In conjunction with the release of the abstracts for the upcoming 2019 ASCO Annual Meeting, a virtual press cast previewed five noteworthy studies that showcase the range of research that will be presented at the meeting.
Topics included the effect of a low-fat diet on breast cancer mortality, identification of a greater than expected number of targetable molecular alterationsin a pediatric MATCH trial, response of rare pediatric tumors with certain gene fusions to the targeted agent entrectinib, optimization of chemotherapy for frail and/or elderly patients with advanced esophageal cancer, and reduction of progression of smoldering to active multiple myeloma by lenalidomide.
Here are summaries of the key findings.
Low-Fat Diet Associated with Reduced Breast Cancer Mortality (Abstract 520)
Observational studies of the effect of dietary fat on breast cancer have produced equivocal results. To address this, the Women’s Health Initiative (WHI) Dietary Modification (DM) trial, a randomized, controlled study looked at the influence of diet breast cancer incidence and mortality.
The WHI-DM trial (NCT00000611) enrolled 48,835 post-menopausal women age 50 to 79 years who were randomly assigned to dietary intervention (n=19,541) or usual diet (comparison group, n=29,294) from 1993 to 1998. Dietary intervention, which continued for 8.5 years, included reducing fat intake to 20% of calories and increasing intake of vegetables, fruit, and grains, similar to the DASH (dietary approaches to prevent hypertension) diet.
Trial endpoints included deaths from and after breast cancer. Cumulative follow-up data have been collected for a median of 19.6 years. Baseline fat intake was at least 32% of calories. Most women in the diet group increased daily intake of vegetables, fruit, and grains and reduced daily fat consumption to 25% of calories; most did not reach the 20% goal.
In the diet group versus the comparison group, there was a significantly lower risk of death from breast cancer (HR, 0.85; 95% CI, 0.74, 0.96; P=.01) and from any cause after a diagnosis of breast cancer (HR, 0.79; 95% CI, 0.64, 0.96; P=.025).
The authors call this the only study providing randomized clinical trial evidence that an intervention can reduce a woman’s risk of dying from breast cancer, although this analysis was not pre-specified in the original trial design, dietary components were assessed by participant recall, and there was no way to measure adherence to the diet.
At the meeting, the effect of the same dietary modification in a subgroup of women with poor metabolic function, defined as obesity, diabetes, elevated cholesterol, or hypertension, will also be presented (Abstract 1539).
More Actionable Targets than Expected Found in Pediatric MATCH Trial (Abstract 10011)
The NCI-COG (Children’s Oncology Group) Pediatric MATCH (Molecular Analysis for Therapy Choice) trial was designed to address whether a precision oncology approach, i.e., treating tumors with agents selected to target specific genetic alterations, would be useful in the pediatric cancer setting.
NCI-COG Pediatric MATCH will enroll at least 1000 children with tumors that have not responded to standard treatment. The initial step is to screen tumors for potential targets, followed by treatment with therapy matched to alterations found in the tumors independent of tumor type. Treatment is in individual phase 2 clinical trials, of which there are currently 10, one for each current single-agent targeted therapy being tested.
There were 422 patients enrolled, from 93 of the 124 COG sites that had the study open, between July 24, 2017 and the data cutoff for this analysis at the end of last year. Tumor samples were received from 92% of enrolled patients and accounted for over 60 different tumor types including central nervous system (CNS) and non-CNS tumors. Turnaround time was 15 days from tumor receipt to treatment assignment.
Study researchers projected a match rate of 10% based on adult data. So far, 24% of screened patients with cancer that did not respond to treatment were eligible for treatment with a targeted agent. Of these, 39 patients (10%) have enrolled in a treatment trial. The trial is ongoing and is expected to add at least four additional single targeted agents. Combination therapies are being considered for future trials.
