Jason Harris

The addition of the oral hypoxia-inducible factor 2α (HIF-2α) inhibitor belzutifan (MK-6482) to cabozantinib (Cabometyx) led to disease control in a majority of patients with previously treated advanced clear cell renal cell carcinoma (ccRCC), according to preliminary results from a phase 2 trial (NCT03634540) presented at the 2021 Genitourinary Cancers Symposium.

Lead author Toni K. Choueiri, MD, presented early findings from a cohort of 52 patients treated in the ongoing study. He cautioned that the results looked favorable but were very preliminary.

“These preliminary, interim results for the combination of belzutifan and cabozantinib showed promising activity in previously treated metastatic clear cell RCC,” said Choueiri, director of the Lank Center for Genitourinary (GU) Oncology at Dana-Farber Cancer Institute (DFCI)/Brigham and Women’s Hospital and the Jerome and Nancy Kohlberg Chair and Professor of Medicine at Harvard Medical School. “We believe that targeting the underlying pathology of clear cell RCC, targeting the transcription factor HIF-2α with belzutifan and targeting downstream with the VEGF receptor inhibitor, among other kinases, cabozantinib could be an effective treatment for patients with metastatic clear cell RCC.”

Investigators analyzed 41 patients for efficacy. The confirmed objective response rate (ORR) was 22% (9/41); all responses were partial responses. Investigators also observed another 5 (12%) unconfirmed partial responses. Twenty-eight (68%) patients had stable disease as best responses. The median duration of response was not reached, and all confirmed responses were still ongoing as of data cutoff of October 15, 2020. The median time from enrollment to data cutoff was 8.9 months.

Investigators are still enrolling a cohort of untreated patients into the study.

Eligible patients were assigned to 120 mg belzutifan plus 60 mg cabozantinib orally once daily for 21 days. This efficacy analysis includes patients who received at least 1 dose of treatment and had an opportunity for at least 6 months of follow-up.

The progression-free survival (PFS) rate was 78% at 6 months and 65% at 12 months. Choueiri noted that 95% of patients were alive at 6 months.

“The median should not be considered real given only 1 patient was at risk at month 17, [but] the median PFS here was 16.8 months,” he said.

David A. Braun, MD, PhD, a physician and investigator with Dana-Farber, urged caution. He delivered a discussant on Choueiri’s presentation. “The median follow up was only about 11 months and the minimum follow up only 5.6 months. This is interesting and potentially exciting, but we really need to have further follow-up.

“When we look at the PFS curve, which looks impressive, it’s a median of 16.8 months. But, again, there are very few patients that are out that far. It’s definitely preliminary.”

Nearly all (98%) of patients experienced any-grade treatment-related adverse events (TRAEs). Grade 3 TRAEs were fairly common (60%), but there was no incidence of grade 4/5 TRAEs.

Six (12%) patients discontinued belzutifan due to treatment-emergent AEs and 8 (15%) discontinued cabozantinib. Seven (13%) patients experienced serious TRAEs.

In July 2020, the FDA granted breakthrough therapy designation to belzutifan for the treatment of patients with von Hippel-Lindau (VHL) disease-associated RCC with nonmetastatic RCC tumors smaller than 3 cm in size unless immediate surgery is required. The agency also granted orphan drug designation to belzutifan for VHL disease.

 Both designations were based on data from a phase 2 trial evaluating patients with VHL-associated clear cell RCC that was presented at the 2020 American Society of Clinical Oncology Annual Meeting.

Results showed that the agent induced a confirmed ORR of 27.9% (95% CI, 17.1-40.8); all responses were partial response. Notably, most of the patients on the trial (86.9%) experienced a reduction in the size of their target lesions.

Previous data from a phase 1/2 trial (NCT02974738) showed encouraging single-agent activity with belzutifan in patients with heavily pretreated clear cell RCC, a benefit that was observed across all International Metastatic RCC Database risk groups analyzed.

