Matthew Fowler

Investigators observed encouraging antitumor activity in patients with muscle-invasive bladder cancer (MIBC) who were ineligible for cisplatin receiving treatment with neoadjuvant enfortumab vedotin (Padcev) IBC) who were ineligible for cisplatin.

The preliminary results from cohort H of the phase 1b/2 EV-103 trial (NCT03288545) were presented at the 2022 Genitourinary Cancers Symposium in San Francisco, California.

Investigators reported a pathological complete response (pCR) rate of 36.4% (95% CI, 17.2%-59.3%) among those treated with enfortumab vedotin (n = 22), as well as a pathological downstaging (pDS) rate of 50.0% (95% CI, 28.2%-71.8%).

“This first disclosure of data supports the ongoing phase 2 and 3 programs evaluating enfortumab vedotin alone or in combination with pembrolizumab in MIBC,” Daniel P. Petrylak, MD, professor of medical oncology and urology at the Yale Cancer Center, said in his presentation of the data.

Eligibility required patients to be ineligible for cisplatin, have clinical T2-T4N0M0 disease, and no upper tract or urethral tumors. Additionally, a urothelial carcinoma histology of greater than 50% was required. Patients also needed to have an ECOG performance status of 0 to 2, be medically fit for radical cystectomy plus pelvic lymph node dissection, and have undergone transurethral resection of bladder tumor within 90 days of the first day of cycle 1.

Patients received 1.25 mg/kg of neoadjuvant enfortumab vedotin monotherapy on days 1 and 8 per 21-day cycle for 3 cycles. Within 4 weeks of treatment, patients underwent radical cystectomy plus pelvic lymph node dissection followed by imaging every 12 weeks for the first 2 years and then every 24 weeks after.

The primary end point was pCR by central pathology review. Secondary end points included pDS by central review, event-free survival, disease-free survival, overall survival, safety, patient-reported outcomes, and biomarkers.

The median age of the study population was 74.5 years. All patients were White and most patients were male (90.9%) and a current or former smoker (95.5%). Most patients had an ECOG performance status of 0 (59.1%) followed by 1 (36.4%) and 2 (4.5%).

The most common reason for cisplatin-ineligibility was creatine clearance between less than 60 to 30 or more mL per minute (50.0%), followed by grade 2 or greater hearing loss (40.9%). A total of 86% of patients completed all 3 cycles of neoadjuvant therapy.

Any grade enfortumab vedotin–related treatment emergent adverse effects (TEAEs) were seen in all patients, with common TEAEs including fatigue (45.5%), alopecia (36.4%), dysgeusia (36.4%), diarrhea (27.3%), nausea (27.3%), peripheral sensory neuropathy (27.3%), dry eye (22.7%), and maculopapular rash (22.7%). Four patients experienced grade 3 or higher TEAEs, and no grade 4 TEAEs or deaths were reported. Grade 3 TEAEs related to treatment with enfortumab vedotin included asethenia, dehydration, erythema multiforme, and hyperglycemia.

Three enfortumab vedotin–related TEAEs leading to dose interruptions, 2 TEAEs leading to dose reductions, and 3 TEAEs leading to discontinuations were observed in the safety analysis. Most AEs of special interest were grade 1 and 2. Any grade AEs of interest included peripheral neuropathy (36.4%), skin reaction (63.6%), hyperglycemia (22.7%), ocular disorder (40.9%), and infusion-related reactions (9.1%). Grade 3 or greater AEs of special interest were skin reactions (9.1%) and hyperglycemia (13.6%).

“The observed safety profile of neoadjuvant enfortumab vedotin monotherapy in patients with cisplatin-ineligible MIBC is consistent with the known AE profile of enfortumab vedotin in other settings,” Petrylak concluded.

1. Petrylak DP, Flaig TW, Mar N, et al. Study EV-103 Cohort H: Antitumor activity of neoadjuvant treatment with enfortumab vedotin monotherapy in patients (pts) with muscle invasive bladder cancer (MIBC) who are cisplatin-ineligible. 

. 2022;40(suppl 6):435. doi: 10.1200/JCO.2022.40.6_suppl.435

Articles

“This first disclosure of data supports the ongoing phase 2 and 3 programs evaluating enfor-tumab vedotin alone or in combination with pembrolizumab in MIBC,” said Daniel P. Petrylak, MD.

Encouraging antitumor activity seen with neoadjuvant enfortumab vedotin in patients with cisplatin-ineligible MIBC

A meta-analysis of phase 3 trials published in 

 showed the strong metastasis-free survival (MFS) boost delivered with a combination of abiraterone acetate (Zytiga), prednisolone, and androgen deprivation therapy (ADT) with or without enzalutamide (Xtandi) versus treatment with ADT alone in patients with high-risk non-metastatic prostate cancer.

A total of 180 MFS events were observed in the combination therapy arms of the trials compared with 306 events in the ADT-alone control groups after a median follow-up of 72 months. Of the events that took place in the combination groups, 52% were deaths compared with 38% in the control groups. Six-year MFS was 82% and 69% in the combination therapy and control groups, respectively.

