Atezolizumab and Chemotherapy Prolongs Survival in Locally Advanced or Metastatic UC

Enrique Grande, MD

Enrique Grande, MD

Atezolizumab (Tecentriq) as monotherapy or in combination with platinum-based chemotherapy may improve progression-free survival (PFS) in patients with locally advanced or metastatic urothelial carcinoma (mUC), based on theresults from the phase III IMvigor130 trial.

The rationale for this study was testing if synergy exists between immunotherapy and chemotherapy in this patient population, Enrique Grande, MD, explained.

“We are looking for the synergy between chemotherapy with immunotherapy. It is believed that chemotherapy is inducing the release of more neoantigens because of the break of the tumor cells. When more neoantigens are released to the tumor microenvironment, it may enhance the activity of the immune system because of the addition of immunotherapy,” Grande, medical oncologist, MD Anderson Cancer Center — Madrid, toldTargeted Oncology.

The phase II multicenter, randomized, placebo-controlled study enrolled patients with mUC who were platinum-ineligible and randomized them into 3 arms, 1:1:1. Patients either received atezolizumab plus chemotherapy (arm A), atezolizumab alone (arm B), or chemotherapy plus placebo (arm C). Every 9 weeks, tumors were assessed to track potential disease progression. Arms A and C were compared for the coprimary endpoints of PFS and overall survival (OS) by RECIST 1.1 criteria. The investigators also compared the arms for final PFS and interim OS.

At 11.8 months median follow-up, the median PFS in arm A (8.2 months) was nearly 2 months longer than arm C (6.3 months), (HR, 0.82; 95% CI, 0.70-0.96;P = .007). For the OS comparison, arm B (15.7 months) had a better response than arm C (13.1 months) (HR, 1.02; 95% CI, 0.83-1.24). Grande stated that this may be a signal that atezolizumab monotherapy can be used as a first-line treatment in patients with mUC.

IMvigor130 also looked at the safety profile of the atezolizumab/chemotherapy combination. Reportedly, toxicities were consistent with those seen in each of the agents alone.

Overall, it was concluded that the addition of atezolizumab to platinum-based chemotherapy prolonged PFS better than chemotherapy alone.

In an interview withTargeted Oncologyat the 2019 ESMO Congress, where he presented the phase III efficacy and safety results from the IMvigor130 trial, Grande discussed the trial of atezolizumab monotherapy versus atezolizumab plus chemotherapy in patients with mUC in full detail.

TARGETED ONCOLOGY: Can you discuss prognoses for patients with locally advanced or mUC?

Grande: We have been treating patients with mUC since the 1980s with cisplatin-base chemotherapy schemes. In the last 3 or 4 decades, we didn't have any new treatment or combinations that were superior in terms of efficacy to cisplatin, gemcitabine, or the old regimen, MVAC. Both regimens are toxic, but they are the threshold for activity in this field.

We know that patients who are eligible to receive cisplatin have better prognoses than cisplatin-ineligible patients. Patients who are ineligible for cisplatin are receiving less-active treatments, like carboplatin-based chemotherapy.

TARGETED ONCOLOGY:What is the rationale for your study? Does it serve an unmet need?

Grande: We don't have anything other than cisplatin-based chemotherapy or carboplatin-based chemotherapy to offer to our patients. The median expected OS in the first-line treatment of patients with mUC ranges from 9 months for those patients who are ineligible to receive cisplatin, up to 15 months in eligible patients.

In daily practice, most of the patients are not receiving cisplatin-based chemotherapy. It's not because they are ineligible for cisplatin, but because the investigators or the physicians decide that they are not fit enough to receive these toxic regimens. We need to find patients who benefit from less-toxic drugs and improve the value of activity for the chemotherapy that we've all been offering our patients for decades.

TARGETED ONCOLOGY: Can you discuss the trial design?

