Roche: OAK Data Differentiates Tecentriq In Second-Line Lung Cancer

ESMO data suggest that patients with no expression of PD-L1 who took Tecentriq were able to generate an immune response, a result Genentech believes reflects the particular mechanism of action compared to PD-1 inhibitors like Opdivo and Keytruda.

With additional data from the Phase III OAK trial in hand, Roche has high hopes that the evidence that its PD-L1 inhibitor Tecentriq appears to generate new immunity in patients with no PD-L1 expression will help differentiate the product in the competitive programmed death checkpoint inhibitor space.

The company presented OAK data for Tecentriq (atezolizumab) in second-line NSCLC at the European Society of Medical Oncology annual meeting in Copenhagen on Oct. 9, following an earlier top-line release. (Also see "Roche Raises IO Credentials On Tecentriq Lung Cancer Data" - Scrip, 1 Sep, 2016.)

Roche is bullish about prospects for approval soon for a broad population in the US: Tecentriq has breakthrough therapy status in NSCLC and the filing for a second-line indication has priority review and an Oct. 19 user fee date. The drug is currently approved in bladder cancer.

Genentech Inc.’s Dan Chen, global head of cancer immunotherapy, believes the OAK data highlights advantages for the drug, possibly due to the difference in mechanism of action.

As the third programmed death inhibitor to market, but the first to bind to PD-L1, Roche has attempted to play up the difference between PD-1 and PD-L1 agents – releasing an explanatory video on its website (see video).

However, to date there has been little evidence of differentiation.

Tecentriq binds to PD-L1 expressed on tumor cells and tumor infiltrating immune cells, blocking its interactions with both PD-1 and B7.1 receptors. It does not block the PD-L2 ligand.

Open Media

Source: Genentech/Roche

In contrast, PD-1 inhibitors like Merck & Co. Inc.’s Keytruda (pembrolizumab) and Bristol-Myers Squibb Co.’s Opdivo (nivolumab) inhibit PD-1 signaling by blocking the PD-L1 and PD-L2 ligands.

Lung cancer is the biggest market for the checkpoint inhibitors and it has been highly competitive. Keytruda and Opdivo are both approved for second-line lung cancer, but Opdivo’s label covers treatment of patients with all levels of PD-L1 expression whereas Keytruda is approved for those with over 50% expression. Keytruda is also under review for second-line NSCLC with more than 1% expression, which would broaden use in that line of therapy, and for first-line NSCLC in tumors with over 50% expression.

Roche is facing a challenging launch, and demonstrating a difference for the PD-L1 mechanism would be a help. But Biomedtracker analyst Robert Jeng thinks it will be a difficult sell. "Atezolizumab looked pretty similar to nivolumab in the second line setting in OAK," he reported from the conference. The one area he did see Tecentriq could have a clear entry in the second-line market were in patients who were never smokers, "where atezolizumab might have slightly higher activity than average. Otherwise, I think nivolumab's lead time to market might be hard to overcome."

Trial Details

The OAK study tested Tecentriq versus docetaxel chemotherapy in 1,225 patients with all levels of PD-L1 expression and squamous as well as non-squamous disease; efficacy was measured for the first 850 patients enrolled. Tecentriq was given at a flat dose of 1,200 mg every three weeks, which is a “nice convenience factor,” Chen commented in an interview.

Tecentriq succeeded on two co-primary endpoints – overall survival in all randomized patients and in a PD-L1 selected population.

For the overall population, median overall survival was 13.8 months compared to 9.6 months. The 13.8 months is “unprecedented in this disease indication,” Chen said.

Median survival rates at 12 and 18 months – 55% and 40%, respectively – were also unprecedented in this indication, he added.

Chen acknowledged that the hazard ratio of 0.73 was similar to what has been seen in studies of other drugs. But he also points out that unlike studies of PD-1 inhibitors, there was significant crossover from the control arm to cancer immunotherapy – at least 17% – so median survival in the control arm was higher than usual.

Chen believes that the results for those with no expression of PD-L1 are highly noteworthy. In this subset, the median survival was 12.6 months for Tecentriq vs. 8.9 months for the control arm, a result with a hazard ratio of 0.75 (see table).

Evidence Of New Immune Response

Even though patients had no pre-existing anticancer immunity they had almost the same survival benefit and “that has not been seen in this field before,” Chen said.

The survival curves separated after two months in this subgroup, which is the time it would take to generate a new immune response.

“That’s a pretty important piece of new information as we think about this field. And given that it hasn’t been seen in other studies, one possibility is that Tecentriq is able to induce this because it inhibits interaction between PD-1 and B7.1,” Chen said.

Chen also highlighted results for those with the highest level of PD-L1 expression; median survival was 20.5 months for the Tecentriq patients versus 8.9 months for control, with a hazard ratio of 0.41 (p value of <0.0001). The curves were just as impressive as the numbers for this result, he said.

Median survival and the hazard ratio are “better than we have ever seen in a PD-L1 selected population,” in the second or third line space the exec said.

“That’s a pretty strong overall package for us to have our interactions with FDA around,” Chen said.

OAK: Overall Survival Results
Study group	ITT first 850 randomized patients		TC1/2/3 or IC1/2/3 (PD-L1 expression on ≥ 1% tumor cells or immune cells)		TC0 or IC0 (PD-L1 expression on <1% tumor cells and immune cells)
Treatment arm	Tecentriq	Docetaxel	Tecentriq	Docetaxel	Tecentriq	Docetaxel
Number	425	425	241	222	180	199
Median OS	13.8 months	9.6 months	15.7 months	10.3 months	12.6 months	8.9 months
Hazard ratio	HR 0.73 (95% CI: 0.62-0.87; p = 0.0003)		HR 0.74 (95% CI: 0.58 - 0.93; p=0.0102)		HR 0.75 (95% CI 0.59 to 0.96; p=0.0205)
Source: Roche

As with the PD-1 immunotherapies, Tecentriq had a much better side effect profile compared to chemotherapy. The rate of Grade 3-4 treatment related adverse events was 15% vs. 43% for docetaxel. No treatment-related deaths were associated with the test drug whereas there was one for docetaxel.

The most common side effects in the test drug arm were musculoskeletal pain (11% vs. 4%) and pruritis (8% vs. 3%).

The company was particularly interested in looking at autoimmune toxicities and found the data very reassuring. The rate of pneumonitis, a side effect of particular concern in lung cancer, at any grade was only 1% and the Grade 3-4 rate was 0.7%. The rates of colitis and hepatitis at any grade was 0.3%.

“It was nice to see that in our largest experience in lung cancer with Tecentriq that you weren’t seeing a lot of severe autoimmune toxicity,” Chen said.

Overall the safety looked very good and Tecentriq data compares very favorably, he said.

The OAK data suggest it’s possible to generate durable survival while preserving a clean safety profile, particularly as it relates to generation of autoimmunity, which is important not just for Tecentriq as a monotherapy but as the company builds the entire franchise, Chen said.

“You want to synergize anticancer immunity you don’t want to synergize toxicity,” Chen said.