Matthew Fowler

A subgroup analysis of the phase 3 CLEAR trial presented at the 2021 ASCO Annual Meeting showed that the overall survival (OS) benefit with frontline pembrolizumab (Keytruda) plus lenvatinib (Lenvima) observed in the overall population was sustained across risk-defined subgroups.

Risk group stratification was performed using International Metastatic RCC Database Consortium (IMDC) criteria. Beyond OS, benefits in progression-free survival (PFS) and overall response rate (ORR) were also observed for the pembrolizumab/lenvatinib arm across the risk-defined subgroups.

“Overall, our results indicated that lenvatinib plus pembrolizumab has improved efficacy parameters and outcome parameters compared to sunitinib in all subgroups of patients,” Viktor Grünwald, MD, of the University Hospital Essen in Essen, Germany, explained in his presentation of the data.

Of the 1069 patients enrolled in the multicenter, open-label, randomized phase 3 CLEAR study, 335 were assigned to the lenvatinib plus pembrolizumab arm and 357 were assigned to the sunitinib arm. Median patients age in the lenvatinib plus pembrolizumab and sunitinib arms was 64 years (range, 34-88) and 61 years (range, 29-82), respectively.

By IMDC risk groups, the lenvatinib plus pembrolizumab population had 31.0% with favorable-risk disease, 59.2% intermediate, and 9.3% poor risk. Patients in the sunitinib group had 34.7% with favorable risk, 53.8% intermediate, and 10.4% poor risk.

Focusing on PFS, patients in the IMDC–intermediate/poor risk subgroup treated with lenvatinib plus pembrolizumab had a median PFS of 22.1 months compared with 5.9 months for patients treated with sunitinib (HR, 0.36; 95% CI, 0.28-0.47). In the IMDC–favorable risk subgroup, the median PFS was 28.1 months compared with 12.9 months, respectively (HR, 0.41; 95% CI, 0.48-0.62).

The OS data also favored lenvatinib plus pembrolizumab in both the IMDC–intermediate/poor risk (HR, 0.58; 95% CI, 0.42-0.80) and IMDC–favorable risk subgroups (HR, 1.15; 95% CI, 0.55-2.40), although evaluating OS was considered inadequate due to too few events.

A 72.4% ORR was observed in the lenvatinib plus pembrolizumab arm compared with 28.8% ORR in the sunitinib arm when evaluating the IMDC–intermediate/poor risk subgroup (odds ratio, 6.60; 95% CI, 4.39-9.90). For the IMDC–favorable risk subgroup, the ORRs were 68.2% and 50.8%, respectively (odds ratio, 2.00; 95% CI, 1.17-3.42).

The investigative team also analyzed efficacy data via target kidney lesions, with median PFS favored in the lenvatinib plus pembrolizumab arm (22.1 months) over the sunitinib arm (7.5 months) for patients with target lesions (HR, 0.40; 95% CI, 0.25-0.65). For patients without target kidney lesions, corresponding medians were 25.8 months and 9.4 months, respectively (HR, 0.38; 95% CI, 0.30-0.49).

The ORRs were consistently favored in the lenvatinib plus pembrolizumab arms regardless of target kidney lesion status. Specifically, the ORR was 71.8% compared with 27% with target kidney lesions (odds ratio, 10.55; 95% CI, 4.54-24.52) and 70.8% versus 38.5% without target kidney lesions (odds ratio, 3.78; 95% CI, 2.66-5.37).

In the intent-to-treat population of patients in the lenvatinib plus pembrolizumab arm, complete responses were maintained in 79.3% of patients at 24 months and 74.3% of patients at 36 months.

More, in the 6-month landmark analysis, confirmed response or a reduction in target lesions of more than 75% were observed in 12.4% of patients in the lenvatinib plus pembrolizumab arm compared with 4.5% of patients in the sunitinib arm.

