Matthew Fowler

Combining the PD-1 inhibitor pembrolizumab (Keytruda) with the TKI lenvatinib (Lenvima) showed promising efficacy across treatment lines in patients with metastatic renal cell carcinoma (RCC), according to data from the phase 1b/2 KEYNOTE-146 study published in 

Of particular note, the combination achieved an objective response rate (ORR) of 55.8% at week 24 among patients previously treated with immune checkpoint inhibitors. The ORR was 72.7% among treatment-naïve patients and 41.2% among previously treated immune checkpoint inhibitor–naïve patients.

“This large trial of the TKI lenvatinib in combination with pembrolizumab demonstrated encouraging antitumor activity with a manageable safety profile, irrespective of previous therapies,” the study’s investigators wrote. “Lenvatinib plus pembrolizumab might, therefore, be a future potential standard-of-care treatment for patients with metastatic clear cell RCC after disease progression with [immune checkpoint therapy].”

The study’s patient population included 145 patients in the RCC cohort enrolled between July 21, 2015, and October 16, 2019. Investigators focused on the patients with clear cell histology and included 22 patients in the treatment-naïve group, 17 patients in the previously treated immune checkpoint inhibitor–naïve group, and 104 patients in the immune checkpoint inhibitor–pretreated group.

Patients aged 18 years or older with select solid tumors and an ECOG performance status of 0 or 1 were enrolled in the study. The patient population was treated with lenvatinib 20 mg orally once daily with pembrolizumab 200 mg intravenously once every 3 weeks.

Patients who were pretreated with an immune checkpoint inhibitor had received 2 or more doses of an immune checkpoint inhibitor and progressed on or after treatment. Among this group, 92% of patients reported that an immune checkpoint inhibitor was their most recent therapy. The median duration of treatment for patients who were previously treated with an immune checkpoint inhibitor therapy was 6.8 months, and 1.6 months for the median time from the end of the most recent immune checkpoint inhibitor regimen to the first dose of the experimental combination.

The overall objective response rate at the data cutoff point of August 18, 2020, was 77.3% among treatment-naïve patients, 52.9% among previously treated immune checkpoint inhibitor–naïve patients, and 62.5% among immune checkpoint inhibitor–pretreated patients.

After a median follow up of 18.9 months, the median progression-free survival assessed by investigators was 24.1 months for treatment-naive patients, 11.8 months for previously treated immune checkpoint inhibitor–naïve patients, and 12.2 months for immune checkpoint inhibitor–pretreated patients. At the data cutoff, 68%, 71%, and 57% of patients in each respective group had disease progression or died.

With a median follow-up of 29.5 months, the median overall survival (OS) among the treatment-naïve patient population was not reached (NR; 95% CI, 28.6-NR). Additionally, the median OS was 30.3 months (95% CI, 28.7-NR) with a median follow-up of 50.8 months for previously treated immune checkpoint inhibitor–naïve patients and was NR (95% CI, NR-NR) at a median follow-up of 16.6 months for pretreated patients.

In terms of safety, all but 1 of the 145 patients analyzed experienced at least 1 treatment-related adverse effect (TRAE). Of those events, 57% of patients experienced a grade 3 TRAE and 7% of patients experienced a grade 4 TRAE. Common TRAEs included fatigue, diarrhea, and hypertension, with hypertension (21%) being the most common grade 3 TRAE. Serious TRAEs were observed in 25% of patients, and 3 treatment-related deaths were reported.

“The results from this study provide evidence of preliminary efficacy and safety of lenvatinib plus pembrolizumab in patients with metastatic clear cell renal cell carcinoma, irrespective of previous therapies,” the investigators concluded. “This combination is being further investigated in phase 3 trials involving patients with various tumor types, including a study in advanced or metastatic renal cell carcinoma.”

The study’s limitations included its non-randomized design and heterogenous patient population. Efficacy-related conclusions were limited due to the small sample size of treatment-naïve and previously treated ICI-naïve patients.

1. Lee CH, Shah AY, Rasco D, et al. Lenvatinib plus pembrolizumab in patients with either treatment-naive or previously treated metastatic renal cell carcinoma (Study 111/KEYNOTE-146): a phase 1b/2 study. 

. 2021;22(7):946-958. doi:10.1016/S1470-2045(21)00241-2

Articles

The combination achieved a high objective response rate among patients previously treated with immune checkpoint inhibitors. 

Pembrolizumab plus lenvatinib shows promise metastatic kidney cancer

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.

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.

Matthew Fowler

Articles

Pembrolizumab plus lenvatinib shows promise metastatic kidney cancer

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