In 55 patients enrolled to the dose escalation/expansion cohort of the trial, the ORR was 24% with the agent, while the disease control rate was 80%. The ORR was comprised of 13 confirmed PRs. Moreover, the median progression-free survival (PFS) reported with belzutifan in the overall patient population studied was 11.0 months. At 1 year, 49% of patients remained progression free.

Choueiri TK, Bauer TM, McDermott DF, et al. Phase 2 study of the oral hypoxia-inducible factor 2α (HIF-2α) inhibitor MK-6482 in combination with cabozantinib in patients with advanced clear cell renal cell carcinoma (ccRCC). 

. 2021;39(suppl 6; abstr 272). doi: 10.1200/JCO.2021.39.6_suppl.272

FDA grants breakthrough therapy designation to Merck’s novel HIF-2α inhibitor MK-6482 for treatment of certain patients with Von Hippel-Lindau disease-associated renal cell carcinoma. News release. Merck. July 29, 2020. Accessed February 13, 2021. bit.ly/3qkNRGK

Jonasch E, Donskov F, Iliopoulos O, et al. Phase II study of the oral HIF-2α MK-6482 for Von Hippel-Lindau disease–associated renal cell carcinoma. 

. 2020;38(suppl 15):5003. doi:10.1200/JCO.2020.38.15_suppl.5003

Choueiri TK, Plimack ER, Bauer TM, et al. Phase I/II study of the oral HIF-2 α inhibitor MK-6482 in patients with advanced clear cell renal cell carcinoma (RCC). 

2020;38(suppl 6):611. doi:10.1200/JCO.2020.38.6_suppl.611

Articles

The addition of the oral hypoxia-inducible factor 2α inhibitor belzutifan to cabozantinib led to disease control in a majority of patients with previously treated advanced clear cell renal cell carcinoma, according to preliminary results from a phase 2 trial presented at the 2021 Genitourinary Cancers Symposium.

High Disease Control Rate Achieved With Belzutifan and Cabozantinib in ccRCC

Results from the phase 3 CheckMate-274 trial showed that nivolumab (Opdivo) following surgery improved disease-free survival (DFS) compared with placebo for patients with muscle-invasive urothelial carcinoma (MIUC), according a presentation given during the 2021 ASCO Genitourinary Cancer Symposium.

Investigators found that adjuvant nivolumab conferred a median DFS benefit in both the intent-to-treat (ITT) and PD-L1­–positive populations. In the ITT population, DFS in those treated with nivolumab was 21.0 months compared with 10.9 months with placebo (HR, 0.70; 98.31% CI, 0.54-0.89; 

“This corresponds to a 30% reduction in the risk of disease recurrence or death with nivolumab,” said lead author Dean Bajorin, MD, the Frederick R. Adler Senior Faculty Chair at Memorial Sloan Kettering Cancer Center in New York, New York. “The median DFS is nearly double with nivolumab compared to placebo.”

In the PD-L1 positive population, the median DFS in those treated with nivolumab was not reached compared with 10.8 months in the placebo group (HR, 0.53; 98.87% CI, 0.34-0.84; 

 < .001). “This corresponds to a 47% reduction in the risk of disease recurrence or death with nivolumab,” Bajorin said.

A subgroup analysis of the ITT population found there were no differences age, sex, region or performance status, he added.

The monoclonal antibody also improved median non–urothelial tract recurrence-free survival (NUTRFS), a secondary endpoint, and the exploratory endpoint of distant metastasis free survival (DMFS) in both the ITT and the PD-L1 positive patient populations.

In the ITT population, those treated with nivolumab experienced NUTRFS of 24.6 months versus 13.7 months in the placebo group (HR, 0.72; 95% CI, 0.58-0.89). In the PD-L1–positive population, NUTRFS in those treated with nivolumab was not reached versus 10.9 months in the placebo group (HR, 0.54; 95% CI, 0.38-0.77).

