Audrey Sternberg

Findings from the prospective phase 2 ODEZA trial showed that darolutamide (Nubeqa) was associated with a cognitive function benefit versus enzalutamide (Xtandi) in patients with metastatic castration-resistant prostate cancer (mCRPC).1

The findings, which were shared during the 2021 ESMO Congress, specifically showed that episodic memory by computerized cognitive assessment was significantly improved in patients who received darolutamide compared with those treated with enzalutamide. Darolutamide was associated with better verbal learning and verbal memory compared with enzalutamide, with nonsignificant trends towards executive function also noted.

“The favorable effect of darolutamide on episodic memory over enzalutamide was observed for both the acquisition of new information, as well as for the recall of that information after a brief delay,” the authors of the poster, who were led by Emeline Colomba, MD, of the Department of Cancer Medicine at Institut Gustave Roussy of University of Paris Saclay in Villejuif, France, wrote.

Low blood-brain barrier penetrance is a known benefit of darolutamide vs other antiandrogen agents, such as enzalutamide. Results of the ODENZA trial that were previously reported at the 2021 American Society of Clinical Oncology Annual Meeting indicated that numerically more patients reported preferring darolutamide than enzalutamide, although these correlations did not reach statistical significance. Of note, fatigue was a key influencing factor for preference and was reported in 21% of patients receiving darolutamide vs 36% with enzalutamide

Patients with mCRPC (n = 249) were randomized 1:1 to either darolutamide at 1200 mg daily for 12 weeks followed by enzalutamide at 160 mg daily for 12 weeks or the reverse sequence. The current assessment looks at cognitive assessment, a key secondary end point of the study, using computerized tests to determine changes from baseline during each 12-week period.

Criteria for evaluation included detection test (DET) for psychomotor function and an identification test (IDT) for visual attention, which comprised an attention composite score; a working memory, or One Back Test (OBT), and an executive function, or Groton Maze Learning test (GML), which comprised an executive function composite score; and a verbal learning, or International Shopping List test (ISL), and a verbal memory testing, or International Shopping List test–delayed recall (ISRL), comprising a memory composite (episodic memory) score.

Cognitive data were available in 193 patients in total. Effects sizes were considered clinically meaningful at 0.5 or greater.

The memory composite score demonstrated a statistically significant benefit of darolutamide (

<.001), with a least square (LS) mean difference of 0.35 and an effect size of 0.54. Performance on verbal learning by ISL were significantly improved with darolutamide and effects were clinically meaningful, both at the second period (0.62; 

 < .0001). Performance on verbal learning was also better with darolutamide at the second period (0.4; P = .01) and overall (0.29; 

 = .0075), although these effects were less clinically meaningful.

Between darolutamide and enzalutamide, the effect sizes for both the executive function and attention composite scores were 0.15, with LS mean differences of 0.09 and 0.12, respectively (

Overall, investigators noted that composite scores were in line with individual scores and that moderate benefit with darolutamide was noted for episodic memory.

1. Colomba E, Jonas SF, Yymard J-C, et al. Objective computerized cognitive assessment in men with metastatic castrate-resistant prostate cancer (mCRPC) randomly receiving darolutamide or enzalutamide in the ODENZA trial. Presented at: 2021 European Society for Medical Oncology Congress; September 16-21, 2021. Virtual. Abstract 603P.

2. Colomba E, Jonas SF, Yymard J-C, et al. ODENZA: A French prospective, randomized, open-label, multicenter, cross-over phase II trial of preference between darolutamide and enzalutamide in men with asymptomatic or mildly symptomatic metastatic castrate-resistant prostate cancer (CRPC). J Clin Oncol. 2021;39(suppl 15):5046. doi:10.1200/JCO.2021.39.15_suppl.5046

Articles

Episodic memory by computerized cognitive assessment was significantly improved in patients who received darolutamide compared with those treated with enzalutamide.

