Avelumab in combination with best supportive care as frontline maintenance in patients with advanced or metastatic urothelial carcinoma who had not progressed on first-line platinum-based chemotherapy led to improvements in both progression-free and overall survival.
The use of avelumab (Bavencio) in combination with best supportive care (BSC) as frontline maintenance in patients with advanced or metastatic urothelial carcinoma who had not progressed on first-line platinum-based chemotherapy led to improvements in both progression-free and overall survival (OS), according to findings from an analysis of the phase 3 JAVELIN Bladder 100 study, which were presented during the 2020 ESMO Congress.1
Moreover, the progression-free survival (PFS) and OS benefit were significantly longer with avelumab/BSC versus BSC alone, regardless of the type of induction chemotherapy regimen that was administered, and irrespective of the level of response to frontline chemotherapy.
“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.
In June 2020, the FDA approved avelumab as a maintenance treatment for patients with locally advanced or metastatic urothelial carcinoma that has not progressed with first-line platinum-based chemotherapy,2 based on the overall findings from the JAVELIN Bladder 100 study that were presented during the 2020 ASCO Virtual Scientific Program.3 Here, data showed a 7.1-month improvement in median OS with avelumab as frontline maintenance treatment plus BSC versus BSC alone.3
Overall, the median OS was 21.4 months with avelumab (95% CI, 18.9-26.1) versus 14.3 months with BSC alone (95% CI, 12.9-17.9), which led to a 31% reduction in the risk of death in the overall patient population (HR, 0.69; 95% CI, 0.56-0.86; 2-sided P = .001).
“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.
In the multicenter, international, open-label, parallel-arm, randomized phase 3 JAVELIN Bladder 100 trial, investigators explored frontline avelumab maintenance therapy in combination with BSC (n = 350) compared with BSC alone (n = 350) in a total of 700 participants with unresectable locally advanced or metastatic urothelial cancer whose disease did not progress on 4 to 6 cycles of standard gemcitabine paired with either cisplatin or carboplatin.
Patients enrolled on the trial had experienced a complete response (CR), a partial response (PR), or stable disease (SD) with chemotherapy. Treatment was given between 4 to 10 weeks post induction chemotherapy. Fifty-one percent of patients had PD-L1–positive tumors.
Avelumab was administered at 10 mg/kg intravenously every 2 weeks in 4-week treatment cycles. 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 co-primary end points of the trial were OS in all randomized patients as well as in those with PD-L1–positive tumors. Secondary endpoints of the trial were comprised of PFS, antitumor activity, safety, pharmacokinetics, immunogenicity, predictive biomarkers, and patient-reported outcomes in the co-primary patient populations.
Subgroup baseline characteristics 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%).
Notably, 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.
The median follow-up was 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; 95% CI, 0.52-0.75; P <.001). Additionally, the HR for PFS favored avelumab in the PD-L1–positive subgroup, as well (HR, 0.56; 95% CI, 0.43-0.73).
Additional results 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; 95% CI, 0.40-0.79; P = .0003).
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 (95% CI, 3.6-6.8) versus 2.0 months (95% CI, 1.9-3.6) for chemotherapy alone (HR, 0.63; 95% CI, 0.50-0.81). The median OS was 25.3 months (95% CI, 18.6–not estimable [NE]) with avelumab versus 16.5 months (95% CI, 0.51-0.94) without (HR, 0.69; 95% CI, 0.51-0.94).
For patients who received frontline chemotherapy with gemcitabine/carboplatin plus avelumab, the median PFS was 3.0 months (95% CI, 2.0-3.7) versus 1.9 months (95% CI, 1.9-2.0) for chemotherapy alone (HR, 0.59; 95% CI, 0.44-0.80). The median OS was 19.9 months (95% CI, 16.0-24.0) and 12.9 months (95% CI, 9.4-16.2), respectively (HR, 0.66; 95% CI, 0.47-0.91).
“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.
Moreover, the survival benefits with frontline maintenance avelumab plus BSC were observed irrespective of best response to induction chemotherapy. For patients who achieved a CR (n = 179), the median PFS was 7.4 months (95% CI, 4.3-16.5) and 3.8 months (95% CI, 2.1-5.6) for avelumab/BSC and BSC alone, respectively (HR, 0.65; 95% CI, 0.45-0.96). The median OS was not estimable in either arm (HR, 0.81; 95% CI, 0.47-1.38).
In those who achieved a PR (n = 326), the median PFS in the avelumab arm was 3.1 months (95% CI, 2.0-3.7) and 1.9 months (95% CI, 1.9-1.9) with BSC alone (HR, 0.58; 95% CI, 0.44-0.75). The median OS was 19.2 months (95% CI, 15.4-24.7) and 12.1 months (95% CI, 10.1-14.3), respectively (HR, 0.62; 95% CI, 0.46-0.83).
Finally, for patients who achieved SD (n = 195), the median PFS was 3.7 months (95% CI, 2.0-7.4) and 2.1 months (95% CI, 1.9-3.6) in the avelumab and BSC-alone arms, respectively (HR, 0.61; 95% CI, 0.42-0.87). The median OS was 19.9 months (95% CI, 18.2–NE) for avelumab-treated patients and 14.0 months (95% CI, 10.7-19.4) for those just receiving BSC (HR, 0.70; 95% CI, 0.46-1.05).
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.
A modest survival benefit was observed in patients with liver lesions at baseline (HR, 0.92), but was greater in those without (HR, 0.65).
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).