Small Molecules Making Big News in Cancer Treatment
Size doesn’t matter as long as long as you can get the job done.
That said, one may be forgiven the impression that larger molecules—antibodies and related constructs, or T cells themselves being used in immunotherapies—were preferentially presented at American Association of Cancer Research annual conference. (Clickhere for part one our ACCR coverage)
Granted, these presentations were sexier for their sheer innovation. However, a number of small molecules, elegant in their mechanism of action, were also the cause of considerable clinical excitement.
“It’s fantastic to look out and see thousands of attendees here for the session which we’ve shaped to reflect the broad spectrum of scientific areas of cancer research,” said Scott Lowe, PhD, Memorial Sloan Kettering Cancer Center, making his comments at the opening plenary session.
Indeed, one area of keen interest was the activity of isocitrate dehydrogenase (IDH) mutations in the pathogenesis cancer; IDH dysfunction was the theme of an entire scientific symposia at AACR, and an anti-IDH mutant drug was the topic of one of the more provocative data sets presented for small molecule anti-cancer agents.
That molecule, AG-221, manufactured by Agios Pharmaceuticals, was associated with therapeutic improvement in a population of individuals with very poor prognoses—that of advanced-stage acute myeloid leukemia (AML). "The typical patient in the trial had relapsed or refractory AML,” said Eytan Stein, MD, Memorial Sloan Kettering Cancer Center. “And some of the patients had received bone marrow transplants. In general, expected survival is less than 10%.”
Speaking at a press briefing, Dr. Stein described his study that treated 22 late-stage AML patients with AG-221.
“The idea that altered cellular metabolism is linked to the pathogenesis of malignant neoplasm’s was postulated as early as 1926,” said Dr. Stein, explaining his approach. “That’s when biochemist and Nobel laureate Otto Warburg observed that tumors had a “remarkable” dependence on nonoxidative fermentation of sugar in to lactic acid.”
It took Warburg’s lab mate, Otto Krebs (of the eponymously named Cycle) to figure out the particulars of sugar metabolism, and another many years further before the connection to a dysfunction in the cycle and cancer was made, via a mutant form of the IDH enzyme, IDH2. The key observation being: “Cancer-associated IDH mutant produces 2-hydroxyglutarate (2-HG) and that metabolite blocks normal cellular differentiation of the myeloblast,” explained Dr. Stein. This, in turn, prevents the progenitor cells from growing in to their final, healthful types (neutrophils, etc), and results in the leukemic phenotype.
Previous work showed that mutant IDH2 is present in 10-15% of cases of AML. Thus, the current study.
Results for AG-221in this setting were striking. Of the 22 patients treated so far, 7 were evaluable at the time of report, of these, three had achieved complete hematologic response, two had complete response without platelet recovery, one had a partial response, and one patient had disease progression.
Overall, a 90% reduction in 2-HG was observed.
"It's still early clinical data,” said Dr. Stein, “and we are excited about it. But we will have to see what happens with the other patients who are still on study. At this point, I would say these are extremely exciting results."
Echoing this enthusiasm at the press briefing was Patricia LoRusso, DO, Karmanos Cancer Institute, Detroit. "To get these kinds of responses in patients who have progressed on chemotherapy, and then are treated with AG-122 and get a complete response—this is pretty exciting for these patients, because usually these patients die."
Breaking the Cycle
Two other small molecules that garnered notice at AACR are pursuing the same target: cyclin-dependant kinase (CDK) 3 and 4; CDKs are responsible for driving all cycle cellular growth and proliferation. In cancer, arresting proliferation is key.
“Our study grew out of a preclinical observation that hormone receptor-positive breast cancer cells are dependent on CDK-4/6 for their growth,” said Richard Finn, MD, University of California, Los Angeles.
In his investigation, the CD-4/6 inhibitor, palbociclib, manufactured by Pfizer, was tested in combination with the estrogen blocker, letrozole, compared with letrozole alone in estrogen-positive, metastatic breast cancer patients.
Results from 132 patients showed that those taking the palbociclib/letrozole combination experienced a median progression-free survival of 20.1 months vs. just 10.2 months with letrozole alone.
A second CDK-4/6 inhibitor compound, LY2835219 (Eli Lilly) was tested in 47 patients with metastatic breast cancer. Results for this first-in-class drug revealed 9 partial responders, and 24 patients experiencing stable disease, translating to a clinical benefit rate of 61%, as reported by Amita Patnaik, MD, of South Texas Accelerated Research Therapeutics in San Antonio.
Of interest, 7 of the 9 responders in this study were not receiving concurrent letrozole. Dr. Patnaik took this to indicate that the drug had significant single agent activity.
Will these data translate into even better outcomes for patients with hormonal therapy? Only time will tell.