“[Patients] with high-risk non-metastatic prostate cancer who receive ADT with combination therapy have significantly better metastases-free survival and overall survival than those who receive ADT alone,” the investigators wrote. “Two years of abiraterone and prednisolone added to ADT and, if indicated, radiotherapy should be considered a new standard treatment for non-metastatic prostate cancer with high-risk features.”

The meta-analysis focused on 2 two randomized phase 3 trials conducted utilizing the Systemic Therapy in Advancing or Metastatic Prostate cancer: Evaluation of Drug Efficacy (STAMPEDE, MRC-PR08) platform. The first compared ADT with ADT plus abiraterone and prednisolone and the second analyzed ADT compared with ADT plus abiraterone, prednisolone, and enzalutamide.

Eligibility criteria required patients to have confirmed prostate adenocarcinoma, a WHO performance status of 0 to 2, and no evidence of distant metastases via conventional imaging. Additionally, patients were required to have high-risk disease or be relapsing with high-risk features.

Protocol recommended that patients receive standard of care ADT for 3 years. Radiotherapy was required after randomization for node-negative patients and encouraged for node-positive patients. The combination therapy regimen consisted of abiraterone acetate at 1000 mg and prednisolone at 5 mg, with or without enzalutamide at 160 mg.

The primary end point for the meta-analysis was MFS. Some key secondary end points included overall survival (OS), cancer-specific survival, failure-free survival, progression-free survival, and toxicity.

A total of 1974 non-metastatic patients were randomly assigned within both trials, including 455 to the control group and 459 to the combination therapy group in the abiraterone trial from November 15, 2011, to January 17, 2014. In the abiraterone and enzalutamide trial, 533 patients were randomized to the control group and 527 received the combination therapy from July 29, 2014, to March 31, 2016.

The median age of patients was 68 years (IQR, 63-73) and the median prostate-specific antigen level was 34 ng/ml (IQR, 14.7-47). Additionally, 39% of patients were node positive. The median time from randomization to combination therapy initiation was 1.4 weeks (IQR, 1.0-2.7), and median time from ADT initiation to combination therapy was 8.4 weeks (IQR, 5.1-11.3).

MFS was significantly longer in the combination therapy groups (not reached [NR]; IQR, not estimable [NE]–NE) vs the control groups (NR; IQR, 97-NE; HR, 0.53; 95% CI, 0.44-0.64; 

A subgroup analysis of 294 MFS events in the abiraterone trial and 192 events in the abiraterone and enzalutamide trial highlighted a notable effect in both trials, respectively (abiraterone trial: HR, 0.54; 95% CI, 0.43-0.68;

 <.0001; abiraterone/enzalutamide trial: HR, 0.53, 95% CI, 0.39-0.71; 

 <.0001); thus, there was no evidence of a further MFS boost with the addition of enzalutamide to abiraterone versus abiraterone alone (interaction HR, 1.02; 95% CI, 0.70-1.50; 

 = 0.91), and there was no evidence of between-trial heterogeneity.

In terms of OS, a total of 147 deaths and 236 deaths in the combination therapy and control groups were observed, respectively. OS was longer in the combination therapy groups (median, NR; IQR, NE–NE) compared with the control groups (median, NR; IQR, 103–NE; HR, 0.60; 95% CI, 0.48-0.73; 

 <.0001). The 6-year survival rate was 86% in the combination therapy groups compared with 77% in the control groups.

Grade 3 or higher adverse effects (AEs) during the first 24 months were observed in 29% of patients in the abiraterone trial control group and 32% of patients in the abiraterone and enzalutamide trial control group. The combination therapy groups had rates of grade 3 or higher AEs of 37% and 57% in the abiraterone trial and abiraterone enzalutamide trials, respectively.

“These results might suggest that, by preventing relapse and death from prostate cancer, patients treated with combination therapy are more likely to live longer and die from another cause,” the investigators wrote.

1. Attard G, Murphy L, Clarke NW, et al. Abiraterone acetate and prednisolone with or without enzalutamide for high-risk non-metastatic prostate cancer: a meta-analysis of primary results from two randomised controlled phase 3 trials of the STAMPEDE platform protocol. 

. Published online December 23, 2021. doi:10.1016/S0140-6736(21)02437-5

The combination of abiraterone acetate, prednisolone, and androgen deprivation therapy (ADT) with or without enzalutamide delivers a strong metastasis-free survival boost versus treatment with ADT alone in patients with high-risk non-metastatic prostate cancer.

Analysis shows strength of abiraterone/ADT efficacy in non-metastatic prostate cancer

Among patients with high-risk nonmetastatic prostate cancer, 2-year outcomes showed a sustained survival benefit with treatment involving abiraterone acetate (Zytiga) and prednisolone (AAP) with or without enzalutamide (Xtandi) added to androgen deprivation therapy (ADT).