Darolutamide linked to cognitive benefit over enzalutamide in prostate cancer

A posthoc analysis from the phase 3 CLEAR trial in renal cell carcinoma (RCC) suggests that the failure of lenvatinib (Lenvima) plus everolimus (Afinitor) to improve overall survival (OS) versus sunitinib (Sutent) in the primary analysis was impacted by a difference in subsequent anticancer therapies received in the 2 study arms.

Data presented during the 2021 ASCO Annual meeting showed that fewer patients in the lenvatinib/everolimus arm were treated with subsequent anticancer treatments compared with the sunitinib arm. After adjusting for receipt of subsequent regimens for RCC, the hazard ratio for OS shifted below 1.0 and support the clinical benefit of therapy with lenvatinib plus everolimus in this population. These results are supported by prior data that show the combination led to a statistically significant benefit to progression-free survival (PFS) versus sunitinib (HR, 0.65; 95% CI, 0.53-0.80; 

“These post hoc analyses of patients with advanced RCC who were treated in the first-line setting in CLEAR demonstrated that differences in subsequent anticancer medication affected the comparison of OS for the lenvatinib plus everolimus versus sunitinib arm,” Thomas Hutson, DO, PharmD, of the Urologic Cancer Research and Treatment Center at Baylor University Medical Center in Dallas and professor of medicine at Texas A&M College of Medicine, and colleagues wrote in their poster presentation.

A 2-stage estimation approach was used to adjust for effects of subsequent therapy on OS outcomes for lenvatinib/everolimus versus sunitinib, with a data cutoff of August 28, 2021. Median follow-up duration for each arm was 27 months and 26 months, respectively.

Duration of study treatment was shorted with sunitinib at 7.8 months versus 11.0 months with lenvatinib/everolimus. For those who did go on to receive other medications, duration from randomization to initiation of subsequent therapy was shorter with sunitinib versus the combination, at 6.62 months versus 8.03 months, respectively. For those whose next therapy was a PD-1/PD-L1 inhibitor, the median duration to initiation was 7.64 months with sunitinib and 9.69 months with lenvatinib/everolimus.

In the overall population, the Kaplan-Meier estimate for OS showed comparable efficacy of the 2 regimens (HR, 0.95; 95% CI, 0.51-1.76). However, the investigators noted that more patients in the sunitinib arm (57.7%) had any subsequent therapy versus those treated with lenvatinib/everolimus (46.8%). After adjusting for the confounding effects of subsequent medication, the adjusted hazard ratio for OS was 0.84 (95% CI, 0.64-1.12) in favor of lenvatinib/everolimus. In both models, the median OS for either arm had not yet been reached.

The most commonly used medications in the second-line setting were PD-1/PD-L1 inhibitors (43.1% vs 35.3%), VEGF inhibitors (33.6% vs 28.0%), CTLA-4 inhibitors (5.0% vs 6.2%), and mTOR inhibitors (4.8% vs 0.8%). Looking at patients who received subsequent PD-1/L1 inhibitors alone, the hazard ratio for OS was 0.89 (95% CI, 0.68-1.19).

Despite a higher rate of treatment-emergent adverse effects (TEAEs) resulting in death noted in the experimental arm (n = 355; 12.4%) versus the control (n = 340; 6.8%), the investigators contributed a majority of these to progressive disease (9.6% vs 6.2%). Overall, the toxicity profiles of each regimen were consistent with their known safety profiles.

Patient baseline characteristics of the 2 study arms were well balanced, with a few notable exceptions. Median age was 62 years (range, 32-89) for lenvatinib/everolimus and 61 years (range, 29-82) for sunitinib. More patients in the sunitinib (77.0%) than the lenvatinib/everolimus (72.8%) arm had prior nephrectomy. PD-L1 expression and risk stratification by MSKCC and International Metastatic RCC Database criteria were well balanced.

Treatment of patients on the CLEAR trial remain ongoing across the 3 study arms comparing the combinations of lenvatinib plus either everolimus or pembrolizumab versus control therapy with sunitinib. Results of the lenvatinib/pembrolizumab arm of the trial are being considered by the FDA as supporting evidence for the approval of the combination as frontline therapy of RCC.

