Gina Mauro

Subgroup data from the pivotal phase 3 JAVELIN Bladder 100 trial showed that frontline maintenance with avelumab (Bavencio) plus best supportive care (BSC) improved median overall survival (OS) in Japanese patients with advanced urothelial cancer.

The trial enrolled patients who had not progressed on frontline chemotherapy and randomized them to avelumab plus BSC versus BCS alone. The subgroup findings showed a median OS of 24.7 months versus 18.7 months in patients who received the combination (n = 36) versus BSC alone (n = 37), respectively (HR, 0.81). In Japanese patients with PD-L1–positive tumors, the median OS was 18.6 months and 19.4 months, respectively (HR, 1.00; 95% CI, 0.41-2.41). However, the 95% confidence intervals were wide due to the small number of patients.

The findings were consistent with the overall study population of JAVELIN Bladder 100, lead study author Norihiko Tsuchiya, MD, of the Department of Urology at Yamagata University Faculty of Medicine, and co-investigators, stated in a poster presentation during the 2021 Genitourinary Cancers Symposium.

“The interpretation of findings in the Japanese subgroup is limited by the small number of patients compared with the overall trial population,” Tsuchiya noted. “Overall, these results support the consideration of avelumab [as first-line] maintenance as a potential new standard of care in Japanese patients with advanced urothelial cancer that has not progressed with [first-line] platinum-containing chemotherapy.”

In the phase 3 JAVELIN Bladder 100 study (NCT02603432), investigators sought to determine the efficacy and safety of avelumab plus BSC versus BSC alone as a frontline maintenance therapy in 700 patients with locally advanced or metastatic urothelial cancer that did not progress on frontline chemotherapy with cisplatin/gemcitabine or carboplatin/gemcitabine.

Following a treatment-free interval of 4 to 10 weeks, patients were randomized to receive avelumab at 10 mg/kg intravenously every 2 weeks plus BSC or BSC alone until disease progression, unacceptable toxicity, or withdrawal.

PD-L1 status was defined using the Ventana SP263 immunohistochemistry assay. Patients were stratified by best response to first-line chemotherapy (complete response [CR] or partial response [PR] vs stable disease [SD]).

The primary end point of the trial was OS in the primary analysis populations, which included all randomized patients and PD-L1–positive patients. Secondary end points were progression-free survival (PFS) and objective response rate (ORR) per RECIST v1.1 criteria by blinded independent central review, safety and tolerability, and patient-reported outcomes. 

Overall results, which were presented at the 2020 ASCO Virtual Scientific Program, showed that avelumab plus BSC demonstrated significantly prolonged OS versus BSC alone (HR, 0.69; 

 <.001). The benefit was also seen in PD-L1–positive patients (HR, 0.56; 

 Based on these data, the FDA approved the combination of avelumab and BSC in June 2020 as a frontline maintenance regimen in this setting.

In this analysis, investigators evaluated the outcomes of all patients enrolled in sites in Japan (n = 73) in the same trial. Baseline characteristics of Japanese patients compared with the overall population were similar; however, of note, Japanese patients weighed less (62.9 kg on avelumab and 61.9 kg on BSC) versus the overall group (72.4 kg and 73.0 kg, respectively) and were more likely to have upper tract disease as the site of their primary tumor (Japanese, 58.3% and 56.8%; overall, 30.3% and 23.1%). Japanese patients were also less likely to have received gemcitabine/carboplatin as their first-line chemotherapy regimen (Japanese, 25.0% and 21.6%; overall, 42.0% and 34.9%) and were less likely to experience a CR or PR to first-line chemotherapy (Japanese, 61.1% and 59.5%; overall, 72.3% and 72.0%).

Additional findings showed that the median PFS in Japanese patients was 5.6 months with avelumab/BSC compared with 1.9 months with BSC alone (HR, 0.63). In PD-L1–positive patients who were Japanese, the median PFS was 5.6 months and 1.9 months, respectively (HR, 0.62).

In all Japanese patients, the ORR in the avelumab/BSC arm was 5.6% versus 0% with BSC. The ORR on the avelumab arm was comprised of 1 CR and 1 PR; 3 patients had stable disease, 7 patients had non-CR/non-progressive disease (PD), 17 patients had PD, and 7 patients were not evaluable. The disease control rates were 33.3% and 27.0% with avelumab/BSC and BSC alone, respectively. The response rate data were comparable with the overall study population.

Twenty-two (61.1%) Japanese patients on avelumab/BSC discontinued treatment and received subsequent therapy compared with 30 (81.1%) on BSC alone. In the avelumab arm, subsequent therapy included a PD-1/PD-L1 inhibitor (38.9%), FGFR inhibitor (2.8%), and other (52.8%); these rates were 67.6%, 0%, and 54.1% in the BSC-alone arm. The investigators noted that more Japanese patients on BSC received a subsequent checkpoint inhibitor compared with the overall study population (43.7%).

Regarding safety, the tolerability in the avelumab arm was consistent with the overall study population, and no safety concerns in the Japanese subgroup was identified. All-grade treatment-emergent adverse effects (TEAEs) occurred in 100% of patients on avelumab and 56.8% on BSC; grade 3 or higher TEAEs occurred in 50.0% and 8.1% of patients, respectively. On avelumab, these included anemia (11.1%), pyelonephritis (5.6%), urinary tract infection (2.8%), increased amylase (5.6%), increase in blood triglycerides (5.6%), and fatigue (2.8%).

TEAEs led to treatment discontinuation in 4 patients on avelumab, and 1 patient died due to sepsis.

