Avelumab Considered a Gold Standard for Advanced Urothelial Carcinoma After 1L Chemotherapy

Avelumab (Bavencio) is considered a new standard-of-care treatment for patients with advanced urothelial carcinoma (UC) who have not progressed on frontline platinum-containing chemotherapy after the agent demonstrated overall survival (OS) improvement for this patient population in a phase 3 clinical trial setting.

“Avelumab maintenance regimen can be easily incorporated into standard clinical practice for a wide range of patients with this challenging disease,” wrote the authors of a report published in Cancer Treatment Reviews; the first author was Petros Grivas, MD, PhD.

The exploration of avelumab maintenance was brought on by the limited efficacy agents could achieve after patients with UC progress on frontline treatment.

Outcomes Before Avelumab

Research has shown that first-line chemotherapy can elicit objective responses or lead to stable disease in 65% to 75% of patients. However, these responses are not durable with a median progression-free survival (PFS) of about 6 to 8 months and median OS of approximately 9 to 14 months. There has also been activity shown with the use of immune checkpoint inhibitors (ICIs) like pembrolizumab (Keytruda) and atezolizumab (Tecentriq), both as a monotherapy and as a combination with chemotherapy as salvage therapy after progression on frontline therapy.

According to data from clinical trials like KEYNOTE-052 (NCT02335424) and IMvigor210 (NCT02108652), pembrolizumab can achieve a median OS of 11.3 months, and atezolizumab can achieve a median OS of 15.9 months. Later studies, including IMvigor130 (NCT02807636) and KEYNOTE-361 (NCT02853305), showed that unlike ICI monotherapy, combinations of ICI and chemotherapy provided no significant improvement in OS compared with chemotherapy alone.

The promise of agents available for the treatment of patients with UC does not carry over into later-line settings, which is very problematic because advanced UC comes with a higher symptom burden and other impactful characteristics, especially for patients treated with frontline chemotherapy. A strategy often utilized following frontline chemotherapy is switch maintenance, which has been shown to help bring combination immunotherapy into the frontline setting instead of the second-line setting. The antitumor activity achieved in patients with UC on chemotherapy paved the way for maintenance therapies in the frontline setting.

In a prior interview with Targeted Oncology, Grivas shared the rationale for maintenance avelumab use in frontline UC, saying; “The question has been, can we maintain or sustain the benefit that we see in many patients with the front-line chemotherapy, the induction chemotherapy, in terms of response or stable disease? Since we cannot give chemotherapy forever because of potential AEs, can we sustain or maintain this benefit with immunotherapy in this switch maintenance approach?”

Avelumab as Frontline Maintenance in UC

The frontline avelumab maintenance strategy was investigated in patients with UC by way of the phase 3 JAVELIN Bladder 100 study (NCT02603432), an international, randomized study. The study enrolled 700 patients UC who had no progression after 4 to 6 cycles of platinum-based chemotherapy in the frontline setting. Patients were randomized 1:1 to either avelumab 10 mg/kg given by intravenous fusion every 2 weeks in combination with best supportive care (BSC) compared with BSC alone. Each arm included 350 patients. Stratification factors in the study included the best response to chemotherapy and the site of metastasis at the start of frontline chemotherapy.

The primary end point of the study was OS in all patients randomized in the study, as well as in patients with PD-L1 expression in their tumors.

JAVELIN Bladder 100 revealed a significant improvement in OS when avelumab maintenance was brought into the frontline setting of UC. In all randomized patients, the median OS was 21.4 months compared with 14.3 months with best supportive care (BSC) alone (hazard ratio [HR], 0.69; 95% CI, 0.56-0.86; P = .001), achieving a 31% reduction in the risk of death. In the PD-L1–positive population, the median OS was not reached in patients who received avelumab compared with 17.1 months in the BSC arm (HR, 0.56; 95% CI, 0.40-0.79; P < .001). The benefit of avelumab was also observed across the subgroup populations of the study.