“All patients with complete response to lenvatinib plus pembrolizumab at 6 months were alive at 2 years; similar survival rates were observed for patients who had more than a 75% reduction in target lesions,” wrote the investigators in their poster of the data.

“Notably, patients with complete response or near complete response derived tremendous benefit from this type of combination,” continued Grünwald in his presentation.

The CLEAR study randomized patients 1:1:1 to receive oral lenvatinib 20 mg once daily plus intravenous pembrolizumab 200 mg every 3 weeks, lenvatinib 18 mg plus oral everolimus (Afinitor) 5 mg once daily, or oral sunitinib 50 mg once daily for 4 weeks on and 2 weeks off.

The study’s primary end point was PFS, with focal secondary end points of OS and ORR. Safety was also evaluated.

These results suggest that lenvatinib plus pembrolizumab could be considered as a potential new treatment option in the first-line setting for patients with advanced RCC.

video with Dr. Grünwald discussing these results

1. Grünwald V, Powles T, Kopyltsov E, et al. Analysis of the CLEAR study in patients (pts) with advanced renal cell carcinoma (RCC): Depth of response and efficacy for selected subgroups in the lenvatinib (LEN) + pembrolizumab (PEMBRO) and sunitinib (SUN) treatment arms. 

 39, 2021 (suppl 15; abstr 4560). 10.1200/JCO.2021.39.15_suppl.4560.

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Benefits in progression-free survival and overall response rate were also observed for the pembrolizumab/lenvatinib arm across risk-defined subgroups. 

Pembrolizumab/lenvatinib survival benefit sustained across RCC risk subgroups

Ultra-high single-dose radiotherapy (SDRT) demonstrated comparable efficacy and safety as curative hypofractionated stereotactic body radiotherapy (SBRT) in patients with organ-confined prostate cancer, according to study findings published in 

Data from the randomized, phase 2 PROSINT clinical trial (NCT02570919) presents an opportunity to further evaluate indications for SDRT as an alternative treatment option for patients with intermediate-risk prostate cancer, according to the researchers.

“This proof-of-concept parallel-group randomized clinical trial confirms that 24 Gy SDRT is feasible and safe in the treatment of organ-confined prostate cancer,” wrote the investigators. “The 5 × 9 Gy SBRT prostate immobilization and high-precision technique had been previously proven feasible and safe.”

The study population included 30 men with intermediate-risk prostate cancer randomized to either the SBRT or SDRT treatment arms. The median ages for each arm were 66.3 years and 73.6 years for the SBRT arm and SDRT arm, respectively.

The primary end point of the trial was toxic effects, with key secondary end points focusing on prostate-specific antigen (PSA) responses and quality of life. Patient-reported quality of life was measured using the International Prostate Symptom Score (IPSS) and Expanded Prostate Cancer Index Composite (EPIC)–26 questionnaires.

Data on the toxic effects found that grade 1 (HR, 0.41; 90% CI, 0.13-1.27) and grade 2 or greater (HR, 1.07; 90% CI, 0.21-5.57) cumulative late actuarial urinary toxic effects were similar. More, comparable data was observed for actuarial grade 1 late gastrointestinal (GI) toxic effects (HR, 0.37; 90% CI, 0.07-1.94), while no grade 2 or greater late GI toxic effects were observed.

For both arms, the PSA levels declined to under 0.5 ng/mL by the 36-month point. In the favorable intermediate-risk disease population, there were no PSA relapses observed, while the actuarial 4-year PSA relapse-free survival for the unfavorable disease population was 75.0% in the SBRT arm and 64.0% in the SDRT arm (HR, 0.76; 90% CI, 0.17-3.31).

The EPIC-26 quality-of-life analysis for both arms found that the median score for the genitourinary and GI domains dropped at the 1-month point, followed by a return to pre-treatment scores at the 3-month observation. For the IPSS analysis, 20% of patients receiving SDRT (90% CI, 3%-37%) had late urinary flare symptoms occur at 9 to 18 months.