“Nivolumab is the first systemic immunotherapy to demonstrate a statistically significant and clinically meaningful improvement in outcomes when administered as adjuvant therapy to patients with muscle-invasive urothelial carcinoma,” he said. “These results support nivolumab monotherapy as a new standard of care in the adjuvant setting for patients with high-risk MIUC after radical surgery regardless of PD-L1 status and prior neoadjuvant chemotherapy.”

The randomized, double- blind CheckMate-274 (NCT02632409) evaluated the efficacy and safety of adjuvant nivolumab versus placebo in patients with high-risk MIUC after radical surgery. Patients (N = 709) were randomized 1:1 to receive nivolumab 240 mg administered once every 2 weeks or placebo for up to 1 year of adjuvant treatment. Eligible patients had radical surgery within 120 days with or without neoadjuvant cisplatin or were ineligible/declined cisplatin-based chemotherapy, and were disease-free as evidenced by imaging.

The primary endpoint of the study was DFS in the ITT population and in patients with tumor PD-L1 expression ≥ 1%. The median follow-up was 20.9 months for nivolumab and 19.5 months for placebo.

In total, 353 patients were randomized to nivolumab and 356 patients to placebo. In the nivolumab arm, 53.3% of patients discontinued treatment, and in the placebo arm, 56.3% of patients discontinued. This was mostly commonly due to disease recurrence.

Among patients in the nivolumab arm, the tumor of origin was urinary bladder carcinoma in 79% of patients and upper tract disease in 21% of patients. In the placebo arm, the tumor of origin was urinary bladder in 78.9% of patients and upper tract disease in 21.1% of patients. About 40% patients in both arms were PD-L1 positive and about 43% had received prior cisplatin based neoadjuvant chemotherapy.

The safety of nivolumab was consistent with previously reported studies in patients with solid tumors. Grade 3 or higher treatment-related adverse events (TRAEs) occurred in 17.9% of patients in the nivolumab arm and 7.2% of patients in the placebo arm. Any-grade TRAEs leading to discontinuation occurred in 12.8% in the nivolumab arm and 2% of patients in the placebo arm. The most common TRAEs in the nivolumab arm were pruritis, fatigue, diarrhea, and rash.

Nivolumab is approved as a monotherapy for the treatment of platinum-resistant urothelial carcinoma.

Bajorin DF, Witjes JA, Gschwend J, Schenker M. First results from the phase 3 CheckMate 274 trial of adjuvant nivolumab vs placebo in patients who underwent radical surgery for high-risk muscle-invasive urothelial carcinoma (MIUC). Presented at: 2021 ASCO Genitourinary Cancer Symposium; February 11-13, 2021. Virtual. Abstract 391.

Results from the phase 3 CheckMate-274 trial showed that nivolumab following surgery improved disease-free survival compared with placebo for patients with muscle-invasive urothelial carcinoma, according a presentation given during the 2021 ASCO Genitourinary Cancer Symposium.

Adjuvant Nivolumab Extends Disease-Free Survival in Muscle-Invasive Urothelial Carcinoma

Following neoadjuvant chemotherapy with or without pembrolizumab (Keytruda) in patients with high-risk early-stage breast cancer, the presence of circulating tumor DNA (ctDNA) was a biomarker for response and distant recurrence-free survival (DRFS), according to findings from a biomarker analysis of the I-SPY 2 trial presented during the 2020 San Antonio Breast Cancer Symposium.

Investigators led by Mark Jesus M. Magbanua, PhD, a postdoctoral researcher at the University of California San Francisco, determined that early clearance of ctDNA during neoadjuvant chemotherapy treatment was significantly associated with increased likelihood of achieving pathological complete response (pCR). Furthermore, ctDNA clearance appeared to be an early surrogate marker for therapy response assessment, and residual ctDNA after neoadjuvant treatment was a significant predictor for metastatic recurrence and death.

