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Roche Registration GmbH has withdrawn its application to extend the use of atezolizumab to the treatment of patients with early or locally advanced triple-negative breast cancer in Europe.
Roche Registration GmbH has withdrawn its application to extend the use of atezolizumab (Tecentriq) to the treatment of patients with early or locally advanced triple-negative breast cancer (TNBC) in Europe, according to a press release issued by ESMO.1
The application to extend the use of atezolizumab was supported by findings from the ongoing phase 3 IMpassion031 study (NCT03197935) of 333 patients who received either the immunotherapy or placebo in combination with nab-paclitaxel and anthracycline-based chemotherapy prior to undergoing surgery. The main efficacy measure was how many participants no longer had tumors in their breasts or lymph nodes following surgery.
Of the 333 patients, 165 were randomized to atezolizumab plus chemotherapy and 168 were randomized to placebo plus chemotherapy. The median follow-up in the investigative arm was 20.6 months (range, 8.7-24.9), and it was 19.8 months (range, 8.1-24.5) in the control arm.
Results indicated that 58% (95% CI, 50%-65%) of patients experienced a pathologic complete response (pCR) with the atezolizumab regimen vs 41% (95% CI, 34%-49%) of those who received chemotherapy alone (95% CI, 6%-27%; one-sided P = .0044).2 In the subset of patients who had PD-L1 positivity, the pCRs were 69% (95% CI, 57%-79%) and 49% (95% CI, 38%-61%) in the investigative (n = 53/77) and control (n = 37/75) arms, respectively (95% CI, 4%-35%; one-sided P = .021).
The company withdrew the application on June 23, 2021, and the European Medicines Agency (EMA) was informed on July 23, 2021. The decision to withdraw followed an evaluation done by the EMA in which the agency prepared questions for the company. After reviewing the company’s responses to the questions, unresolved issues remained.
As such, the provisional opinion of the EMA was that the use of atezolizumab could not be extended. The agency noted that the activity of the agent in the main study was not sufficient to establish that the agent was effective enough when given with other options prior to surgery for patients with TNBC. As such, at the time of the withdrawal, the EMA concluded that the benefits of atezolizumab did not outweigh the risks for this population.
“This withdrawal is based on the reason that the Committee for Medicinal Products for Human Use considers that the IMpassion031 study data provided do not allow the committee to conclude on a positive benefit-risk balance for the use of [atezolizumab] in the proposed indication,” Roche Registration GmbH stated in the letter to the EMA.3 “The withdrawal does not have any impact on ongoing clinical trials with atezolizumab as monotherapy or in combination with other agents.”
The monoclonal antibody has been authorized for use in the European Union since September 2017. In August 2019, atezolizumab was approved for use in combination with nab-paclitaxel (Abraxane) in the treatment of adult patients with unresectable locally advanced or metastatic TNBC whose tumors have PD-L1 expression of 1% or higher, and who have not previously received chemotherapy for metastatic disease.4
The regulatory decision was supported by data from the phase 3 IMpassion130 study (NCT02425891), which showed that the combination resulted in a 38% reduction in the risk of disease worsening or death vs nab-paclitaxel alone. The median progression-free survival in the investigative and control arms was 7.5 months vs 5.0 months, respectively (HR, 0.62; 95% CI, 0.49-0.78; P < .0001), in patients who had PD-L1 positivity.
Results from the second interim analyses indicated that the doublet also resulted in a clinically meaningful improvement in overall survival (OS) over chemotherapy alone, at 25.0 months vs 18.0 months, respectively (HR, 0.71; 95% CI, 0.54-0.93). OS data in the subgroup of patients with PD-L1–positive disease had not formally been evaluated because the hierarchical design of the study as statistical significance was not met for OS in the intention-to-treat (ITT) population. The median OS in the ITT population was 21.0 months with atezolizumab plus nab-paclitaxel vs 18.7 months with nab-paclitaxel alone (HR, 0.86; 95% CI, 0.71-1.02; P = .078).
In March 2019, the FDA approved the combination for adult patients with unresectable locally advanced or metastatic TNBC whose tumors express PD-L1.5 April 2021, the FDA’s Oncologic Drugs Advisory Committee voted 7 to 2 in support of maintaining the indication of atezolizumab plus nab-paclitaxel for use in adult patients with unresectable locally advanced or metastatic TNBC whose tumors are PD-L1 positive.6
Susan Halabi, PhD, and Matthew Ellis, MD, PhD, voted against the continued approval of the combination. In explaining her decision, Halabi stated, “This is a difficult decision for me. I was almost on the fence. I voted no, the main reason is while I do appreciate there is a huge unmet need, my concern is the choice of end points. It seems to me that while PFS may be confirmed in another trial, I am not totally convinced that this will translate into a meaningful benefit for the patient.”