Gina Mauro

The latest findings from the pivotal phase 3 JAVELIN Bladder 100 trial showed that frontline maintenance with avelumab (Bavencio) extended overall survival (OS) and progression-free survival (PFS) across several key subgroups of patients with advanced or metastatic urothelial carcinoma that had not progressed on upfront platinum-based chemotherapy.

The subgroup analysis, which was presented during the 2020 ESMO Virtual Congress, showed a significant OS and PFS improvement with avelumab, irrespective of the degree of response to frontline chemotherapy or the specific induction chemotherapy regimen administered.

“The JAVELIN Bladder 100 saw that avelumab significantly prolonged OS and PFS, and this benefit was regardless of which induction chemotherapy the patient received, or the best response to that chemotherapy,” lead study author Petros Grivas, MD, PhD, associate professor in the Division of Medical Oncology of University of Washington School of Medicine; clinical director of the Genitourinary Cancers Program; and associate professor in the Clinical Research Division at Fred Hutchinson Cancer Research Center, Seattle Cancer Care Alliance, said in a virtual presentation during the meeting.

Previously reported findings from the JAVELIN Bladder 100 study formed the basis of the June 2020 FDA approval of avelumab as a maintenance treatment for patients with locally advanced or metastatic urothelial carcinoma that has not progressed with first-line platinum-based chemotherapy

 Here, data showed a 7.1-month improvement in median OS with avelumab as frontline maintenance treatment plus BSC versus BSC alone.

In the overall patient population, the median OS was 21.4 months with the addition of avelumab versus 14.3 months with best supportive care (BSC) alone, which translated to a 31% reduction in the risk of death in the overall patient population (HR, 0.69; 2-sided 

“Based on these data, the FDA approved avelumab as switch maintenance therapy in the frontline setting […] and subsequently the NCCN and ESMO guidelines changed, showing that this study was completely practice changing,” Grivas said.

The multicenter, international, open-label phase 3 JAVELIN Bladder 100 trial randomized patients to frontline avelumab maintenance therapy in combination with BSC (n = 350) or BSC alone (n = 350). Enrolled patients had unresectable locally advanced or metastatic urothelial cancer that did not progress on 4 to 6 cycles of standard gemcitabine paired with either cisplatin or carboplatin.

Treatment was given between 4 to 10 weeks post induction chemotherapy. Fifty-one percent of patients had PD-L1–positive tumors. BSC included antibiotics, nutritional support, correction of metabolic disorders, as well as symptom control and pain management, and the chemotherapy regimen administered was either gemcitabine/cisplatin (n = 389) or gemcitabine/carboplatin (n = 269).

The baseline characteristics in patient subgroups reflected physician’s choice of first-line chemotherapy regimen. The median age in the gemcitabine/cisplatin–treated group was 66.5 years compared with 72.5 years in the gemcitabine/carboplatin–treated cohort. More patients on gemcitabine/cisplatin had an ECOG performance status of 0 (median, 67%) versus those on gemcitabine/carboplatin (median, 52%).

More patients on gemcitabine/cisplatin (64%) had 60 or higher mL/min creatinine clearance versus those who received gemcitabine/carboplatin (40%). More than half of patients in both chemotherapy groups had visceral metastasis (57.5% vs 51%, respectively), and roughly as well as those who had PD-L1–positive status (51% vs 47%). The best response to chemotherapy was 72% for patients on gemcitabine/cisplatin versus 70% for those on gemcitabine/carboplatin.

Median follow-up periods were 19.6 months in the avelumab arm and 19.2 months in the BSC-alone arm. In the overall patient population, the median PFS was 3.7 months in the avelumab-plus-BSC arm compared with 3.7 months in the BSC-alone arm per blinded independent central review (HR, 0.62; 

 <.001). Additionally, the HR for PFS favored avelumab in the PD-L1–positive subgroup, as well (HR, 0.56).

The results also demonstrated that in the cohort of patients with PD-L1–positive tumors, the median OS had not yet been reached in those who received avelumab versus 17.1 months in those who received BSC alone (HR, 0.56; 

When stratified by chemotherapy regimen, the OS and PFS benefit with avelumab as frontline maintenance was demonstrated irrespective of the induction chemotherapy regimen. With gemcitabine/cisplatin plus avelumab, the median PFS was 4.6 months versus 2.0 months for chemotherapy alone (HR, 0.63). The median OS was 25.3 months with avelumab versus 16.5 months without (HR, 0.69)

Among patients who received frontline chemotherapy with gemcitabine/carboplatin plus avelumab, the median PFS was 3.0 months versus 1.9 months for chemotherapy alone (HR, 0.59). The median OS was 19.9 months and 12.9 months, respectively (HR, 0.66).

