm and very few of such patients in the everolimus arm,” Rini said.

The median duration of study therapy was 7.6 months (range, 0.1-45.9) with belzutifan and 3.9 months (range, 0.03-41.8) with everolimus. Despite longer exposure to treatment, patients in the belzutifan arm experienced comparable or reduced toxicities to those in the everolimus arm. Grade 3 or greater AEs occurred in 62.9% and 62.8% of patients in the belzutifan and everolimus arms, respectively. AEs leading to discontinuation or death occurred in 6.2% and 3.8% of patients in the belzutifan arm, respectively, vs 15.3% and 5.3% in the everolimus arm. Grade 3 or greater treatment-related AEs (TRAEs) occurred in 39.5% and 40.0% of patients in the belzutifan and everolimus arms, respectively. TRAEs leading to death occurred in 0.3% and 0.6% of patients in the belzutifan and everolimus arms, respectively.

Rini also presented the time to first onset of common any-grade AEs attributed to belzutifan, which illustrated that most TRAEs had quick onset. The respective median times to onset for anemia, hypoxia, dizziness, dyspnea, fatigue, nausea, and weight increase were 1.0 month (range, 0.03-27.4), 1.0 month (range, 0.03-21.1), 2.3 months (range, 0.03-34.2), 1.9 months (range, 0.03-25.8), 1.5 months (range, 0.03-29.9), 1.4 months (range, 0.03-24.0), and 3.3 months (range, 0.5-15.0).

“No new safety signals for belzutifan were observed,” Rini said. “The most common any-grade adverse drug reactions had a median time to onset of less than 2 months.”

The median durations of anemia, hypoxia, dizziness, dyspnea, fatigue, nausea, and weight increase were 4.6 months (range, 0.1+ to 47.1+), 0.5 months (range, 0.03 to 31.9+), 1.1 months (range, 0.03-35.2), 3.3 months (range, 0.03 to 39.5+), not reached (range, 0.1 to 43.9+), 1.2 months (range, 0.03 to 38.6), and 16.6 months (range, 0.6 to 40.0+), respectively.

“Final analysis results of LITESPARK-005 support belzutifan as a treatment option in advanced clear cell RCC after PD-[L]1 inhibitor and VEGFR TKI therapy,” Rini concluded.

Disclosures: Dr Rini reported institutional research funding from AVEO, Arcus, MSD, Dragonfly Therapeutics, HiberCell, Incyte, Stata Oncology, ADC Therapeutics, Dracen Pharmaceutical, Janssen, Adela, AstraZeneca, Tempus, Gilead, POINT Biopharma, BMS, Pfizer, Daiichi Sankyo, Genentech, Exelixis, and Surface Oncology; consulting for Eisai, BMS, Pfizer, Genentech, AstraZeneca, Aveo, MSD, Debiopharm, Exelixis, and MashupMD; and study funding, medical writing, and editorial support from Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA (MSD).

Rini B, Suarez C, Albiges L, et al. Final analysis of the phase 3 LITESPARK-005 study of belzutifan versus everolimus in participants with previously treated clear cell renal cell carcinoma. Presented at: ESMO Congress 2024; September 13-17, 2024; Barcelona, Spain. Abstract LBA74.

FDA approves belzutifan for advanced renal cell carcinoma. FDA. December 14, 2023. Accessed September 13, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-belzutifan-advanced-renal-cell-carcinoma

Welireg. Prescribing information. Merck Sharp & Dohme LCC; 2023. Accessed September 13, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/215383s006lbl.pdf

Belzutifan improved PFS and ORR but failed to deliver a significant improvement in OS vs everolimus in pretreated advanced clear cell renal cell carcinoma. 

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