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Genentech's PD-L1 agent approved for bladder cancer
 
 
  Nature Biotechnology 09 August 2016
 
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The US Food and Drug Administration (FDA)'s approval in May of Genentech's Tecentriq (atezolizumab) is the first for a cancer immunotherapy targeting programmed cell death-ligand 1 (PD-L1). It also marks the first new drug introduced in decades to treat advanced bladder cancer, which has been largely incurable and with few treatment options. The regulator's nod gives the S. San Francisco, California, unit of Basel-based Roche an anchor for competing with the two PD-1 drugs approved in the US in the last two years: Bristol-Myers Squibb's Opdivo (nivolumab) and Merck's Keytruda (pembrolizumab). All three companies are battling to establish their drugs in multiple cancer treatment indications, with PD-L1 entrants from AstraZeneca (durvalumab) and a collaboration between Pfizer and Merck KGaA (avelumab) looming large in bladder cancer (Table 1). All of these antibodies interfere with the PD-1/PD-L1 pathway (checkpoint blockade), which potentiates the activation of T cells to attack cancer cells.
 
The approval is a landmark event in immuno-oncology, says Rachel Laing of Bionest Partners in New York. "That Tecentriq works in bladder cancer is further evidence of the ability of PD-1/PD-L1drugs to move into promising new indications." Urothelial carcinoma is the most common type of bladder cancer. According to National Cancer Institute estimates, there will be more than 76,000 new cases of bladder cancer and 16,000 deaths from the disease in the US in 2016. Tecentriq is approved for the treatment of some patients with locally advanced or metastatic urothelial carcinoma during or after platinum-containing chemotherapy (such as Platinol (cisplatin)).
 
Jean Hoffman-Censits, a bladder cancer specialist at Thomas Jefferson University in Philadelphia, says that rarely, if ever, does treatment after platinum chemotherapy failure help patients achieve durable disease control or significantly improve their quality of life. The Tecentriq clinical data show that such gains are now possible. "It is essentially a brand new way of looking at these patients and the medical practice," she says.
 
Bladder cancer patients share many characteristics with the lung cancer population-predominantly male, current or former smokers, often with other medical problems including diabetes, peripheral neuropathy and heart disease. "Off the bat they can be medically frail, often with ongoing indwelling catheters or external catheters, which run the risk of infection," Hoffman-Censits says.
 
Bladder cancer is also an incredibly heterogeneous disease, adds Jonathan Rosenberg of Memorial Sloan-Kettering Cancer Center in New York. Although research had identified bladder cancer patients with abnormalities in expression of HER2, epidermal growth factor receptor, fibroblast growth factor receptor (FGFR) or PI3 kinase, the indication has not been a promising choice for the development of targeted therapies like kinase inhibitors, in part because of the small number of patients in each subgroup. "Until the last five years or so, most of the clinical trials were either unselected or poorly selected to enrich for possible response to targeted therapies," he says. "That's a fundamental underlying problem that we are starting to shake in this disease."
 
Drug companies' lack of interest is also partly to blame for the poor or nonexistent progress. "There has been the perception that these are old and sick patients who cannot tolerate treatments," says Rosenberg.
 
Having Tecentriq make it to the finish line is a game-changer for all of these reasons. "In general, when activity is seen with one agent, there is almost always a stampede of other agents into the same field where you see a potential pathway to approval," Rosenberg says.
 
Genentech chose to move Tecentriq rapidly into late-stage studies in bladder cancer following successful proof-of-concept studies in melanoma and lung cancer as well as bladder cancer. Owing to the unmet medical need, "seeking approval in bladder cancer was immediately perceived as an opportunity, even based on the small fragment of patient data from a phase 1 trial," says Ira Mellman, Genentech vice president of cancer immunotherapy. Tecentriq forged ahead with a breakthrough therapy designation and a priority review from the FDA. On May 18 the PD-L1 inhibitor received accelerated approval based primarily on results of a single-arm phase 2 clinical trial, IMVigor 210. The goal of the trial, which involved 310 patients with locally advanced or metastatic urothelial carcinoma, was to measure the percentage of patients who experienced complete or partial tumor shrinkage. The study also looked at the difference in effect based on positive versus negative expression of the PD-L1 protein on participants' tumor-infiltrating immune cells. As part of the trial design, Genentech screened for patients who expressed PD-L1 prior to therapy. Just under 15% of all evaluable trial participants experienced at least a partial reduction of their tumors, lasting from more than 2.1 to more than 13.8 months at the time of analysis. Those participants with PD-L1-positive expression-26%-experienced tumor shrinkage, compared with 9.5% of participants who were classified as negative for PD-L1 expression. In a 59-patient subgroup whose disease progressed after platinum-containing therapy and surgery, 22% saw their tumors shrink. Participants' overall survival also increased. "Patients whose tumors were not shrinking and didn't give you a partial or complete response nevertheless were living significantly longer and actually showing durable benefit from the drug," Mellman says.
 