All-grade treatment-related AEs (TRAEs) occurred in 75% (n = 27) of patients on avelumab, and 5 patients were reported as having TRAEs grade 3 or higher. Immune-related AEs were reported in 36.1% of avelumab-treated patients, 8.3% of which were grade 3. Additionally, 27.8% of patients on this arm had grade 1/2 infusion-related reactions.

1. Tsuchiya N, Yamaoto Y, Uemura H, et al. Avelumab first-line maintenance plus best support care (BSC) vs BSC alone for advanced urothelial carcinoma: JAVELIN Bladder 100 Japanese subgroup analysis. 

. 2021;39(suppl 6):425. doi:10.1200/JCO.2021.39.6_suppl.425

2. 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. 

. 2020;38(suppl 18):LBA1. doi:10.1200/JCO.2020.38.18_suppl.LBA1

3. FDA approves Bavencio as first-line maintenance treatment for patients with locally advanced or metastatic urothelial carcinoma. News release. Pfizer. June 30, 2020. Accessed March 1, 2021. https://bit.ly/2YO7gVk.

Articles

The subgroup analysis assessed data from the pivotal phase 3 JAVELIN Bladder 100 trial showed.

OS benefit with frontline avelumab maintenance in urothelial cancer sustained in Japanese subgroup 

Treatment with the multikinase inhibitor cabozantinib (Cabometyx) induced an intracranial response rate of 61% among 25 patients with renal cell carcinoma (RCC) and uncontrolled brain metastases, according to the results of a retrospective analysis.

The analysis, which was presented during the 2021 Genitourinary Cancers Symposium, showed that the intracranial response rate included a 13% complete response (CR) rate and a 48% partial response (PR) rate. Further, the stable disease (SD) rate was 30% and the progressive disease (PD) rate was 9%.

In a separate group of patients who had controlled brain disease at baseline (n = 44), the intracranial response rate was 57%, comprising all PRs. The SD and PD rates were 31% and 12%, respectively.

“This is the largest cohort of patients with metastatic RCC with concomitant brain metastases treated by cabozantinib,” lead study author Laure Hirsch, MD, of the Department of Medical Oncology, Cochin Hospital, Paris Descartes University, in Paris, France, said in a poster presentation of the data. “Cabozantinib was associated with high intracranial activity with a considerable response rate in patients with uncontrolled intracranial disease.”

The FDA approved cabozantinib in December 2017 as a treatment for previously untreated patients with advanced RCC. Most recently, in January 2021, the FDA approved the combination of nivolumab (Opdivo) plus cabozantinib for the frontline treatment of patients with advanced RCC.

In the multicenter, international analysis, investigators identified 69 patients with metastatic RCC and brain metastases across 15 institutions who were treated with single-agent cabozantinib. The trial was stratified into 2 cohorts: those with progressing intracranial metastases (n = 25) and those with non-progressing/controlled intracranial metastases (n = 44).

Eighty-seven percent of patients were identified as International Metastatic RCC Database Consortium intermediate or poor risk, and 75% had received cabozantinib in the second- or later-line setting. Sixty-five percent of patients in cohort 1 received prior brain-directed therapy, such as radiation therapy or surgery, versus 93% of patients in cohort 2.

At the time of the analysis, 23% of patients remained on treatment; 52% had discontinued due to disease progression, while 9% stopped treatment for toxicity-related reasons.

Intracranial and extracranial responses were assessed by RECIST v1.1 criteria.

Additional data showed that the extracranial response rate in cohorts 1 and 2 were 52% and 41%, respectively. Two patients were unevaluable in each cohort due to lesion sizes being less than 5 mm.

In cohort 1, the median time-to-treatment failure (TTF) was 9.9 months (95% CI, 5.9-14.0) and the median overall survival (OS) was 14.7 months (95% CI, 7.7-23.0). In cohort 2, the median TFF and OS were 9.0 months (95% CI, 4.6-11.4) and 14.1 months (95% CI, 11.0-22.0), respectively.

Investigators also measured the cumulative incidence of brain progression and safety. In cohort 1, 16% (95% CI, 4%-33%) of patients had disease progression in the brain compared with 9% (95% CI, 3%-12%) in cohort 2.

Regarding safety, no unexpected adverse events (AEs) were reported; the most common AEs included fatigue (79%), diarrhea (46%), and nausea (32%). Nine patients (13%) experienced grade 3/4 AEs, but no neurological toxicities were observed. Thirty-eight patients (55%) required dose reductions.

Hirsch noted that central review of imaging and the addition of more patients to this trial is ongoing.

The ongoing, prospective, multicenter, phase 2 CABRAMETtrial (NCT03967522) is evaluating the safety and efficacy of cabozantinib in patients with metastatic RCC who have brain metastases. Additionally, the phase 3 COSMIC 313 trial (NCT03393337219) is looking at the combination of cabozantinib plus nivolumab and ipilimumab (Yervoy) in previously untreated patients with advanced RCC, including those with brain metastases.

1. Hirsch L, Chanza NM, Farah S, et al. Activity and safety of cabozantinib (cabo) in brain metastases (BM) from metastatic renal cell carcinoma (mRCC): An international multicenter study. 

. 2021;39(suppl 6):310. doi:10.1200/JCO.2021.39.6_suppl.310

The multikinase inhibitor showed significant intracranial and extracranial responses in patients with metastatic renal cell carcinoma and brain metastases.

Cabozantinib hits high intracranial response rate in metastatic kidney cancer

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.

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.

Gina Mauro

Articles

OS benefit with frontline avelumab maintenance in urothelial cancer sustained in Japanese subgroup

Cabozantinib hits high intracranial response rate in metastatic kidney cancer

Avelumab frontline maintenance benefit sustained across subgroups in bladder cancer

Nivolumab/cabozantinib combo impresses as frontline kidney cancer treatment