“What this study shows is that personalized monitoring of ctDNA during neoadjuvant chemotherapy is feasible and provides information that can be combined with imaging and pathology and may help to optimize decision-making for de-escalation or escalation of therapy,” Christos Sotiriou, MD, PhD, head of the Institut Bordet J. C. Heuson Breast Cancer Translational Research Laboratory, Université Libre de Bruxelles, in Belgium.

In results from I-SPY 2 (NCT01042379) published in May, investigators concluded that adding pembrolizumab to neoadjuvant chemotherapy more than doubled the estimated pCR rates for both hormone receptor–positive/HER2 (

)-negative and triple-negative breast cancer.2Magbanua and colleagues hypothesized that ctDNA may be a predictive biomarker for response and survival.

Investigators used a personalized Signatera assay to detect patient-specific variants from whole exome sequencing of pretreatment tumor specimens that provides a ctDNA test customized for the patient’s clonal mutational signature.1,3 Overall, 511 serial plasma samples collected from 138 patients with high-risk hormone receptor–positive/HER2-negative (n = 77) or triple-negative (n = 61) stage II/III breast cancer. Patients received pembrolizumab plus paclitaxel followed by chemotherapy with anthracyclines (n = 42) or standard neoadjuvant chemotherapy only (n = 96).

Plasma was collected at pretreatment (T0), 3 weeks after treatment initiation (T1), prior to administration of anthracyclines (T2), and prior to surgery (T3). ctDNA positivity was defined as detection of a minimum of 2 patient-specific tumor mutation fragments in cell-free DNA.

ctDNA results were available at T0 and T1 for 96% (132/138) of patients. Results were available for 86% (118/136) at T0, T1, and T2.

Compared with patients who were ctDNA-negative at T1, those who were ctDNA-positive were at significantly increased risk for metastatic recurrence and death (HR, 4.35; 95% CI, 1.27-14.69; 

 = .0097). All patients who achieved pCR were ctDNA-negative at T3 (n = 34). Among the 81 patients who did not reach pCR, DRFS was significantly better among the 72 who were ctDNA-negative compared with those who were ctDNA-positive (HR, 0.13; 95% CI, 0.05-0.37).

Patients who were ctDNA-positive at baseline and their cleared ctDNA levels by T1 had the highest pCR rates at 54%. pCR was 38% for patients were negative for ctDNA at T0 and T1; those who did not clear ctDNA by T1 had the lowest pCR rate of 14%).

Among patients who were ctDNA-positive at baseline, pCR was significantly associated with clearance at T1 (OR = 1.92). Investigators found that the association held after adjusting for hormone receptor status and treatment (likelihood ratio [LR], 

 <.001) and treatment arm (pembrolizumab: LR, 

In patients who were ctDNA-negative at T0 to T2, the pCR rate was 41%. pCR rates were highest at 50% in those with early clearance, followed by those with late clearance (19%) and those without clearance (7%).

The correlation between ctDNA and clinical outcomes also was demonstrated in data that I-SPY 2 investigators published in November from an analysis of 291 plasma samples collected from 84 patients with high-risk early breast cancer treated with standard neoadjuvant chemotherapy alone or combined with the AKT inhibitor MK-2206.

Investigators collected blood samples pretreatment (T0), 3 weeks after initiation of paclitaxel (T1), between paclitaxel and anthracycline regimens (T2), and prior to surgery (T3). A personalized ctDNA test was designed to detect up to 16 patient-specific mutations (from whole exome sequencing of pretreatment tumor) in cell-free DNA by ultra-deep sequencing.

Sixty-one (73%) patients were ctDNA-positive at baseline. ctDNA decreased at each successive collection point (T1, 35%; T2, 14%; T3, 9%). Patients who remained ctDNA-positive at T1 were significantly more likely to have residual disease after treatment compared with those who cleared ctDNA (OR, 4.33; 

 = .012). All patients who achieved pCR (n = 17) were ctDNA-negative and reached a favorable DRFS.