Grande: The IMvigor130 trial enrolled patients and treated for mUC with a good performance status equal to 0, 1, or 2 who are ineligible to receive any form of platinum-based chemotherapy. There were 3 arms of treatment of patients who were randomized accordingly. The chemotherapy arm was the control arm, and the decision to use cisplatin/gemcitabine or carboplatin/gemcitabine depended on the investigators. Arm B was atezolizumab as a single agent or atezolizumab plus platinum-based chemotherapy, according to the investigators.

We recruited 1213 patients and they were all stratified according to PD-L1 expression, risk factors group, and the investigator's choice of chemotherapy. The 2 co-primary endpoints of the trial were PFS and OS for the combination arm versus the standard chemotherapy arm, and the OS of the monotherapy arm versus the chemotherapy arm in those patients with overexpression of PD-L1.

TARGETED ONCOLOGY:What was the rationale for exploring atezolizumab specifically?

Grande: We know that urothelial carcinoma has a higher mutational tumor grade. The more mutations the tumor has, the more tumor antigens they release, and the better the simulation will be with these novel checkpoint inhibitors.

We are looking for the synergy between chemotherapy and immunotherapy. It is believed that chemotherapy is inducing the release of more neoantigens because of the break of the tumor cells. When more neoantigens are released to the tumor microenvironment, it may enhance the activity of the immune system because of the addition of immunotherapy. We think that both strategies can be synergistic.

TARGETED ONCOLOGY: What were the results of the study?

Grande: The primary endpoint for the IMvigor130 trial was PFS. We can say that IMvigor130 is a positive trial for the primary endpoint. The combination arm of atezolizumab plus chemotherapy was inducing a longer PFS than with chemotherapy alone. The hazard ratio for this improvement was 0.82, and it improved the median PFS from 6.3 months to 8.2 months with the combination arm. It's a statistically and clinically significant improvement for the combination arm.

TARGETED ONCOLOGY:Were there any subgroups that seemed to derive the most benefit?

Grande: When we analyzed the benefit of the different subgroups of patients, we observed that patients overexpressing PD-L1, patients with a better prognostic factor, patients with a better ECOG performance status, and patients who receive cisplatin, seemed to benefit more than the others. But we need to be careful with extrapolating these data because this is a sub-analysis, and the trial was not set up to prospectively assess this subgroup of patients. This is just hypothesis-generating.

TARGETED ONCOLOGY:Were there any notable toxicities?

Grande: No new toxicities were observed. The toxicities we found in the IMvigor130 trial were consistent with the toxicities of the individual agents. When we added atezolizumab to the chemotherapy arm, we didn't observe more toxicities than in the chemotherapy arm. In fact, the withdrawal rate because of adverse events was exactly the same in the combination arm as in the chemotherapy arm, 34%. In the arm of atezolizumab as a single agent, the withdrawal rate was only 6%. It seems that because of the quality of life and the toxicity profile, some patients may benefit more from atezolizumab monotherapy than the combination therapy or chemotherapy treatment.

TARGETED ONCOLOGY:How do you see these results impacting community practice?

Grande: I think the combination of atezolizumab, and chemotherapy will be added as a new treatment option in patients with untreated mUC. We have an exciting debate now for trying to select the best patients to receive this combination. In addition to that, the IMvigor130 trial supports the use of atezolizumab as a single-agent in the first line, in patients ineligible to relieve cisplatin, and maybe also be regardless of whether they are eligible for cisplatin or not and instead based on the PD-L1 expression. Maybe can discuss in patients with high PD-L1 expression the use of atezolizumab as a single agent rather than chemotherapy.

TARGETED ONCOLOGY:What are the next steps with this research?

Grande: The use of atezolizumab with chemotherapy is another step in the development of metastatic urothelial tumors. We need to know the role of atezolizumab as a single agent in the adjuvant setting after the cystectomy. We need to know the role of atezolizumab as a single agent with or without combination with chemotherapy in the neoadjuvant setting. We also need to know if atezolizumab as a single agent has a role in the earlier stage, in patients with no muscle-invasive bladder cancer so that we can try to prevent cystectomies in these patients.