“The different baseline characteristics were relatively well balanced between best supportive care and the avelumab arm, and this was the case in the subset of patients with complete response, partial response, or stable disease to prior induction chemotherapy,” Grivas said.

The survival benefits with frontline maintenance avelumab plus BSC were observed irrespective of best response to induction chemotherapy (complete response, partial response, or stable disease).

Further, the OS benefit with the addition of avelumab as frontline maintenance therapy in this setting was observed across additional subgroups, regardless of whether patients were younger than 65 years (HR, 0.79) or older (HR, 0.63), had an ECOG performance status of 0 (HR, 0.64) or 1 (HR, 0.74), a creatinine clearance of lower or higher than 60 mL/min (HR, 0.68), and whether patients were PD-L1 positive (HR, 0.56), negative (HR, 0.86), or unknown (HR, 0.69). Regarding the site of baseline metastasis, the HR for patients with visceral metastasis was 0.82 and was 0.54 for those with nonvisceral metastasis; HRs were 0.86 and 0.63 in those with and without lung lesions at baseline, respectively.

Additional subgroup data showed that the addition of avelumab to BSC was reported whether patients were male (HR, 0.64) or female (HR, 0.89); White (HR, 0.67), Asian (HR, 0.70), or other (HR, 0.91); from Europe (HR, 0.64), North America (HR, 0.86), Asia (HR, 0.71), and rest of world (HR, 0.38). The most modest benefit was seen in patients from Australia (HR, 0.96).

1. Grivas P, Park SH, Voog E, et al. Avelumab 1L maintenance + best supportive care (BSC) vs BSC alone with 1L chemotherapy for advanced urothelial carcinoma: subgroup analyses from JAVELIN Bladder 100. Presented at: 2020 Virtual ESMO Congress; September 19-21, 2020; virtual. Abstract 704MO.

2. FDA approves Bavencio as first-line maintenance treatment for patients with locally advanced or metastatic urothelial carcinoma. News release. Pfizer. June 30, 2020. Accessed June 30, 2020. bit.ly/2YO7gVk.

3. Powles T, Park SH, Voog E, et al. Maintenance avelumab + best supportive care (BSC) versus BSC alone after platinum-based first-line (1L) chemotherapy in advanced urothelial carcinoma (UC): JAVELIN Bladder 100 phase III interim analysis. J Clin Oncol. 2020;38(suppl 18):LBA1. doi:10.1200/JCO.2020.38.18_suppl. LBA1.

Articles

An analysis from the pivotal phase 3 JAVELIN Bladder 100 trial showed that the survival benefit observed with frontline maintenance avelumab in the overall population was sustained across several prespecified patients subgroups.

Avelumab frontline maintenance benefit sustained across subgroups in bladder cancer

Combination therapy with nivolumab (Opdivo) and cabozantinib (Cabometyx) significantly improved progression-free and overall survival compared with sunitinib (Sutent) as frontline treatment for patients with advanced renal cell carcinoma (RCC), according to findings from the phase 3 CheckMate-9ER trial.

Data from the trial presented at the 2020 ESMO Virtual Congress showed that the immunotherapy/TKI regimen reduced the risk of disease progression or death by 49% versus sunitinib, with a median progression-free survival (PFS) of 16.6 months versus 8.3 months, respectively (HR, 0.51; 

 <.0001). The median follow-up time was 18.1 months.

Additional results showed that the median overall survival (OS) was not reached in either arm, and there was a 40% reduction in the risk of death with the combination (HR, 0.60; 

“With expanding options for patients with advanced RCC, the overall efficacy, safety, and quality of life benefits, as well as individual patient characteristics, are very important considerations when you select appropriate therapy,” lead study author Toni K. Choueiri, MD, director of the Lank Center for Genitourinary Oncology, director of the Kidney Cancer Center, senior physician with Dana-Farber Cancer Institute, and the Jerome and Nancy Kohlberg Chair and professor of medicine with Harvard Medical School, said in a press conference during the congress. “These results, we believe, support nivolumab and cabozantinib as a potential first-line option in patients with advanced renal cell carcinoma.”

In the international, randomized, phase 3 CheckMate-9ER trial, 651 patients with advanced RCC received the combination of nivolumab and cabozantinib (n = 323) or sunitinib (n = 328) in the first-line setting. Patients must have had previously untreated advanced or metastatic disease, a clear cell component, and any International Metastatic RCC Database Consortium (IMDC) risk score.

The combination demonstrated a benefit across numerous subgroups, including age, sex, PD-L1 expression, bone metastases, IMDC risk group, and geographic region.