Rare Pediatric Tumors with Gene Fusions Respond to Entrectinib in Early Trial (Abstract 10009)
Fusions and alterations in intracellular signaling pathways such as TRKA/B/C, ROS1, and ALK genes act as drivers in some tumors by “locking” the pathways in the “on” position. Entrectinib is an oral inhibitor of these pathways and has the additional advantage of being able to cross the blood-brain barrier to enter the CNS.
Pediatric tumors with mutations in TRKA/B/C, ROS1, and ALK genes are rare, and are being identified more frequently as next-generation sequencing is becoming more common. STARTRK-NG (RXDX-101-03) is phase1/1b clinical trial investigating entrectinib in children with recurrent or refractory solid tumors with these gene alterations. Most had undergone prior surgery and radiation.
Of 29 patients enrolled, 16 were in the phase 1 dose-finding part; an additional 13 patients have been enrolled in the ongoing basket phase 1b part at a dose level of 550 mg/m2(initial recommended dose, n=7) or 400 mg/m2for those unable to swallow intact capsules. Diagnoses included primary CNS tumors (n=6), neuroblastoma (n=3), and extracranial solid tumors (n=4). Median patient age is 7 years.
Responses have been seen in all patients whose tumor had a target gene alteration and no responses were seen in patients whose tumors lacked aberrations in target kinases. Therefore, the trial will continue only for patients with target fusions. Presenter Giles W. Robinson, MD, St. Jude Children’s Research Hospital, Memphis, Tennessee, said, “It gives me great pleasure as pediatric brain tumor doctor to show response in CNS tumors” that would otherwise probably have been fatal.
Dose-limiting toxicities included elevated creatinine, dysgeusia, fatigue, and pulmonary edema. Weight gain, problematic for some patients, also occurred as an on-target drug effect. Side effects have resulted in dose reduction to 400 mg/m2.
Dose-Modified Chemotherapy for Frail and/or Elderly Patients with Advanced Gastroesophageal Cancer (Abstract 4006)
Although the average age of patients at the time of diagnosis of advanced, inoperable gastroesophageal cancer is 75 years, and many patients are frail, standard of care chemotherapy has been developed in trials in patients with an average age of 65 years who are generally not frail. This study was motivated by the finding that a survey of oncologists in the UK used reduced dose chemotherapy regimens that were not evidence-based to treat frail and/or elderly patients with gastroesophageal cancer.
A prior phase 2 trial indicated that a 2-drug regimen was preferable to 3-drug or single agent regimens in this setting. The GO2 phase 3 trial was designed to optimize doses of 2-drug chemotherapy regimens and assess benefits and risks.
Patients (n=514) with a median age of about 76 years who were fit for chemotherapy but not for full-dose, 3-drug regimens were enrolled. There were 2 randomization schemes based on whether the patient was considered either certain or likely to benefit from chemotherapy and basic supportive care (BSC) was not appropriate (certain randomization), or would derive uncertain benefit from chemotherapy with BSC possibly appropriate (uncertain randomization). Presenter Peter S Hall, PhD, University of Edinburgh, Edinburgh, UK, discussed the certain randomization option, where patients were randomly assigned to one of 3 dose levels of combinations of oxaliplatin plus capecitabine.
In addition to assessing progression-free survival (PFS), and a non-inferiority boundary agreed upon by a patient focus group and clinicians, the study also determined which dose level resulted in the best “overall treatment utility (OTU),” a novel concept developed in phase 2, which included cancer control, severity of side effects, patient quality of life (QoL), and oncologist’s assessment of benefit.
The lower doses of chemotherapy were non-inferior to the highest dose for median PFS (4.9 months for the highest dose, 4.1 months for the intermediate dose, and 4.3 months for the lowest dose), as well as for median overall survival (7.5 months, 6.7 months, and 7.6 months, respectively). The lowest dose was associated with the best OTU scores, as a result of fewer side effects and better quality of life (QoL).