The greater response seen in patients with PD-L1 protein expression in tumor-infiltrating immune cells-macrophages, dendritic cells and lymphocytes-led the FDA to simultaneously approve an immunohistochemistry (IHC) assay to detect PD-L1 protein expression levels. The drug label contains information about the assay, which was developed by the Roche subsidiary Ventana Medical Systems in Tucson, Arizona. Although this test can help physicians determine which patients may benefit most from treatment, its use is not required for Tecentriq therapy.
 
Even so, controversy still surrounds PD-L1 expression as a biomarker in immuno-oncology. Generally, and as seen in the IMVigor 210 data, PD-L1 expression doesn't guarantee response nor does its absence preclude response. "It is important to explain to patients that it doesn't matter what your PD-L1 status is because nobody really knows what it means right now," Rosenberg says.
 
In the future, assuming multiple PD-1/PD-L1 drugs are approved in bladder cancer, applying an assay to measure PD-L1 expression may make sense, to be able to restratify patients with the different agents. With only one approved drug in the class, that doesn't matter. There's also the additional problem that, currently, PD-L1 expression is measured with different antibodies from different manufacturers (Nat. Biotechnol. 33, 1217, 2015).
 
Eventually, a complex biomarker signature for bladder cancer immunotherapy is likely to emerge. Bladder cancer is a tobacco-related illness with a high mutation rate, similar to that of melanoma or lung cancer, where mutations are frequent and many neo-antigens are present, says Rosenberg. Results from the IMVigor 210 trial revealed that a high mutation burden was associated with high levels of response and improved survival. Another way of assessing whether a tumor may be amenable to treatment with a checkpoint inhibitor is to look directly at the amount of T-cell infiltration. "There's a lot of CD8+ cell infiltration, probably in the majority of bladder tumors," Rosenberg says. But some have so-called suppressive stroma that likely limit the ability of a checkpoint inhibitor to function, at least as a single-agent therapy.
 
Still, "It's likely that a third or a quarter of bladder tumors have a microenvironment where, once a PD-1/PD-L1 checkpoint inhibitor is used, the immune system will kick in, he says. Work on biomarker signatures is continuing throughout Tecentriq studies, including in a phase 2 study by the group at Queen Mary University of London that published the early Tecentriq biomarker data from phase 1 studies, to test preoperative efficacy of the drug and measure[ dynamic changes in CD3+ and CD8+ T cell populations (Nature 515, 558, 2014).
 
Genentech took a quick-to-market approach focused, initially, on the high unmet need and lack of competition in bladder cancer. "Now, they can start talking about their drug and from there expand into other indications," says Laing. If they can succeed in treating lung or renal cell cancer, "at least some oncologists will have experience and comfort with the drug, as opposed to waiting another year or two and having that conversation," she says.
 
Part of the appeal of checkpoint-blocking immunotherapy drugs is the favorable toxicity profile, says Hoffman-Censits. Both PD-1- and PD-L1-targeting drugs seem to be tolerated when used in second-line treatment, she says. "When you have experience seeing dramatic responses where responses previously were not seen in that line before, it raises a lot of possibilities," Hoffman-Censits says. "We are going to see a lot more information coming out in the next 6 to 12 months and beyond about what the potential benefits are outside of the post-platinum setting," she says, for Tecentriq as well as other PD-1 and PD-L1 inhibitors.
 
Those data are likely to come from combination trials, which companies are already rushing to start. Before clinicians can make rational choices for combining checkpoint inhibitors with other agents, however, scientists must decipher more of the underpinnings of tumor and immune system interactions. This decision-making process stands in contrast to that used with kinase-targeted therapies, where publications have defined the particulars of each node in a pathway, Laing says. And because the stakes are high, the drugmakers are taking a practical approach and going quickly to patients to try to figure out dosing in real time in a clinical trial. "The science is important but you can only do so much of that for immuno-oncology," she says. "So it becomes about looking at the opportunity and the indication, and how you balance a portfolio with different internal and external immuno-oncology assets."
 
Roche/Genentech hasn't done as much external immuno-oncology deal-making as some of the other leaders; Merck and AstraZeneca, for example, have done many deals in the space, Laing says. "Roche can afford to be internally focused," she says. "They have a huge pipeline and don't need to go outside." In addition to its bladder cancer studies, Tecentriq is currently in phase 3 in renal cell carcinoma, lung, breast and colorectal cancers.
 
 
 
 
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