1. Huston TE, Choueiri TK, Motzer RJ, et al. Post hoc analysis of the CLEAR study in advanced renal cell carcinoma (RCC): Effect of subsequent therapy on survival outcomes in the lenvatinib (LEN) + everolimus (EVE) versus sunitinib (SUN) treatment arm. J Clin Oncol. 2021;38(suppl 15):4562. doi: 10.1200/JCO.2021.39.15_suppl.4562

Data presented during the 2021 ASCO Annual meeting showed that fewer patients in the  lenvatinib/everolimus arm were treated with subsequent anticancer treatments compared with patients in the sunitinib arm.

Posthoc analysis yields silver lining for lenvatinib/everolimus OS results in RCC

Health-related quality of life (HRQOL) outcomes from the phase 3 CLEAR trial further support the frontline use of pembrolizumab (Keytruda) plus lenvatinib (Lenvima) in patients with metastatic renal cell carcinoma (RCC).


The findings showed that the combination resulted in HRQOL outcomes and disease-related symptom scores as single-agent sunitinib (Sutent). Conversely, lenvatinib plus everolimus (Afinitor), another regimen examined in a separate experimental arm of the trial, led to similar or worse HRQOL outcomes versus sunitinib.

“The efficacy, safety, and health-related quality of life results from the CLEAR trial support lenvatinib plus pembrolizumab as first-line therapy for patients with advanced RCC,” Robert J. Motzer, MD, PhD, head of the Kidney Cancer Section for the Genitourinary Oncology Service and the Jack and Dorothy Byrne Chair in Clinical Oncology, said when presenting the data at the 2021 ASCO Annual Meeting.

Based on efficacy results from the CLEAR trial (NCT02811861) reported earlier this year,

 the FDA accepted and granted priority review to applications seeking approval of the combination as therapy for the indicated patient population. Data showed that lenvatinib plus pembrolizumab led to a 61% reduction in the risk of disease progression or death versus sunitinib. While the median overall survival (OS) was not yet reached in either arm, the hazard ratio indicated a statistically significant benefit with the combination versus standard therapy (HR, 0.66; 95% CI, 0.49-0.88; 

HRQOL impact for the 3 arms of the trial were performed using 3 scales: the Functional Assessment of Cancer Therapy Kidney Symptom Index–Disease-Related Symptoms (FKSI-DRS), which measures symptoms specific to kidney cancer and for which a higher score equates to better QOL; the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire for Patients with Cancer-Core 30 (EORTC QLQ-C30), which is comprised of 9 multiple item scales and 6 single-item scales to assess function and symptoms in which a higher score indicates poorer QOL; and the European Quality of Life 5-Dimension 3-Level System (EQ-5D-3L) that has 2 scales including a visual analog scale (VAS) and a descriptive system of 5 items.

Longitudinal change from baseline was assessed using a mixed-model analysis and the time to deterioration was assessed using a stratified log-rank test and a Cox model directed at 2 end points. Time to first deterioration was defined as the number of weeks between randomization and the first deterioration event, with time until definitive deterioration defined as the number of weeks between randomization and the earliest deterioration event. There were no adjustments for multiple testing or estimate, with all 

 values and confidence intervals being nominal and descriptive.

In the comparison of lenvatinib/everolimus with sunitinib, least square mean differences indicated similar to worse HRQOL with the experimental regimen across the different assessment scales. There was a statistically significant difference in the EORTC QLQ-C30 global health scale (GHS)/QOL assessment favoring sunitinib (HR, –2.81; 95% CI, –5.08 to –0.54; 

<.05). EORTC QLQ-C30 symptoms scales favoring sunitinib included pain (HR, 2.80; 95% CI, 0.11-5.49; 

<.05), appetite loss (HR, 4.23; 95% CI, 1.34-7.13; 

<.05), and diarrhea (HR, 5.26; 95% CI, 2.61-7.91; 

“For diarrhea, the least mean difference score was greater than 5, which may be considered clinically significant,” said Motzer.

