Bottom Line: The investigational anticancer therapeutic abemaciclib, which targets CDK4 and CDK6, showed durable clinical activity when given as continuous single-agent therapy to patients with a variety of cancer types, including breast cancer, non-small cell lung cancer (NSCLC), glioblastoma, and melanoma, according to results from a phase I clinical trial.
Journal in Which the Study was Published: Cancer Discovery, a journal of the American Association for Cancer Research.
Senior authors: Amita Patnaik, MD, associate director of clinical research at South Texas Accelerated Research Therapeutics in San Antonio, Texas, and Geoffrey I. Shapiro, MD, PhD, director of the Early Drug Development Center at the Dana-Farber Cancer Institute in Boston.
Background: In February 2015, the U.S. Food and Drug Administration (FDA) approved the CDK4/6 inhibitor palbociclib (Ibrance) for use in combination with the aromatase inhibitor letrozole for treating postmenopausal women with estrogen receptor-positive, HER2-negative advanced breast cancer.
The oral CDK4/6 inhibitor abemaciclib is a very different molecule from palbociclib, with distinct attributes that contribute to its discrete therapeutic effects, in particular, its single-agent activity, according to Shapiro. For example, abemaciclib has greater selectivity for CDK4 compared with palbociclib, which may explain why it does not affect white blood cell counts as severely, allowing it to be taken on a continuous schedule without treatment holidays, he said. Abemaciclib also penetrates the central nervous system, whereas palbociclib does not, raising the possibility that it could be used to treat primary or metastatic brain tumors, he added.
How the Study Was Conducted and Results: Patnaik, Shapiro, and colleagues enrolled 225 patients with a variety of types of advanced cancer in the phase I clinical trial designed to evaluate the safety and preliminary efficacy of abemaciclib. In the dose escalation phase, the researchers determined that the maximum tolerated dose was 200 milligrams (mg) every 12 hours; the dose-limiting toxicity was grade 3 fatigue.
In the expansion phase, single-agent abemaciclib was administered to 47 patients with breast cancer, 68 with NSCLC, 17 with glioblastoma, 26 with melanoma, and 15 with colorectal cancer. Among these patients, the most common treatment-related adverse events were fatigue, diarrhea, nausea, vomiting, anorexia, weight loss, kidney dysfunction, and decreased red and white blood cell counts.
Radiographic responses were observed for some patients with breast cancer, NSCLC, and melanoma. Among the 36 patients with hormone receptor-positive breast cancer, 11 had a partial response, with four of the 11 responders having continued prior endocrine therapy, and an additional 18 patients had stable disease. Among the 68 patients with NSCLC, two had a partial response and 31 had stable disease; one patient who had a partial response and 12 who had stable disease were known to have KRAS-mutant NSCLC. Among the 26 patients with melanoma, one had a partial response and six had stable disease. Three of the 17 patients with glioblastoma had stable disease, with two of them continuing to receive treatment without disease progression for 19 and 23 cycles, respectively.
Author Comment: “These data show that abemaciclib is an oral drug that can be taken on a continuous schedule and achieve durable clinical activity against multiple tumors including breast and lung cancers,” said Shapiro.
“The results of the trial supported the FDA decision to grant breakthrough therapy designation to abemaciclib (previously known as LY2835219) for patients with refractory hormone receptor-positive advanced or metastatic breast cancer,” added Patnaik.
Limitations: Patnaik explained that because this study included 225 patients with different types of cancer, confirmatory clinical trials in specific patient populations are necessary to precisely define the role of abemaciclib in cancer care. Multiple clinical trials have already been initiated to evaluate abemaciclib as a treatment for certain groups of patients with breast cancer and NSCLC, as well as children with primary brain tumors and adults with brain metastases, she noted.
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Funding & Disclosures: The study was funded by Eli Lilly and Company. Patnaik has received research funding from Lilly. Shapiro served on an advisory board for Lilly during the conduct of the study; reports receiving personal fees from Lilly, GI Therapeutics, Vertex Pharmaceuticals, and grants from Lilly for work other than reported here; and is an investigator on several trials using other CDK4/6 inhibitors, including palbociclib and ribociclib.
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About the American Association for Cancer Research
Founded in 1907, the American Association for Cancer Research (AACR) is the world’s first and largest professional organization dedicated to advancing cancer research and its mission to prevent and cure cancer. AACR membership includes more than 35,000 laboratory, translational, and clinical researchers; population scientists; other health care professionals; and patient advocates residing in 104 countries. The AACR marshals the full spectrum of expertise of the cancer community to accelerate progress in the prevention, biology, diagnosis, and treatment of cancer by annually convening more than 30 conferences and educational workshops, the largest of which is the AACR Annual Meeting with nearly 19,500 attendees. In addition, the AACR publishes eight prestigious, peer-reviewed scientific journals and a magazine for cancer survivors, patients, and their caregivers. The AACR funds meritorious research directly as well as in cooperation with numerous cancer organizations. As the Scientific Partner of Stand Up To Cancer, the AACR provides expert peer review, grants administration, and scientific oversight of team science and individual investigator grants in cancer research that have the potential for near-term patient benefit. The AACR actively communicates with legislators and other policymakers about the value of cancer research and related biomedical science in saving lives from cancer. For more information about the AACR, visit http://www.AACR.org.
