The combination of nivolumab (Opdivo) and axitinib (Inlyta) achieved meaningful responses in treatment-naïve advanced renal cell carcinoma (RCC), according to results from a phase 1/2 trial (NCT03172754) presented at the 2022 Genitourinary Cancers Symposium.

Among patients with untreated advanced RCC in a phase 2 cohort (n = 44), nivolumab plus axitinib elicited an overall response rate (ORR) of 59.5% (95% CI, 43.3%-74.4%). One patient (2.4%) achieved a complete response and 24 (57.1%) had partial response. Additionally, investigators observed stable disease in 38.1% of patients and progressive disease in 1 patient (2.4%). The disease control rate was 97.6% (95% CI, 87.4%-99.9%).

“The landscape of metastatic RCC has changed dramatically over the past 5 years, with combination therapy, with immunotherapy/TKI combinations, or combined immune checkpoint inhibitors being the standard of care for most patients,” lead study author Matthew R. Zibelman, MD, associate professor, Department of Hematology/Oncology, Fox Chase Cancer Center, said during his presentation.

The phase 1 dose-escalation portion of the trial examined nivolumab and axitinib in patients who had received at least 1 prior line of therapy with a TKI. Patients received 3 mg to 5 mg doses of axitinib twice daily, plus 480 mg of intravenous (IV) nivolumab every 4 weeks. This established 5 mg of axitinib as the recommended phase 2 dose.

Phase 2 investigated the combination in 2 parallel cohorts, with 1 featuring treatment-naïve patients with advanced RCC, and the other enrolling patients with advanced RCC who received at least 1 prior therapy.

Eligible patients in the treatment-naïve arm of the phase 2 study were required to be at least 18 years old with histologically or cytologically confirmed metastatic RCC featuring any clear cell component and at least one measurable lesion as defined by RECIST v1.1.

 Patients needed an ECOG performance status of 0 or 1, and those with autoimmune disease were excluded.

The primary end point of the study was ORR. Secondary end points included progression-free survival (PFS), overall survival (OS), and safety.

The median age of patients in the treatment-naïve cohort was 65 years (interquartile range, 56-72). Most patients were male (84.1%), white (95.5%), and non-Hispanic (93.2%). Patients had an ECOG performance status of 0 (75%), 1 (22.7%), or undetermined (2.3%). Patients were classified with an IMDC risk category score of favorable (0; 40.9%), intermediate (1-2; 52.3%), or poor (3-6; 6.8%).

At a median follow-up of 11.5 months, the median PFS in the treatment-naïve cohort was 16.4 months (95% CI, 10.2-22.2). The estimated 12-month PFS rate was 60.8% (95% CI, 43.2%-74.5%), and the estimated 24-month PFS rate was 25.3% (95% CI, 10.2%-43.7%).

The estimated 12-month OS rate was 87.1% (95% CI, 68.7%-95.1%). The estimated 24-month OS rate was 69.4% (95% CI, 43.5%-85.2%).

Grade 3 adverse effects (AEs) included hypertension (41.5%), diarrhea (9.8%), increased ALT (7.3%), colitis (7.3%), proteinuria (7.3%), hyponatremia (4.9%), arthralgia (4.9%), dyspnea (4.9%), hypotension (4.9%), atrial fibrillation (2.4%), heart failure (2.4%), increased creatinine (2.4%), rectal fistula (2.4%), avascular necrosis (2.4%), and myalgia (2.4%). 

The average daily dose of axitinib was 8.21 mg. Notably, 54.5% of patients had axitinib dose reductions to less than 10 mg per day, and 20.5% discontinued treatment due to AEs associated with axitinib. Additionally, 18.2% of patients discontinued treatment due to nivolumab-related AEs.

Additional follow-up will assess long-term outcomes of nivolumab and axitinib in the treatment-naïve cohort, plus the efficacy of the combination in the previously treated cohort.

“Axitinib remains a well-tolerated VEGF TKI that, with its easy titratability and short half-life, pairs well with anti–PD-1 targeted therapies and can achieve outcomes similar to other combinations [in advanced RCC],” Zibelman concluded.

