ORLANDO, Fla. – Genentech Inc. and Abbvie Inc.'s BCL-2 inhibitor venetoclax in relapsed and refractory chronic lymphocytic leukemia (CLL) is one of the stars of this year's annual meeting of the American Society of Hematology (ASH).

Data from the pivotal M13-982 trial of venetoclax in relapsed or refractory CLL patients is being presented in the late-breaking session on Tuesday. That presentation will cap nearly 50 presentations on the drug in multiple indications being presented at this year's annual meeting, as well as online publication of the phase I trial data in The New England Journal of Medicine on Dec. 6, 2015.

Part of the excitement around venetoclax – which has also gone by the names ABT-199, GDC-0199 and RG-7601 – is that it works, and sometimes works extraordinarily well, in those patients that still have what lead investigator Stephan Stilgenbauer, deputy chairman of the department of internal medicine at Ulm University, called a "dismal" prognosis with current approaches, namely, patients with a chromosome 17p deletion.

While the phase I trial was carried out in both patients with and without that deletion, all of the more than 100 patients in the pivotal trial had p17 deletions. "The most difficult to treat patient population was studied" in the trial, Stilgenbauer said.

That patient population is difficult to treat because the p17 they are lacking includes the tumor suppressor TP53.

Lack of TP53 is "almost universally a bad prognostic factor," David Huang, laboratory head of the division of cancer and hematology at the Walter and Eliza Hall Medical Research Institute, told the audience at a Sunday session on "Overcoming the Barrier of TP53 Dysfunction to Cure Blood Cancers."

"Optimal responses to many of our current therapies rely on TP53 function," Huang explained, even as those therapies "often . . . select for either deletion or particular mutations of P53."

The best possible solution would be to restore P53 function, but "technically, restoring p53 function is very challenging," Huang said, and currently no clinically feasible method to do so exists.

Given that state of affairs, the results of the pivotal trial, which were first made public in August, and are the basis of new drug application filings with both the FDA and the EMEA, are all the more impressive. (See BioWorld Today, Aug. 13, 2015.)

In the trial, the overall response rate was 79.4 percent, with a 7.5 percent of patients having a complete response (CR) and 69.2 percent a partial response (PR).

Furthermore, 18 of 45 patients tested achieved minimal residual disease (MRD) negativity in the peripheral blood, meaning that there was less than one leukemia cell in 10,000. Ten of those patients were also tested for MRD in the bone marrow, where six of the 10 were MRD negative.

Moma Vidakovic, Abbvie's director of oncology operations, told BioWorld Today that the MRD data are an important harbinger of a durable response. "If you achieve MRD negativity, you have a very good chance of staying disease free for a period of time.

Beyond its importance for the individual patients in which it occurs, MRD-negativity is emerging as a useful predictor of progression-free survival (PFS) that could potentially be used as an endpoint in its own right, Nancy Valente, Genentech's vice president of global product development for hematology/oncology, told BioWorld Today.

PFS is a frequent endpoint in clinical trials and has important implications for quality of life, but is also partly a surrogate marker for overall survival (OS), which can take many years to mature. For the RATIFY trial of the multikinase inhibitor midostaurin, which was presented at Sunday's plenary session, investigators had to change their analysis plan when it became clear that under the original plan, the trial would need to run until 2025.

A reliable surrogate marker for PFS that could be assessed at the end of treatment could shorten clinical trials. At the ASH meeting, several abstracts were presented that showed such MRD analysis was a predictor of PFS in CLL, mantle cell lymphoma and multiple myeloma.

Venetoclax' success at treating patients with the p17 deletion stems from its inhibition of BCL2, an anti-apoptotic protein that is a few steps downstream from P53 in the signaling cascade.

BCL2 inhibition can be a strategy to circumvent TP53 dysfunction in CLL. P53 mutations are not limited to any one specific tumor type, however, and in addition to being tested in combination with other drugs and earlier in the course of CLL, the drug is also being tested in other hematological cancers including non-Hodgkin's lymphoma, diffuse large B-cell lymphoma and follicular lymphoma. Venetoclax is also being tested in a phase I trial in combination with tamoxifen in patients with metastatic breast cancer.

Response rates in other tumors are lower, as the universal overexpression of BCL-2 is specific to CLL. Other cancers may benefit from targeting other downstream proteins. Huang said that several different experimental approaches have confirmed that the protein MCL-1 is an important survival factor for myeloma. "MCL1 sits atop the hierarchy of pro-survival factors in myeloma," Huang said.

There are two small molecules that target MCL-1 – obatoclax and A1210477. But for clinical success, Huang said, it will be necessary to develop compounds that are both more potent and more secretive. That necessity, too, has similarities to venetoclax, which is a successor to Abbvie's drug navitoclax (ABT-263). (See BioWorld Today, Jan. 11, 2013.)