To interview Amita Patnaik or Geoffrey I. Shapiro, contact Julia Gunther at julia.gunther@aacr.org or 
215-446-6896.
This release about the first set of tests in patients prescribed an experimental cancer drug, abemaciclib, uses language that mostly hews to the careful tone of the researchers’ journal article. It does not make any premature claims of cure or even extended survival. The release includes sections labeled “Limitations” and “Funding & Disclosures” that highlight these vital elements. We would have liked to see at least some discussion of the possible cost of the drug, especially since a similar drug mentioned in the release is priced around $10,000/month. The release could have explicitly noted that the new drug could fail ongoing trials, instead of using language that implies eventual success. Even with expedited status and favorable study results, it would likely be 1-3 years before this drug could be approved for routine use.
People with cancer are on the lookout for any potential new treatment. Writers of news releases about experimental cancer drugs must be careful not to imply benefits that have not been proven. As this release demonstrates, even when there are no claims of cure or even extended survival, readers can come away with an inflated sense of the likely success of a drug that is only beginning to be tested in people. This study highlights a second agent in a new class of medicines that may broadly target a range of cancer types that may have similar mechanisms of action. Which cancers, at what stage and for which patients still needs to be determined. Moreover, it will need to be compared to other established and experimental medicines to determine its relative benefits and harms.
While one could say it is far too soon to start talking about the cost of a drug that is only beginning to be tested in people, the release compared abemaciclib to a somewhat similar drug, palbociclib (brand name: Ibrance) that is listed at approximately $10,000/month. The release could have referred to the costs of similar drugs… and perhaps included some mention of how long researchers anticipate patients would be treated with this sort of drug. As an aside, the Wall Street Journal reported a fascinating story on how Pfizer set the (just under) $10,000/month list price of Ibrance.
The release is appropriately restrained in its description of the potential benefits of a drug just starting the long process of trials in patients. It specifically reports the number of trial participants whose tumors appeared to respond or at least not advance during the test, without making premature claims of effectiveness. However, we would like to see news releases about early trials of cancer drugs go further, to state explicitly that signs of partial responses or stable disease do not imply potential cures or even extended survival. More emphatic cautionary statements seem particularly appropriate to releases like this one that point out an experimental drug has been given “breakthrough therapy designation” by the FDA, which is a technical definition that the FDA notes is frequently misinterpreted by the public and even health care professionals. Since it referenced “durable response,” it would have been nice to see the release include a definition. In brief, the term refers to the length of time that a partial or complete response is observed as a result of treatment.
The release notes that “the most common treatment-related adverse events were fatigue, diarrhea, nausea, vomiting, anorexia, weight loss, kidney dysfunction, and decreased red and white blood cell counts.” Although the release does not go into specific detail about the number of patients who reported side effects, or the degree of severity of the side effects, the list of harms seems adequate for a drug just beginning the clinical trial process.
The release clearly summarizes what the researchers reported in their article in the Cancer Discovery medical journal; that is, that this test involving just a couple of hundred patients showed the drug could be tolerated at doses that seem to show some effects on some tumors. We applaud the news release for including a paragraph labeled “Limitations” that stated only 225 patients with different forms of cancer were involved, so further tests are needed to determine what role this drug might have in cancer care. The release would have been stronger if it had spelled out that the study was performed in patients who had failed prior treatments so readers won’t assume this drug could be used for first line therapy.
The release does not exaggerate the seriousness of the cancers that were studied.
The release includes a “Funding & Disclosures” paragraph. It lists funding by Eli Lilly and Company. It also lists some of the payments and other connections between key researchers and the company. We like the format used for this EurekAlert version of the release, which also notes the funder in a box just to the right of the release’s headline.
The release spells out some specific features of abemaciclib that explain why researchers think it has potential advantages over a similar drug that is already FDA-approved. However, this comparison puts the new drug in an entirely positive light, which it has yet to demonstrate it deserves. We’ll dock points for that concern here. Since the comparison with the competing drug also speaks to abemaciclib’s novelty, we’ll award a Satisfactory for that criterion (see below) so as not to double-ding the release.
The release notes that abemaciclib is now being tested in trials designed to “define the role of abemaciclib in cancer care.” However, it never explicitly states that these trials might end up finding that the drug does not ultimately provide sufficient advantages over existing treatments. Its reference to “investigational” in the title and text may be enough to give some readers the tip-off that this drug won’t be available anytime soon. However, we recommend news release writers make it abundantly clear when a drug is only available as part of research trials and that it is not available for use in routine clinical practice. The statement, “FDA decision to grant breakthrough therapy designation,” may lead a reader to think this could be available for use more broadly.
The release explains that although there are other drugs that attack cancer cells in a similar way, this drug has some differences. As noted above, the release casts all the differences with existing drugs as advantages, when of course these features have yet to be adequately tested.
The release avoids unjustified claims, although the overall cast is entirely positive, leaving it to journalists and other readers to balance the rosy image with some skepticism.
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