“This study offers encouraging perspectives on the feasibility and safety of 24 Gy SDRT in organ-confined prostate cancer,” wrote the investigators. “Despite the limitation of a small sample size, the SDRT PSA end points recapitulate the outcomes of curative extreme hypofractionated 5 × 9 Gy SBRT reported here and in the recent literature.”

The main limitations of the phase 2 trial include the single-institution design, the small sample size of 30 patients, and the median follow-up limited to only 48 months.

Due to the data found from this phase 2 clinical trial, the investigative team suggests further studies to evaluate SDRT as a cost-effective and safe treatment option for this cohort of patients with prostate cancer.

“SDRT provides advantages in patient convenience as a result of the reduced number of visits,” wrote the investigators. “This could potentially lead to same-day planning and treatment, as well as provide significant cost savings, an issue already addressed relative to SBRT schemes, a major consideration in today’s increasingly cost-conscious environment.”

1. Greco C, Pares O, Pimentel N, et al. Safety and Efficacy of Virtual Prostatectomy With Single-Dose Radiotherapy in Patients With Intermediate-Risk Prostate Cancer. 

 March 11, 2021. doi:10.1001/jamaoncol.2021.0039

Ultra-high single-dose radiotherapy demonstrated comparable efficacy and safety as curative hypofractionated stereotactic body radiotherapy.  

Ultra-high single-dose radiotherapy effective for intermediate-risk prostate cancer

An analysis from the phase 3 PROSPER trial shared during the Oncology Nursing Society’s 46th Annual Congress highlighted the significant role oncology nurses play in ensuring optimal update of enzalutamide (Xtandi) in patients with nonmetastatic castration-resistant prostate cancer (nmCRPC).

“As treatment options expand, nurses will play an increasingly important role in the clinical management of patients with nmCRPC, including patients treated with enzalutamide,” the investigators wrote,

Monique Williams, lead author and study presenter from Leidos Biomedical Research Inc., explained that nurses are in a unique position to provide adequate care and education to patients with nmCRPC.

Among other things, Williams mentions patient education, multidisciplinary team management, the monitoring of adverse events and comorbidities, drug interaction management, and overall holistic care as integral implications in this practice setting for nurses.

To maintain routine healthcare and mitigate potential comorbidities during treatment such as hypertension, cardiovascular disease, diabetes, and psychiatric illness, nurses should engage other specialists or primary physicians.

More, as far as the safety profile of patients, the early identification of adverse events is key, as it improves medication adherence. Telehealth visits are also beneficial to allow convenience to patients and promote compliance.

Nurses need to ask patients about all their prescription and over-the-counter medications to avoid possible interactions with treatment. These include any herbal supplements a patient might be taking.

Overall, nurses should emphasize a holistic care plan for patients, taking into account the patient’s biological, social, psychosocial, and spiritual well-being. These steps should emphasize and provide referrals, encourage exercise, promote a healthy diet, suggest nonpharmaceutical resources to reduce pain and stress, and advise on sleep hygiene.

“In recent years, the development of novel hormone therapies (NHTs), such as enzalutamide, has changed the treatment landscape for men with nmCRPC and nurses will play a critical role in their management,” wrote the investigators in their poster of the data.

The trial randomly assigned 1401 patients to receive either enzalutamide 140 mg/day plus androgen-deprivation therapy (ADT; n = 933) or placebo plus ADT (n = 468).

Overall, the median treatment duration for the cohort was 33.9 months for patients in the enzalutamide group compared with 14.2 months for patients in the placebo group. More, median metastatic-free survival, which serves as a surrogate for overall survival in patients with nmCRPC, was recorded at 36.6 months for the enzalutamide group versus 14.7 months for the placebo group.

When compared with the placebo treatment, enzalutamide treatment was associated with a 27% lower risk of death, representing a significant improvement in treatment outcomes. Median overall survival with enzalutamide compared with placebo was 67.0 months versus 56.3 months, respectively.