The objective response rate (ORR0 was also doubled with nivolumab/cabozantinib in this setting compared with sunitinib, at 55.7% versus 27.1%, respectively (

 <.0001). In the combination arm, the complete response (CR) rate was 8.0%, the partial response (PR) rate was 47.7%, and the stable disease (SD) rate was 32.2%. Additionally, 5.6% of patients had progressive disease (PD) and 6.5% were not evaluable or not assessed. In the sunitinib arm, the CR, PR, and SD rates were 4.6%, 22.6%, and 42.1%, respectively. Moreover, 13.7% of patients had PD and 17.1% of patients were not evaluable or not assessed.

Regarding safety, the incidence of the most common, any-grade and high-grade treatment-related adverse events (TRAEs) were similar in both arms. More than 50% of patients on the combination required dose reductions of cabozantinib due to adverse effects (AEs). TRAEs led to treatment discontinuations in 15.3% of those in the nivolumab/cabozantinib arm and in 8.8% of those on sunitinib. Specifically, 3.1% of patients discontinued both nivolumab and cabozantinib due to AEs, 5.6% discontinued only nivolumab, and 6.6% discontinued only cabozantinib.

The overall rate of serious AEs was similar between the 2 groups; however, liver toxicity was more common with cabozantinib/nivolumab. Nineteen percent of patients on the combination required corticosteroids due to immune-related AEs, 4% of whom needed corticosteroids for at least 30 days.

Beyond improved treatment response and survival benefits, the combination was found to provide an improved HRQoL compared with sunitinib. HRQoL was maintained over time with nivolumab/cabozantinib versus sunitinib, which had a consistent deterioration per Functional Assessment of Cancer Therapy- Kidney Symptom Index (FKSI)-19 total score. The between-arm differences were significant at nearly all time points.

Disease-related symptoms (DRS) also improved with nivolumab/cabozantinib. Those who received sunitinib experienced a decline per FKSI-Disease-DRS.

Both nivolumab and cabozantinib are currently approved in separate indications in RCC. In April 2018, the FDA approved nivolumab plus ipilimumab (Yervoy) as a frontline treatment for intermediate- and poor-risk patients with advanced RCC. Prior to that, in 2015, the PD-1 inhibitor was approved for use as a single agent in the treatment for patients with metastatic RCC following prior antiangiogenic therapy. In 2017, cabozantinib was approved by the FDA for use in previously untreated patients with advanced RCC and was initially approved as a treatment for those who had progressed on 1 prior antiangiogenic treatment.

1. Choueiri TK, Powles T, Burotto M, et al. Nivolumab + cabozantinib vs sunitinib in first-line treatment for advanced renal cell carcinoma: first results from the randomized phase 3 CheckMate 9ER trial. Ann Oncol. 2020;31(4). Abstract 696O.

The combination significantly improved progression-free and overall survival compared with sunitinib in frontline renal cell carcinoma.

Nivolumab/cabozantinib combo impresses as frontline kidney cancer treatment

The addition of the AKT inhibitor ipatasertib to abiraterone acetate (Zytiga) and prednisone delayed disease progression and induced superior antitumor activity in patients with metastatic castration-resistant prostate cancer (mCRPC) whose tumors had PTEN loss.

Data from the phase 3 IPATential150 trial presented at the 2020 ESMO Congress showed that at a median follow-up of 19 months, the median radiographic progression-free survival (rPFS) was 18.5 months with ipatasertib plus abiraterone/prednisone compared to 16.5 months with placebo plus abiraterone/prednisone (HR, 0.77; 

 = .0335) in a subgroup of patients with mCRPC and PTEN loss. The estimated 1-year event-free survival rates were 64.4% versus 63.3%, respectively.

While there was a numerical benefit in median rPFS with ipatasertib in the study’s intent-to-treat (ITT) population (HR, 0.84; 19.2 vs 16.6 months), the difference did not meet the statistical threshold for superiority established in the study design. The 1-year event-free survival rates in the ITT population were 65.3% and 63.0% in the ipatasertib and control arms, respectively.

Also of note, ipatasertib was associated with improved prostate-specific antigen (PSA) progression and PSA response rates.

“Combined androgen receptor (AR) and AKT blockade with ipatasertib plus abiraterone improves clinical outcomes over AR blockade with abiraterone alone for [patients with] 

-loss mCRPC, a poor-prognosis subset,” lead study author Johann de Bono, MD, Regius Professor of Cancer Research, and a professor in Experimental Cancer Medicine at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, said in a virtual presentation during the meeting.