Lenalidomide Reduces the Risk of Progression from Smoldering to Active Multiple Myeloma (Abstract 8001)
Smoldering or asymptomatic multiple myeloma (SMM) is a precursor to symptomatic MM. The goal of the phase 2/3 E3A06 trial was to determine if early intervention in intermediate or high risk SMM using low-intensity, single-agent lenalidomide could prevent progression to MM. The primary endpoint was time to develop MM.
In phase 2, the safety of 25 mg daily of lenalidomide for 3 out of every 4 weeks was determined. Phase 3 randomly assigned patients to the same dose of lenalidomide (n=90) or to observation (n=92). Prophylactic aspirin was administered with the lenalidomide.
Time to develop MM was delayed with the use of lenalidomide (2-year PFS probability 0.93; 95% CI, 0.88-0.99) compared with observation (2-year PFD probability 0.76; 95% CI 0.66-0.87). Treatment-related grade 3 and 4 hematologic and non-hematologic adverse events were observed with lenalidomide; 51% of patients in the phase 3 portion discontinued due to toxicity, although there was no difference in QoL reported between the 2 groups.
Three-year PFS was 91% in the lenalidomide group, compared with 66% in the observation group (HR 0.28, P=.0005). Follow-up is too short to determine the effect of treatment on overall survival. The investigators will follow patients who discontinued to see if limited doses of lenalidomide can delay progression of SMM to MM. This study shows early intervention, at least in patients with higher risk SMM, can prevent MM and its associated end organ damage.
By Lynne Lederman, PhD
PS – Don’t forget to sign up for our ASCO ’19 Preview webinar featuring Lee Schwartzberg, MD, Zev Wainberg, MD, and Rich Leff, MD. Register here.
By Jay Grisolano, PhD and Stephanie Ritz, PhD
Approximately a quarter of breast cancer patients are classified as HER2-positive, according to Kantar Health’s 2016 Treatment Architecture data. 1 Effective targeted agents for the HER2 receptor, such as Herceptin (trastuzumab; Roche) and Perjeta (pertuzumab; Roche), have been developed for this particular patient segment and have greatly improved clinical outcomes for these patients. Despite these major advances, the need for improved early stage treatments still exists to keep disease from reaching an incurable stage. Currently, up to one in three early stage HER2+ patients treated with Herceptin in combination with chemotherapy eventually recur.2 In an effort to address this unmet need, Roche is conducting the Phase 3 APHINITY trial (NCT01358877) evaluating the combination of Herceptin, Perjeta, and chemotherapy in the adjuvant setting, hoping to improve upon these outcomes.
The triplet combination of Herceptin, Perjeta, and chemotherapy was initially approved in the HER2+ metastatic setting for first-line patients based on data from the Phase III CLEOPATRA trial, showing addition of Herceptin and Perjeta to chemotherapy improved median progression-free survival (PFS) and median overall survival (OS).3 In addition, the triplet has already demonstrated efficacy in early stage disease. The Phase II NEOSPHERE study (NCT00545688) compared Herceptin plus docetaxel with or without Perjeta in the neoadjuvant setting. Results reported at ASCO 2015 and published in Lancet Oncology showed a significantly improved complete response without an increase in cardiotoxicity (Herceptin / docetaxel: pCR 21.5%; Herceptin / docetaxel / Perjeta: pCR 39.3%, p=0.0063). Additionally, the risk of disease progression or recurrence was reduced by 31% and 40%.4 Based on these data, the triplet neoadjuvant regimen was granted approval in September 2013.