Looking at pembrolizumab/lenvatinib versus sunitinib, least square mean differences indicated similar to better HRQOL with the experimental regimen across the different EORTC QLQ-C30 functional and symptom scales. Physical functioning (HR, 3.01; 95% CI, 0.48-5.54; 

<.05), fatigue (HR, –2.80; 95% CI, –5.52 to –0.08; 

<.05), dyspnea (HR, –2.79; 95% CI, –5.33 to ­–0.25; 

<.05), and constipation (HR, –2.19; 95% CI, –4.19 to –0.18; 

Time to first deterioration by EORTC QLQ-C30 also favored the immune checkpoint inhibitor/tyrosine kinase inhibitor combination over sunitinib for physical functioning, with a median duration of 15.29 weeks versus 12.71 weeks, respectively (HR, 0.81; 95% CI, 0.68-0.98; 

= .03). Similarly, the median duration to onset was 39.29 weeks versus 21.14 weeks, respectively, for dyspnea (HR, 0.79; 95% CI, 0.64-0.97; 

= .02) and was 18.29 weeks versus 9.14 weeks for appetite loss (HR, 0.82; 95% CI, 0.68-0.98; 

= .03). By EQ-5D-3L, the EQ-VAS similarly favored pembrolizumab plus lenvatinib, at 9.43 weeks versus 9.14 weeks (HR, 0.83; 95% CI, 0.70-0.99; 

Across all 3 scales, time to definitive deterioration—defined as the number of weeks between randomization and the earliest deterioration event with no subsequent recovery above the deterioration threshold or no subsequent HRQOL assessment data—was significantly improved with the combination of pembrolizumab and lenvatinib versus sunitinib.

By the FKSI-DRS total score, the median time to definitive deterioration was 134.14 weeks with pembrolizumab/lenvatinib versus 117.43 weeks with sunitinib (HR, 0.70; 95% CI, 0.53-0.92; 

 <.01). Corresponding medians for EORTC QLQ-C30 GHS/QOL (114.29 vs 75.14 weeks; HR, 0.60; 95% CI, 0.47-0.77; 

 <.0001), EORTC QLQ-C30 Physical Functioning (134.14 vs 78.14 weeks; HR, 0.52; 95% CI, 0.41-0.67; 

 <.0001), and EQ-5D-3L VAS (124.86 vs 74.86 weeks; HR, 0.67; 95% CI, 0.53-0.85; 

 <.01) all showed statistically significant benefits to time to definitive deterioration with combination therapy.

“The results suggest that patients who receive lenvatinib and pembrolizumab had longer maintenance of quality of life and symptom control than those in the sunitinib group,” Motzer said. “Other factors that could potentially influence outcome and the time to definitive deterioration analysis include dose modification of lenvatinib for toxicity and then recovery of score based on better tolerability with the lower dose.”

He noted that longer time on treatment through progression-free survival gain or treatment beyond progression led to patients having more assessments and more time to recover. Further analyses will be examined in future research.

“It is notable that almost all comparisons of time to definitive deterioration favor lenvatinib and pembrolizumab over sunitinib,” Motzer concluded.

1. Motzer RJ, Porta C, Alekseev B, et al. Health-related quality-of-life (HRQoL) analysis from the phase 3 CLEAR trial of lenvatinib (LEN) plus pembrolizumab (PEMBRO) or everolimus (EVE) versus sunitinib (SUN) for patients (pts) with advanced renal cell carcinoma (aRCC). 

. 2021;39(suppl 15):4502. doi: 10.1200/JCO.2021.39.15_suppl.4502

2. Motzer RJ, Porta C, Eto M, et al. Phase 3 trial of lenvatinib (LEN) plus pembrolizumab (PEMBRO) or everolimus (EVE) versus sunitinib (SUN) monotherapy as a first-line treatment for patients (pts) with advanced renal cell carcinoma (RCC) (CLEAR study). 

. 2021; 39(suppl 6):269. doi: 10.1200/JCO.2021.39.6_suppl.269

The health-related quality of life data come from the phase 3 CLEAR trial. The FDA is currently reviewing efficacy data from this trial supporting an application for pembrolizumab plus lenvatinib in frontline renal cell carcinoma. 