Zibelman MR, Carducci MA, Ged Y, et al. A phase I/II study of nivolumab and axitinib in patients with advanced renal cell carcinoma. 

. 2022;40(suppl 6):291. doi:10.1200/JCO.2022.40.6_suppl.291

Study of nivolumab and axitinib in patients with advanced renal cell carcinoma. ClinicalTrials.gov. Updated November 17, 2021. Accessed April 14, 2022. https://clinicaltrials.gov/ct2/show/NCT03172754

Articles

The combination of nivolumab and axitinib achieved meaningful responses in treatment-naïve advanced renal cell carcinoma, according to results from a phase 1/2 trial (NCT03172754) presented at the 2022 Genitourinary Cancers Symposium.

Nivolumab Plus Axitinib Generates Promising Responses in Untreated Advanced RCC

A novel combination comprised of the investigational bispecific antibody CTX-009 and paclitaxel was found to produce responses in 4 subtypes of biliary tract cancer with favorable safety and tolerability, according to interim results from an ongoing phase 2 trial (NCT04492033).

The regimen elicited an overall response rate (ORR) of 42% among 10 patients; these patients achieved partial responses (PRs) with the combination. To date, 9 of the PRs were confirmed by RECIST v1.1 criteria and the tenth PR is pending confirmation.

Moreover, 22 of the 24 patients enrolled to the trial achieved stable disease or better, which translated to a clinical benefit rate (CBR) of 92%. Notably, 7 patients continued to receive the regimen at the cutoff date; 5 of these patients had been on treatment for longer than 9 months.

“We are excited by these impressive interim phase 2 results and believe CTX-009 is a promising investigational drug,” Thomas Shuetz, MD, PhD, chief executive officer and scientific founder of Compass Therapeutics, Inc., stated in a press release. “In the initial data review of this trial, reported in November 2021, CTX-009 exhibited a 29% ORR and a 100% CBR. We are very encouraged by the performance of CTX-009 across a larger patient population, particularly the maturing of the dataset, with the ORR moving from 29% in 17 evaluable patients to 42% in all 24 patients enrolled.”

The prospective, multicenter, open-label, Simon Two-Stage adaptive design trial was launched to examine the use of CTX-009 plus paclitaxel for the treatment of patients with advanced, unresectable, metastatic or recurrent biliary tract cancer who had an ECOG performance status of 0 or 1.

At a data cutoff date of April 14, 2022, a total of 24 patients were enrolled to the trial and received treatment with at least 1 cycle of CTX-009 and paclitaxel.

The primary end point of the trial was ORR, based on the proportion of patients whose best overall responses was evaluated to be complete response or PR per independent radiology review. Secondary end points included assessments of multiple standard measures of disease progression.

The median age of patients was 61.5 years; 54.2% of patients had an ECOG performance status of 0, and 45.8% had a status of 1. Moreover, 37.5% of patients had intrahepatic cholangiocarcinoma, 12.5% had extrahepatic cholangiocarcinoma, 29.2% had gallbladder cancer, and 20.8% had ampullary cancer. Moreover, 45.8% of patients previously received 1 therapy and 54.2% received at least 2 prior therapies. The majority (95.8%) of patients previously received gemcitabine plus cisplatin.

The first phase of the trial was conducted in Korea and included 24 patients who received CTX-009 at 10 mg/kg biweekly plus paclitaxel at 80 mg/m

 weekly, every 3 out of 4 weeks. In November 2021, data pertaining to the first 17 evaluable patients showed 5 PRs with the regimen. Based on those findings, the trial was able to proceed to the second phase.

Updated data show that the regimen continued to be well tolerated. The most common toxicity associated with CTX-009 and paclitaxel, respectively, were hypertension and neutropenia.

Of the 24 patients enrolled to the trial, all experienced at least 1 toxicity related to CTX-009 and/or paclitaxel. The most common all-grade toxicities included anemia (12.5%), asthenia (25.0%), fatigue (16.7%), edema (16.7%), pyrexia (16.7%), neutropenia (54.2%), thrombocytopenia (20.8%), headache (16.7%), proteinuria (20.8%), dysphonia (12.5%), dyspnea (25%), epistaxis (33.3%), pulmonary hypertension (16.7%), and hypertension (50%).