Further, the time to PSA progression was recorded as longer in patients treated with enzalutamide when compared with patients treated with placebo. Also, these PSA responses were significantly associated with metastatic-free survival.

The safety profile was similar to that of the existing profiles for enzalutamide treatment. Common adverse events in the enzalutamide group included cardiovascular events, falls, fatigue, and fractures.

“As oncology nurses, we are on the front lines of patient care. We are likely the most accessible healthcare professionals,” explained Williams in her presentation of the data. “We will be assessing patients with nmCRPC, providing education, and coordinating the care for enzalutamide-treated patients. It is key that nurses properly educate on the once daily administration of enzalutamide.”

1. Williams M, Hussain M, Sternberg CN, et al. Treatment with Enzalutamide in Men with Non-metastatic Prostate Cancer from the PROSPER Trial. Presented at: Oncology Nursing Society 46th Annual Congress.

Role was highlighted in analysis of phase 3 PROSPER trial of enzalutamide in patients with nonmetastatic castration-resistant prostate cancer.

Nurses play significant role in multidisciplinary management of patients receiving enzalutamide

 Interdisciplinary Prostate Cancer Congress® Leonard G. Gomella, MD, FACS, chairman of the Department of Urology at the Sidney Kimmel Cancer Center, discussed the current state of the treatment paradigm in non-muscle invasive bladder cancer (NMIBC) and highlighted novel agents emerging on the horizon.

The management of NMIBC starts with the resection of all visible disease, with a focus on the existing standard of care, intravesical Bacillus Calmette–Guérin (BCG), for patients with this disease, according to Gomella.

“Non-muscle invasive bladder cancer management is something commonly encountered by urologists,” Leonard G. Gomella, MD, FACS, chairman of the Department of Urology at the Sidney Kimmel Cancer Center, explained in his presentation. “Initial management [is to] resect all visible disease and think about enhanced cystoscopy as a way to complete that process. If [the disease is] high-grade, consider intravesical BCG therapy; [and with] low-volume, just usually do follow-up cystoscopy.”

The standard approach utilized by most care providers for BCG intravesical immunotherapy is known as the SWOG protocol, in which patients receive an initial 6-weekly induction dose, followed by 3 weekly doses at 3 months and every 6 months following initial treatment for up to 2 or 3 years.

Along with a robust response, BCG therapy is typically well tolerated. Some common adverse events associated with BCG treatment include fever, hematuria, and granulomatous prostatitis.

While BCG is the current standard of care for NMIBC, BCG failures do exist. Specifically, recurrence and progression can happen with treatment via BCG, with 1- and 5-year recurrence rates of 15% to 61% and 31%to 78%, respectively. As for progression, the 1- and 5-year rates are up to 17% and up to 45%, respectively. These existing data strengthen the need for additional therapeutic options for patients with this disease.2

“There’s no question that BCG is probably the best-known immuno-oncology agent,” explained Gomella. “In reality, we’ve been using BCG for bladder cancer certainly since the FDA approval way back in 1990, and it’s really become the standard of care for non-muscle invasive bladder cancer.”

Among patients who are eligible for BCG, data suggests up to 40% may not respond to treatment or will become refractory to BCG. For high-risk patients who fit this description, Gomella explains that radical cystectomy should be considered as the first option. If patients are unwilling to undergo cystectomy or prefer another therapy, Gomella continued to say that intravesical chemotherapy, among other therapies, represent an option although noting its limited success.

For intravesical chemotherapy, monotherapy treatment is less efficacious than BCG, with paclitaxel, docetaxel, doxorubicin, epirubicin, and valrubicin (Valstar) among the drugs utilized in this treatment. Gomella noted that valrubicin is the only drug that has received FDA approval for this indication.