HRQOL data back frontline pembrolizumab/lenvatinib in advanced RCC

Bristol Myers Squibb announced the FDA's acceptance and granting of priority review for its supplemental biologics license application for nivolumab (Opdivo) as adjuvant therapy for patients with surgically resected, high-risk muscle-invasive urothelial carcinoma.

This designation was granted based on data from the pivotal phase 3 CheckMate 274 trial (NCT02632409), a randomized, double-blind, multicenter study examining the efficacy of the PD-1 inhibitor as adjuvant therapy versus placebo in the indicated patient population.

“After patients undergo surgery for muscle-invasive urothelial carcinoma, they continue to face uncertainties given the high rate of disease recurrence and the lack of safe and effective treatment options,” Dana Walker, MD, MSCE, vice president and development program lead of genitourinary cancers at Bristol Myers Squibb, said in a press release. “Based on the ground-breaking disease-free survival results from CheckMate-274, we believe Opdivo has the potential to change the future of treatment for muscle-invasive urothelial carcinoma. We look forward to working with the FDA towards the goal of bringing the first adjuvant immunotherapy option to these patients in the US.”

Results of the trial were previously reported at the 2021 Genitourinary Cancers Symposium

, with the experimental arm showing a statistically significant improvement in the primary end point of disease-free survival (DFS).2

Investigators found that the experimental therapy following surgery resulted in a 30% reduction in the risk of disease recurrence or death in the intent-to-treat (ITT) population (HR, 0.70; 98.31% CI, 0.54-0.89; 

 < .001). In patients with PD-L1–positive tumors, or those with expression of at least 1%, the reduction in risk of disease recurrence or death was 47% (HR, 0.53; 98.87% CI, 0.34-0.84; 

 < .001). Numerically, median DFS in the ITT population was better with nivolumab at 21.0 months versus 10.9 months with placebo. In the PD-L1 positive population, median DFS was not reached with nivolumab compared with 10.8 months in the placebo group.

A secondary end point of non–urothelial tract recurrence-free survival was improved with nivolumab for patients in the ITT population (HR, 0.72; 95% CI, 0.58-0.89) and PD-L1–positive subgroup (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,” lead author Dean Bajorin, MD, the Frederick R. Adler Senior Faculty Chair at Memorial Sloan Kettering Cancer Center in New York, New York, said during a presentation of the data at the symposium. “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.”

Patients recruited to the trial (n = 709) were randomized 1:1 to receive adjuvant nivolumab at 240 mg every 2 weeks or placebo for up to 1 year. Eligible patients had radical surgery within 120 days and were disease-free as evidenced by imaging. Experience with neoadjuvant cisplatin was allowed, but was not required.

The median follow-up times for the nivolumab (n = 353) and placebo (n = 356) arms were 20.9 months and 19.5 months, respectively. In the nivolumab arm, 53.3% of patients discontinued treatment versus 56.3% in the placebo arm, and was most commonly due to disease recurrence. The safety profile of the experimental regimen was consistent with the known safety profile of the agent in patients with solid tumors.

The target action date for a decision of this application was set by the FDA as September 3, 2021.

1. U.S. Food and Drug Administration Accepts for Priority Review Bristol Myers Squibb’s Application for Opdivo (nivolumab) as Adjuvant Treatment for Patients with Muscle-Invasive Urothelial Carcinoma. News release. Bristol Myers Squibb. April 30, 2021. Accessed April 30, 2021. 

2. 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). 

. 2021;39(suppl 6):391. doi:10.1200/JCO.2021.39.6_suppl.391

The agency made the designation on the basis of recently reported data from the phase 3 CheckMate 274 trial that found a statistically significant improvement in disease-free survival in patients treated with the PD-1 inhibitor.

Audrey Sternberg

Articles

Darolutamide linked to cognitive benefit over enzalutamide in prostate cancer

Posthoc analysis yields silver lining for lenvatinib/everolimus OS results in RCC

HRQOL data back frontline pembrolizumab/lenvatinib in advanced RCC

FDA grants priority review to nivolumab as adjuvant treatment for muscle-invasive urothelial carcinoma