Treatment-emergent toxicities that were grade 3 or higher and that were experienced in more than 1 patient included neutropenia (50%), hypertension (16.7%), anemia (12.5%), and thrombocytopenia (8.3%). All of these toxicities were noted to be manageable through the use of standard therapy.

Compass Therapeutics reports positive interim phase 2 data of CTX-009 in combination with paclitaxel in biliary tract cancers. News release. Compass Therapeutics, Inc. May 4, 2022. Accessed May 4, 2022. 

A novel combination comprised of the investigational bispecific antibody CTX-009 and paclitaxel was found to produce responses in 4 subtypes of biliary tract cancer with favorable safety and tolerability, according to interim results from an ongoing phase 2 trial.



CTX-009/Paclitaxel Combo Demonstrates Antitumor Activity, Favorable Tolerability in Biliary Tract Cancer

The investigational RNA interference (RNAi) therapy, ARO-HIF2, reduced levels of hypoxia inducible factor-2 alpha (HIF2α) expression and had acceptable tolerability when used in patients with clear cell renal cell carcinoma (RCC), according to data from the phase 1b AROHIF21001 trial (NCT04169711).

Findings from the trial, which were presented during the 

2022 ASCO Genitourinary Cancers Symposium

, showed that of 26 evaluable patients, 9 experienced a median reduction in HIF2α mRNA of 30% (range, -19% to -59%) by qPCR.

In the subset of patients who received ARO-HIF2 at 225 mg (n = 7) the median reduction in HIF2α mRNA was 46% (range, -22 to -47). In those who were administered 525 mg of ARO-HIF2 (n = 10), the median reduction in HIF2α mRNA was 27% (range, -19 to -39). In the subset of patients who were given 1050 mg of the agent (n = 9), the median reduction in HIF2α mRNA was 44% (range, -28 to -49).

Additionally, 14 patients achieved a median reduction in HIF2α protein of 26% (range, -1700 to -98) by immunohistochemistry (IHC). The HIF2α protein reduction rates in the 225-mg, 525-mg, and 1050-mg cohorts were 26% (range, -26 to -82), 47% (range, 0 to -90), and 0% (range, 1700 to -98), respectively.

“This ongoing phase 1 study provides initial proof of target engagement based on reductions in HIF2α expression, as well as an acceptable safety profile in response to escalating doses of ARO-HIF2,” lead study author James Brugarolas, MD, PhD, of UT Southwestern Medical Center, and colleagues, wrote in a poster on the findings.

HIF2α is usually expressed at low levels and targeted for degradation by the von Hippel-Lindau (VHL) tumor suppressor protein. However, VHL inactivation, which is a causative event of clear cell RCC, prompts tumorigenesis through uncontrolled HIF2α accumulation. The synthetic double-stranded RNAi trigger, ARO-HIF2, which includes an alpha-v beta3 targeting ligand, was developed to silence HIF2α expression.

The AROHIF21001 trial enrolled patients with advanced or metastatic clear cell RCC that progressed during or after at least 2 prior regimens which must have included a VEGF-targeted therapy and a checkpoint inhibitor therapy.

 To be eligible for participants, patients needed to be at least 18 years of age, have an ECOG performance status of 0 or 1, a life expectancy that was longer than 3 months, and organ function that was considered to be acceptable at the time of the screening.

Exclusion criteria included a history of untreated brain metastases, having received prior systematic therapy or radiation therapy within 2 weeks of the first dose of study treatment, or having previously undergone solid organ or stem cell transplantation. Moreover, patients could not be receiving current treatment with immune checkpoint inhibitors, nor could they have received prior HIF2 inhibitors within 6 months before their first dose of study treatment.

Intravenous ARO-HIF2 was administered weekly at 225 mg in cohort 1 (n = 7), 525 mg in cohort 2 (n = 10), and 1050 mg in cohort 3 (n = 9). Moreover, tumor growth was evaluated by biopsy at baseline and again at 2 weeks. Additionally, patients were evaluated for safety each week. Every 8 weeks, participants were examined for tumor response by RECIST criteria.