Of the 43 patients who did not achieve pCR, 86% were ctDNA-negative at T3. DRFS was 93%, nearly identical to those who achieved pCR (HR, 1.4; 95% CI, 0.15-13.5).However, those who did not achieve pCR, ctDNA positivity was associated with a significantly worse DRFS (HR, 10.4; 95% CI, 2.3–46). Sixty-seven percent of those who were ctDNA positive at T3 experienced metastatic recurrence.

“This study shows that personalized ctDNA monitoring is a powerful new tool that can help evaluate novel therapies faster, in conjunction with other biomarkers like pCR and MRI imaging response,” said coauthors Laura J. Esserman, MD, MBA, and Laura J. van ‘t Veer, PhD. Both are professors at the University of California San Francisco and Giants of Cancer Care® award winners. “This technology may also help guide clinical decisions in the neoadjuvant setting, including the type and timing of surgery and whether to switch treatment modalities,” they said.

Magbanua MJM, Wolf D, Renner D, et al. Personalized circulating tumor DNA (ctDNA) as predictive biomarker in high-risk early stage breast cancer (EBC) treated with neoadjuvant chemotherapy (NAC) with or without pembrolizumab (P). Presented at: 2020 San Antonio Breast Cancer Symposium; December 8-11, 2020. Abstract PD9-02.

Nanda R, Liu MC, Yau C, et al. Effect of pembrolizumab plus neoadjuvant chemotherapy on pathologic complete response in women with early-stage breast cancer: an analysis of the ongoing phase 2 adaptively randomized I-SPY2 trial. 

. 2020;6(5):676-684. doi:10.1001/jamaoncol.2019.6650

New publication from I-SPY 2 trial highlights Signatera's ability to predict treatment outcomes in neoadjuvant breast cancer patients. News release. Natera, Inc; November 30, 2020. Accessed December 11, 2020. https://prn.to/3lZoUOk

Magbanua MJM, Swigart LB, Wu HT, et al. Circulating tumor DNA in neoadjuvant-treated breast cancer reflects response and survival [published online November 20, 2020]. 

Following neoadjuvant chemotherapy with or without pembrolizumab in patients with high-risk early-stage breast cancer, the presence of ctDNA was a biomarker for response and distant recurrence-free survival.

ctDNA Biomarker for Responses, Outcomes Observed for High-Risk Patients With Early Breast Cancer

Treatment with IGM-2323, a bispecific IgM antibody, resulted in tumor shrinkage in 9 of 14 patients with CD20-positive relapsed/refractory (R/R) non-Hodgkin lymphoma (NHL) in a phase 1 study, according to the preliminary findings presented during the 2020 American Society of Hematology (ASH) Annual Meeting.

Elizabeth Budde, MD, PhD, an assistant professor in the Department of Hematology and Hematopoietic Cell Transplantation at City of Hope National Medical Center in Duarte, California, called these results “particularly encouraging.”

“IGM-2323 is generally well tolerated, with no DLTs [dose-limiting toxicities] and no neurotoxicities despite minimal premedication,” she said. “IGM-2323 showed evidence of early clinical activity, with responses observed in a [patient following treatment with] CAR [chimeric antigen receptor] T-cell [therapy] despite low doses tested to date.”

IGM-2323 targets CD20 and CD3 and is engineered with 10 high affinity and high-specificity binding site to CD20 and a single high-specificity binding site to CD3. Investigators initiated the multicenter, open-label phase 1 dose escalation trial (NCT04082936) to assess the safety, pharmacokinetics, and preliminary efficacy of intravenous IGM-2323 in patients with R/R B cell NHLs. Sixteen patients were enrolled and treated at escalating dose levels of IGM-2323 as of the October 30, 2020 data cutoff. Dose escalation continues toward the anticipated recommended phase 2 dose range of 100 mg to 1000 mg.