Between 40% and 50% of patients with mCRPC have loss in PTEN, which is associated with worse prognosis and reduced benefit from AR blockade. Reciprocal cross talk has been demonstrated between AR and PI3K/AKT signaling, as AR blockade can activate PI3K/AKT signaling and enable prostate cancer cell survival.

The phase 3 IPATential150 study randomized 1101 patients with asymptomatic or mildly symptomatic previously untreated mCRPC (ITT population) in a 1:1 ratio to ipatasertib or placebo plus abiraterone and prednisone. Patient characteristics at baseline were well balanced between the 2 study arms, as well as between the ITT population and the 

-loss subgroup (n = 521). Overall, the median age was 69.5 years, and 69.2% of patients were white. A total 17.9% of patients had previously received a taxane, and about half of patients had a PSA-only progression factor. Most patients had site of metastatic disease in the bone (84.2%), followed by the lymph nodes (39.1%), lung or liver (11.9%), and other (6.5%).

At the time of the data analysis, 377 patients on the placebo/abiraterone arm were still on the study compared with 367 on the ipatasertib arm, with 33% and 36%, respectively, were on treatment. In the placebo arm, 177 patients discontinued the study compared with 180 on the ipatasertib arm, with 25% of placebo-treated patients and 22% of ipatasertib-treated patients discontinuing due to death.

The ipatasertib regimen was associated with an rPFS benefit across several patients subgroups: ECOG performance status of 0 (HR, 0.76); at least 75 years old (HR, 0.67); lactate dehydrogenase levels that are the upper limit of normal and higher (HR, 0.77); no prior taxane-based treatments (HR, 0.74); and the presence of liver/lung metastases (HR, 0.66).

-loss population defined by next-generation sequencing (NGS; n = 208). Here, the median rPFS was 19.1 months with ipatasertib compared with 14.2 months with placebo (HR, 0.65; 

-loss subgroup, was 61% with ipatasertib/abiraterone, with a 19% complete response (CR) rate and a 41% partial response (PR) rate; these rates in the placebo arm were 39%, 6%, and 32%, respectively. The median duration of response (DOR) was 17.7 months (95% CI, 14.0–not estimable) with ipatasertib and 13.9 months (95% CI, 12.1-18.0) with placebo.

The ORR was 61% with ipatasertib in the ITT population, with an 18% CR rate and a 43% PR rate; the placebo/abiraterone arm experienced a 44% ORR, a 9% CR rate, and a 34% PR rate. The median DOR was 15.9 months with ipatasertib compared with 16.2 months with placebo.

The PSA response rates were 84% and 72% with ipatasertib and placebo, respectively, in the 

 = .0012). In the ITT population, the PSA response rates were 81% and 76%, respectively (

 = .0183). Additionally, time to PSA progression favored the ipatasertib arms in both the 

 = .0013) and the ITT population (HR, 0.73; 95% CI, 0.62-0.85; 

At the time of the analysis, the OS data were immature; however, the investigators noted an early trend showing survival favoring the ipatasertib arm in the 

-loss group (HR, 0.91) and ITT population (HR, 0.93).

Regarding safety, grade 3/4 and 5 adverse effects (AEs) were higher with ipatasertib (70.1% and 4.4%, respectively) versus placebo (39.0% and 3.7%). Serious AEs in the experimental and placebo arms were 39.6% and 22.7%, respectively. Additionally, more patients on ipatasertib versus placebo discontinued treatment (21.1% vs 5.1%) and had dose reductions (39.9% vs 6.2%). Grade 3/4 AEs with ipatasertib reported more than 2% than with placebo included rash, diarrhea, hyperglycemia, increased alanine aminotransferase, increased aspartate aminotransferase, and dehydration. In an effort to mitigate drug discontinuations, de Bono said the institution of prophylactic loperamide and antihistamines can manage diarrhea and cutaneous AEs, respectively.

1. de Bono JS, Bracarda S, Sternberg CN, et al. IPATential150: efficacy and safety from the phase III study of ipatasertib plus abiraterone vs placebo plus abiraterone in metastatic castration-resistant prostate cancer. Presented at: 2020 ESMO Virtual Congress; September 19-21, 2020; Virtual. Abstract LBA4.

The addition of the AKT inhibitor ipatasertib to abiraterone acetate and prednisone improved radiographic progression-free survival, with overall survival data still eagerly anticipated. 

Author | Gina Mauro

Articles

Avelumab frontline maintenance benefit sustained across subgroups in bladder cancer

Nivolumab/cabozantinib combo impresses as frontline kidney cancer treatment

Ipatasertib/abiraterone regimen delays progression in mCRPC with PTEN loss