Atezolizumab: Another Immunotherapy Active in Lung Cancer

Zosia Chustecka

September 27, 2015

UPDATED September 27, 2015 // VIENNA ― Another immunotherapy is showing promise in the treatment of lung cancer. Positive results with atezolizumab (previously known as MPDL3280A, under development by Genentech) were reported from two phase 2 studies in patients with advanced non–small cell lung cancer (NSCLC).

One immunotherapy, nivolumab (Opdivo, Bristol-Myers Squibb), is already approved for use in NSCLC and has shown "unprecedented" survival compared with chemotherapy in two large phase 3 clinical trials. Several large trials with other immunotherapies are under way, so the race is on for which one will reach the market next.

Atezolizumab is an inhibitor of cell programmed death ligand 1 (PDL1) and is in several phase 3 trials in a number of tumor types. It has received breakthrough designation from the US Food and Drug Administration for use in the treatment of NSCLC in patients whose tumors have high expression of PDL1 and whose disease worsened during or after standard treatments.

The new data were reported here at European Cancer Congress (ECC) 2015.

One of the studies (POPLAR) was a randomized trial with docetaxel (multiple brands) as the control arm and showed that atezolizumab significantly improved overall survival (OS). In the overall patient population (n = 287), median OS was 12.6 months with atezolizumab vs 9.7 months with docetaxel (hazard ratio [HR], 0.73; P =.040).

But patients who had high expression of PDL1 showed even better results. In a subgroup of patients with tumors that had high or medium-to-high PDL1 expression, the median OS with atezolizumab was 15 months. However, in patients with little or no expression of PDL1, there was no difference between atezolizumab and docetaxel (median OS, 9.7 in both groups).

Treatment-related adverse events (grade 3 or 4) were reported by 11% of patients receiving atezolizumab and 39% receiving docetaxel.

The other study (known as BIRCH) was a single-arm study in which atezolizumab (1200 mg IV every 3 weeks) was used as first-line therapy in 667 patients with PDL1-positive advanced NSCLC. To find patients for this trial, more than 30,000 were screened; about 34% were found to test positive, said lead author Benjamin Besse, MD, from the Gustave Roussy Institute, Villejuif, France.

PDL1 expression was assessed for both tumor cells and immune cells using an investigational immunohistochemistry test being developed by Roche Diagnostics.

These patients were divided into three cohorts on the basis of how many previous therapies they had received: cohort 1 had no prior therapy, cohort 2 had received one prior chemotherapy, and cohort 3 had received at least two prior therapies.

The primary end point was overall response rate (ORR), which was 26%, 24%, and 27%, respectively, for the three cohorts for patients who had high expression of PDL1, and 19%, 17%, and 17% for patients who had medium to high expression of PDL1.

At 6 months, the OS rate was 79%, 80%, and 75%, respectively. These OS data are not mature, commented Dr Besse, but they are in line with what was seen from the POPLAR study, he said.

"Higher PDL1 expression correlates with greater response rates and could be used to identify patient for treatment," Dr Besse concluded.

Discussant for the papers, Luis Paz-Ares MD, PhD, from the Hospital Universitario Virgen Del Roccio, in Seville, Spain, said these data from BIRCH are interesting and have not been seen before, but he questioned the value of having an open-label trial in nearly 700 patients. This may be important for the registration process for the new drugs, but it does not inform clinical development of the field as a whole, he said.

The results from POPLAR with atezolizumab are in line with what has been reported for nivolumab in the CheckMate 057 trial, which showed median OS of 12.2 months for nivolumab vs 9.4 months for docetaxel (HR, 0.73; P = .0015).

"These are different agents from the same class but very similar data," he said.

In addition, the data on nivolumab also show better responses in patients with high expression of PDL1 and no benefit in patients who are PDL1-negative, although different assays were used. This is showing a pattern, he suggested, and the data are similar.

He wondered, however, how practical it would be in the clinic to use the new assay that measured PDL1 expression in both tumor and immune cells.

In closing, Dr Luis Paz-Ares noted that there are now several phase 3 trials ongoing, all pitching an immunotherapy (atezolizumab, pembrolizumab [Keytruda, Merck Sharp & Dohme Corp], and durvalumab [under development by MedImmune]) against chemotherapy with docetaxel, and these results are eagerly awaited.

Will Change Treatment

Discussing the new results in a commentary prepared by the European Society for Medical Oncology (ESMO), Martin Reck, MD, chief oncology physician in the Department of Thoracic Oncology, Hospital Grosshansdorf, Germany, noted that atezolizumab is the second checkpoint inhibitor to show superior efficacy and better tolerability compared with standard second-line chemotherapy in patients with pretreated NSCLC.

Along with the other drugs in this class, this immunotherapy approach "is set to substantially change treatment strategies for patients with refractory lung cancer," he said. "In particular, the option for long-lasting responses and stabilization in combination with an attractive tolerability profile will impact clinical practice," he added.

"In the BIRCH trial, the PDL1 antibody atezolizumab showed a remarkable activity in a large number of patients regardless of the line of treatment," Dr Reck commented. "The profile of adverse events is in line with reported data from other PD1/PDL1 checkpoint inhibitors, and overall tolerability looks quite favorable. The efficacy, as shown by the response rate, was in correlation with PDL1 expression on tumor and immune cells, favoring tumors with high PDL1 expression.

"In confirmation, the randomized POPLAR trial reported a superior overall survival for unselected patients who received atezolizumab as second-line treatment compared to docetaxel," Dr Reck said, and noted that here, too, efficacy could be correlated to the PDL1 expression status.

However, he added that these data "have to be validated by a large, randomized, phase 3 trial, which is ongoing.

"Whether patients should be selected using a biomarker strategy still needs to be determined and remains a significant challenge, based on the multiple different companion diagnostics that are in use," he also cautioned.

Both studies were funded by Genentech.

European Cancer Congress (ECC) 2015: Abstracts LBA14 and LBA16. Presented September 27, 2015.

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