Subgroup populations in the study included various frontline chemotherapy combinations, those who had a best response to frontline chemotherapy, patients with varying sites of metastasis, and those with PD-L1 expression in their tumors. One hundred eighty three patients who received avelumab in the study previously received gemcitabine plus cisplatin versus 206 patients who received BSC in the study, the OS HR for these patients was 0.69 (95% CI, 0.51-0.94). One hundred forty seven patients in the avelumab arm compared with 122 in the BSC arm received prior gemcitabine plus carboplatin, and the HR for OS was 0.66 (95% CI, 0.47-0.91). Finally, 20 patients in the avelumab combination arm versus 20 in the control arm received prior treatment with gemcitabine plus cisplatin and carboplatin, and OS favored the avelumab arm (HR, 0.75; 95% CI, 0.25-2.25).

Among patients who achieved a best response to first-line chemotherapy, 253 in the experimental arm and 252 in the control arm achieved a complete or partial response to prior treatment with an OS result favoring avelumab (HR, 0.69; 95% CI, 0.53-0.89). In addition, 97 patients treated with avelumab in the study versus 98 in the BSC arm had stable disease as their best response, and this result also favored the avelumab arm (HR, 0.70; 95% CI, 0.46-1.05).

In terms of metastatic site, 191 patients in each arm had visceral metastases (HR, 0.82; 95% CI, 0.62-1.09). Nonvisceral metastases were found in 159 patients in each arm and a significant improvement was observed with avelumab (HR, 0.54; 95% CI, 0.38-0.76).

Moreover, avelumab showed significant benefit for patients with positive PD-L1 status (HR, 0.56; 95% CI, 0.40-0.78), but was not significant for those with no PD-L1 expression (HR, 0.86; 95% CI, 0.62-1.18).

Regarding the study findings, Grivas et al wrote; “Improved OS has not been reported to date with [first-line] ICI monotherapy or combination approaches. Thus, the total OS benefit seen with the JAVELIN Bladder 100 approach represents a major advance in this patient group.”

Future Study of Avelumab as Frontline Maintenance

Ongoing questions around the use of avelumab in the frontline maintenance setting for patients with UC include whether cisplatin-ineligible patients can receive ICI, as well as those who received chemotherapy for an extended period of time, had a response to chemotherapy, were older, had renal impairment, had a Bajorin risk of 0 to 2, as well as those from other biomarker subgroups.

In the JAVELIN Bladder 100 study, based on guidelines, patients with an ECOG performance status of 2 or greater, a creatinine clearance < 30 mL/min, congestive heart failure or another major cardiac comorbidity, or persisting grade ≥ 3 sensory neuropathy were excluded to account for the unknown impact of the agent on the cisplatin-ineligible population. Information about frontline avelumab maintenance in this subgroup may come from real-world studies.

Moreover, a patient’s response to prior chemotherapy is an important biomarker for response to any therapy. It is suggested by Grivas et al that these patients be followed for a longer period of time to assess the duration of response.

The review of these phase 3 data overall brought on advice for how to consider patients with UC for frontline avelumab maintenance. In short, age, renal impairment, and Bajorin risk should not impact an oncologist’s decision to use this treatment strategy, according to Grivas et al. However, the administration recommendation should be followed to maintain the benefit and limited the toxicities of the agent.

“Irrespective of these questions, level 1 evidence supports the use of avelumab as a standard of care for 1L maintenance treatment of advanced UC that has not progressed with platinum-containing chemotherapy,” wrote Grivas et al.

_Reference:

_{Grivas P, Agarwal N, Pal S, et al. Avelumab first-line maintenance in locally advanced or metastatic urothelial carcinoma: Applying clinical trial findings to clinical practice.
Cancer Treat Rev. 2021;22(97):102187. doi:10.1016/j.ctrv.2021.102187}