Results from a combined analysis of the multistage STAMPEDE trial (NCT00268476) presented during the 2021 ESMO Congress demonstrated that for patients in the AAP-based therapy groups, metastasis-free survival (MFS) was improved versus those in the ADT alone group (HR, 0.53; 95% CI, 0.44-0.64; 

 = 2.9 × 10-11), for a 6-year rate improvement from 69% to 82%.

“We show that 2 years of abiraterone [acetate]–based therapy significantly improves metastasis-free survival and overall survival of high-risk nonmetastatic prostate cancer starting androgen deprivation therapy and should be now considered a new standard of care,” Gerhardt Attard, MD, FRCP, PhD, a clinician scientist and team leader at University College London Cancer Institute, and honorary medical oncology consultant at University College London Hospital, explained in his presentation of the data.

Eligible patients needed to have histologically confirmed prostate adenocarcinoma, intention to treat with long-term ADT, a WHO performance score of 0 to 2, and provided written consent. All patients received standard-of-care ADT for 3 years plus local radiotherapy with no overlapping controls.

Results of the STAMPEDE trial previously showed that patients with metastatic prostate cancer benefit from the addition of AAP to ADT; however, results in the nonmetastatic setting are still under investigation.

 This multistage, multiarm, phase 2/3 platform trial continued long-term follow-up in nonmetastatic patients from 2017 but did not record any further efficacy data on this cohort.

A total of 1974 patients were randomized 1:1 to each treatment arm, with patient baseline characteristics that were well-balanced. The median age was 68 years, the median PSA level was 34 ng/mL, 39% of the population was node-positive, and 3% had relapsed after prior treatment. Total median follow-up was 72 months, but follow-up was longer for the AAP versus APP plus enzalutamide comparison (85 vs 60 months).

The prespecified subgroup analysis by randomization period did not find any significant evidence for differing effect between the AAP plus ADT (HR, 0.54; 95% CI, 0.43-0.68; 

 = 3.2 × 10-7) and AAP and enzalutamide plus ADT groups (HR, 0.53; 95% CI, 0.39-0.71; 

“This is in keeping with reports [of patients with] metastatic castration-resistant prostate cancer reported after we completed accrual that have shown no benefit in overall survival for this combination,” explained Attard in his presentation. “This really gives us 2 groups that independently confirm the benefit of abiraterone-based treatment in this population.”

There was no statistically significant evidence of treatment effect heterogeneity observed among baseline randomization factors including nodal status, age at randomization, WHO performance status at randomization, regular NSAID/aspirin use at baseline, or use of radiation therapy as part of treatment.

In the overall survival examination, significant benefit of either AAP-based regimen versus ADT alone was noted (HR, 0.60; 95% CI, 0.48-0.73; 

 = 9.3x10-7), resulting in absolute benefit 6-year rate improvement from 77% to 86%.

No statically significant overall survival difference was seen in the subgroup analysis by randomization period for the AAP vs AAP plus enzalutamide groups, with hazard ratios of 0.63 (95% CI, 0.48-0.82; 

Regarding prostate cancer–specific survival, there was a benefit noted in the AAP-based treatment arms vs ADT alone (HR, 0.49; 0.37-0.65; 

 = 1.3 × 10-6). For progression-free survival, data favored the AAP-based therapy regimens (HR, 0.44; 95% CI, 0.36-0.54; 

In the first 2 years of treatment, 118 grade 3 adverse effects (AEs) were reported in the ADT alone group compared with 151 events in the AAP-based treatment group. Grade 4 or higher AEs were seen in 12 and 17 patients from the ADT alone and ADT plus AAP groups, respectively. Adding enzalutamide to AAP treatment increased toxicities in patients with no significant improvement in efficacy.

1. Attard G, Brown L, Clarke N, et al. Abiraterone acetate plus prednisolone (AAP) with or without enzalutamide (ENZ) added to androgen deprivation therapy (ADT) compared to ADT alone for men with high-risk non-metastatic (M0) prostate cancer (PCa): Combined analysis from two comparisons in the STAMPEDE platform protocol. Presented at: 2021 European Society for Medical Oncology Congress. September 16-21, 2021. Abstract LBA4.

2. James ND, de Bono JS, Spears MR, et al. Abiraterone for Prostate Cancer Not Previously Treated with Hormone Therapy. 

. 2017;377(4):338-351. doi:10.1056/NEJMoa1702900

"2 years of abiraterone-based therapy significantly improves metastasis-free survival and overall survival of high-risk nonmetastatic prostate cancer starting androgen deprivation therapy and should be now considered a new standard of care,” said Gerhardt Attard, MD, FRCP, PhD.

2-year data for abiraterone regimen show sustained OS benefit in nonmetastatic prostate cancer

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

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

Matthew Fowler

Articles

Encouraging antitumor activity seen with neoadjuvant enfortumab vedotin in patients with cisplatin-ineligible MIBC

Analysis shows strength of abiraterone/ADT efficacy in non-metastatic prostate cancer

2-year data for abiraterone regimen show sustained OS benefit in nonmetastatic prostate cancer

Pembrolizumab plus lenvatinib shows promise metastatic kidney cancer