The primary end point of the study was to evaluate treatment-emergent adverse effects (TEAEs) associated with ARO-HIF2. Secondary end points included pharmacokinetics and preliminary efficacy per RECIST v1.1 criteria.

Exploratory end points included the assessment of post-dose tumoral expression of HIF genes in response to treatment with the agent, change in tumor integrin expression, correlation of integrin expression with changes in HIF gene expression, and the examination of serum biomarkers of agent activity. The correlation of disease-related gene expression to the activity of the agent is also under exploration. Plasma and urine metabolites will also be assessed.

Spanning cohorts, the mean age was 65.1 years (range, 44-87). Seventy-seven percent of patients were male. Regarding performance status, 42.3% of patients had an ECOG performance status of 0, and 57.7% had a status of 1. Most patients (53.8%) had intermediate-risk disease per International Metastatic RCC Database Consortium criteria; 23.1% had good-risk disease and 15.4% had poor-risk disease.

Additionally, 30.8% of patients received 2 prior lines of therapy, 30.8% received 3 prior lines, and 11.5% received 4 prior lines of therapy. Notably, 26,9% of patients received 5 or more prior lines of treatment. Prior treatment included anti-VEGF therapy (100%) and checkpoint inhibition (100%). Regarding 

 mutation status, 17.6% of patients had frame shift mutations, 29.4% had missense mutations, 5.9% had in frame deletion, 11.8% had no variant, and 35.3% did not have this information available.

Prior data from the trial showcased early signals of activity with ARO-HIF2

 Specifically, 7 of 9 patients who had evaluable tumor samples and received treatment experienced reductions in HIF2α per IHC H-score. Notably, these reductions ranged from -9% to -82%, with a mean reduction of -48%.

Additional data presented during the 2022 Genitourinary Cancers Symposium showed that ARO-HIF2 elicited an objective response rate of 7.7% in all patients, with 2 patients experiencing a partial response. Furthermore, 30.8% of patients achieved stable disease and 50.0% experienced disease progression. One patient was not evaluable for response, and response data were missing for 2 patients. Overall, the disease control rate with the agent was 38.5%.

At least 1 TEAE of any grade occurred in 96.2% of patients. Specifically, 57.7% of patients experienced at least 1 grade 1 or 2 TEAE, 30.8% reported at grade 3 TEAE, 3.8% experienced a grade 4 TEAE, and 3.8% experienced a grade 5 TEAE. Serious TEAEs were reported in 34.6% of patients. Moreover, treatment-related AEs of any grade occurred in 65.4% of patients. One patient discontinued treatment due to TEAEs.

TEAEs of any grade that occurred in more than 4 patients included fatigue (50.0%), dizziness (26.9%), dyspnea (26.9%), nausea (23.1%), abdominal pain (23.1%), neuropathy (19.2%), and constipation (19.2%).

Enrollment for the phase 1 trial remains open and enrollment is ongoing.

Brugarolas J, Beckermann KE, Rini BI, et al. Initial results from the phase 1 study of ARO-HIF2 to silence HIF2-alpha in patients with advanced ccRCC (AROHIF21001). 

 2022;40(suppl 6):339. doi:10.1200/JCO.2022.40.6_suppl.339

Study of ARO-HIF2 in patients with advanced clear cell renal cell carcinoma. ClinicalTrials.gov. Updated April 19, 2021. Accessed May 3, 2022. 

https://clinicaltrials.gov/ct2/show/NCT04169711

Arrowhead announces positive interim results from phase 1b study of ARO-HIF2 for treatment of clear cell renal cell carcinoma. News release. Arrowhead Pharmaceuticals, Inc. July 6, 2021. Accessed May 3, 2022. 

The investigational RNA interference therapy, ARO-HIF2, reduced levels of hypoxia inducible factor-2 alpha expression and had acceptable tolerability when used in patients with clear cell renal cell carcinoma, according to data from the phase 1b AROHIF21001 trial. 

Pipeline Report: May 2022

Articles

Nivolumab Plus Axitinib Generates Promising Responses in Untreated Advanced RCC

CTX-009/Paclitaxel Combo Demonstrates Antitumor Activity, Favorable Tolerability in Biliary Tract Cancer