Ten patients in the study had follicular lymphoma (FL) or marginal zone NHL. Six others had diffuse large B-cell lymphoma (DLBCL) or mantle cell lymphoma. Patients in both groups had received a median of 4 prior therapies (range, 2-6). Patients were required to receive premedication with 10 mg dexamethasone prior to receiving the study drug. Patients were allowed subsequent premedication at investigator’s discretion.

Patients were assigned to 1 of 5 dose levels of IGM-2323: 100 mg (n =1), 30 mg (n = 3), 10 mg (n = 3), 2.5 mg (n = 1), or 0.5 mg (n = 1). All patients were treated weekly for one 21-day cycle.

Investigators initiated dose expansion cohorts in parallel with continued dose escalation to better assess safety and efficacy. One patient was assigned to 50/100 mg titration dose and 3 were assigned to 30 mg.

Of the 14 patients treated in the 0.5-, 2.5-, 10-, 30-, and 50/100-mg dose cohorts, 9 (64.2%) data showed evidence of tumor size reduction. Two patients had partial responses, including 1 patient with FL treated at the 50/100 mg dose level and 1 patient with DLBCL at the 30 mg level who previously failed CAR T-cell therapy. Subsequent to the data cutoff, 2 patients with FL treated in the 50/100 mg titration dose cohort converted to complete responses.

“In contrast to observations with other T-cell engagers, IGM-2323 treatment resulted in a repeatable interferon gamma-dominant immune activation,” Budde said. Following treatment with IGM-2323, the vast majority of patients had levels of interferon-6 gamma, TNFa, and other cytokines above baseline, she added.

“[In patients treated at] 30 mg and above, interferon gamma spikes were repeatedly observed, demonstrating preservation or strengthening of T-cell function.”

Investigators observed no grade 3 treatment-emergent adverse events (TRAEs). The most common grade 2 TRAEs were hypophosphatemia (25%) and infusion-related reactions (19%). Budde added that no grade 3 cytokine release syndrome (CRS) was observed at the 50/100 mg level and said that TRAEs in the study “were generally transient and low grade.”

“Bispecific antibodies that bridge lymphoma cells to T cells have shown promise in treating B-cell malignancies, but existing T-cell engaging antibodies are often associated with toxicity, especially CRS, and have a limited therapeutic window potentially related to downregulation of T-cell function,” Budde said in a news release.

 “IGM-2323 may provide more physiologic T cell activation, with evidence for preservation of T cell activation in the majority of patients in this study, as compared with the global reduction in T cell function associated with existing bispecific T cell engaging antibodies.”

In addition to the 50/100 mg titration dose, investigators are enrolling patients to a 50/300 mg titration dose cohort.

Budde E, Gopal AK, Flinn IW, et al. Preliminary results of a phase 1 dose escalation study of the first-in-class IgM based bispecific antibody Igm-2323 (anti-CD20 x anti-CD3) in patients with advanced b-cell malignancies. 

. 2020;136(suppl 1):45-46. doi:10.1182/blood-2020-134983

IGM Biosciences presents first clinical data from IGM-2323 in non-Hodgkin’s lymphoma at 2020 ASH Annual Meeting. News release. IGM Biosciennces. December 5, 2020. Accessed December 6, 2020. https://bit.ly/33Ne3kn

Treatment with IGM-2323, a bispecific IgM antibody, resulted in tumor shrinkage in 9 of 14 patients with CD20-positive relapsed/refractory non-Hodgkin lymphoma in a phase 1 study.

Jason Harris | Authors

Articles

High Disease Control Rate Achieved With Belzutifan and Cabozantinib in ccRCC

Adjuvant Nivolumab Extends Disease-Free Survival in Muscle-Invasive Urothelial Carcinoma

ctDNA Biomarker for Responses, Outcomes Observed for High-Risk Patients With Early Breast Cancer

IGM-2323 Induces Tumor Shrinkage in R/R Non-Hodgkin Lymphoma