More, systemic pembrolizumab (Keytruda) to treat patients with BCG-refractory bladder cancer was recently approved by the FDA in response to data from the phase 2 KEYNOTE-057 study (NCT02625961).3,4

The median duration of response was 12.7 months (range, 0.0+ to 20.5+ months), with 75% of patients experiencing a complete response duration of 6 or more months and 53% of patients showing a complete response duration of 9 or more months.

“If you have a high-grade BCG failure, valrubicin and systemic pembrolizumab currently are the FDA approved salvage medications,” concluded Gomella. “Again, cystectomy should always be considered and at least presented to the patient.”

Several investigational agents are generating excitement in the field. The FDA granted a priority review designation to the protein-fusion drug Vicineum (VB4-845) in February 2021 for the treatment of patients with high-risk, BCG-unresponsive NMIBC.

The intravesical therapy nadofaragene firadenovec has shown promise in BCG-unresponsive NMIBC. In a phase 3 trial, the complete (CR) response rate with nadofaragene firadenovec was 53.4% at 3 months in patients with carcinoma in situ with or without concomitant high-grade Ta or T1 disease (CIS ± Ta/T1).

The 12-month CR rate was 24.3% and the median duration of CR was 9.69 months. Further, 45.5% of patients with an initial CR, were still free of high-grade recurrence at 1 year.

Also of note, data from the phase 2/3 QUILT 3.032 study (NCT03022825) shared at the 2021 Genitourinary Cancers Symposium showed that the combination of N-803 (Anktiva), a novel interleukin-15 (IL-15) superagonist complex, and BCG achieved CRs in 71% (51/72) of patients with BCG-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without Ta or T1 disease.

1. Gomella LG. Management of Non–Muscle-Invasive Bladder Cancer. Presented at: 14th Annual New York GU Congress. March 12-13, 2021.

2. Chang SS, Boorjian SA, Chou R et al. Diagnosis and treatment of non-muscle invasive bladder cancer: AUA/SUO guideline. 

 2016;196(4):1021-1029. doi: 10.1016/j.juro.2016.06.049

3. FDA approves pembrolizumab for BCG-unresponsive, high-risk non-muscle invasive bladder cancer. FDA. January 8, 2020. Accessed March 12, 2021. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-bcg-unresponsive-high-risk-non-muscle-invasive-bladder-cancer

4. Balar AV, Kamat AM, Kulkarni GS, et al. Pembrolizumab (pembro) for the treatment of patients with Bacillus Calmette-Guérin (BCG) unresponsive, high-risk (HR) non–muscle-invasive bladder cancer (NMIBC): Over two years follow-up of KEYNOTE-057. 

. 2020;38(suppl 15):5041. doi: 10.1200/JCO.2020.38.15_suppl.5041

5. Sesen Bio Announces FDA Acceptance and Priority Review of its Biologics License Application for Vicineum. Posted online February 16, 2021. Accessed February 27, 2021. https://bwnews.pr/3rZcbi0

6. Boorjian SA, Alemozaffar M, Bad Konety BR, et al. Intravesical nadofaragene firadenovec gene therapy for BCG-unresponsive non-muscle-invasive bladder cancer: a single-arm, open-label, repeat-dose clinical trial [published online November 27, 2020]. 

7. Chamie K, Chang S, Gonzalgo M, et al. Phase II/III clinical results of IL-15RαFb superagonist N-803 with BCG in BCG-unresponsive non-invasive bladder cancer (NMIBC) carcinoma in-situ (CIS) patients (cohort A). 

. 2021;39(suppl 6):510. doi:10.1200/JCO.2021.39.6_suppl.510

Investigational agents on the horizon include Vicineum, nadofaragene firadenovec, and N-803 (Anktiva).





Matthew Fowler

Articles

Pembrolizumab/lenvatinib survival benefit sustained across RCC risk subgroups

Ultra-high single-dose radiotherapy effective for intermediate-risk prostate cancer

Nurses play significant role in multidisciplinary management of patients receiving enzalutamide

Gomella details evolving treatment paradigm in NMIBC