Now Roche is pushing to move their triplet combination into the adjuvant setting with APHINITY, results of which were presented today at the 2017 Annual Meeting of the American Society of Clinical Oncology (ASCO).5 APHINITY is an international, double-blind, placebo-controlled Phase III trial evaluating the efficacy of Herceptin plus chemotherapy with or without Perjeta in the adjuvant setting. The study enrolled 4,805 patients of lymph-node-positive and -negative status with confirmed HER2 positivity, as defined by IHC3+ or FISH-/CISH-positive. Patients received 6 to 8 cycles of chemotherapy with Herceptin (8mg/kg) and Perjeta (840 mg)/placebo, followed by Herceptin (6 mg/kg) and Perjeta (420 mg)/placebo alone every 3 weeks for one year (52 weeks) of treatment. At the time of presentation, the primary endpoint of invasive disease-free survival (IDFS) in the overall population was 92.3% in the triplet arm versus 90.6% seen in the control arm (p=0.045) at four years; however, subgroup analysis suggested that clinical benefit for IDFS appeared to be limited to node-positive and hormone receptor-negative cohorts. The disease-free interval and recurrence-free interval was modestly improved (DFI: 93.4% v. 92.3%, p=0.033; RFI: 95.2% vs. 94.3%, p=0.043); however, the addition of Perjeta did not improve the distant recurrence-free interval. No difference was noted in median overall survival at first interim analysis (97.7% v. 97.7%, p=0.467), but only one-quarter of data points needed for final analysis had been collected.
The most common Grade 3/4 adverse events associated with the triplet arm included neutropenia in 16.3% of patients (versus 15.7% in the control arm), febrile neutropenia in 12.1% of patients (versus 11.1% in the control arm, anemia in 6.9% of patients (versus 4.7% in the control arm), and diarrhea in 9.8% of patients (versus 3.7% in the control arm), which was predominately observed during the administration of chemotherapy. Cardiac toxicity was low and similar between the two arms.
Based on these data, it will be interesting to see how physicians adopt the triplet regimen in the adjuvant setting if it gains accelerated approval. Physician attendees vocalized great concerns during today’s session regarding the financial burden of adding Perjeta for a modest 1.7% IDFS benefit, despite its favorable tolerability profile. It may be essential for Roche to find specific subsets of patients who benefit most from the triplet in order for physicians to seriously consider integrating the addition of Pejeta into their practice. Another concern is whether Perjeta retreatment of a patient who recurs with metastatic disease will still be effective. It was mentioned that trials are being initiated to evaluate retreatment with Perjeta. Given the modest efficacy of APHINITY and the current absence of data supporting retreatment with the triplet beyond progression, physicians may to choose to save Perjeta until the metastatic setting. These issues may make it difficult to compete with Puma’s HER2 tyrosine kinase inhibitor, neratinib, which already has a PDUFA date set for July. Data supporting Puma’s application for approval is based on the Phase III ExteNET (NCT02400476) study, which showed a 2% benefit in 2-year DFS (2-year rate: 93.9% vs. 91.6%, p=0.0009) with a relatively well-tolerated toxicity profile.6 Subgroup analysis showed that neratinib may be more effective in ER-positive patients, which could help Puma find its niche in this space should neratinib receive approval.
Nevertheless, APHINITY did meet its primary endpoint showing that addition of Perjeta to Herceptin and chemotherapy as adjuvant treatment achieved a statistically significant improvement in IDFS. These data suggest that the triplet may become an option for adjuvant treatment of HER2+ early breast cancer.
By Liseth Parra, Ph.D., and Stephanie Hawthorne, Ph.D.
A very exciting therapeutic area that has been constantly highlighted throughout ASCO this year is the enormous potential for targeting genomic instability. While genomic stability is a major force of tumor growth, it provides a vulnerable point of tumorigenesis that can be used as an actionable target in clinical oncology. BRCA1 and BRCA2 are responsible for activating DNA damage response pathways as a result of DNA double-strand breaks (DSB) and thus play an important role in maintaining the genetic stability of cells.
Hereditary (germline) mutations in one copy of either the BRCA1 or BRCA2 gene (gBRCA1/2) are associated with a high risk of developing primarily breast and ovarian cancer and represent one of the greatest unmet needs in gynecologic cancers. These mutations account for about 5% to 10% of all breast cancers and about 15% of all ovarian cancers1 and are particularly vulnerable to poly(ADP-ribose) polymerase (PARP) inhibition. PARP proteins normally function in the repair of DSB, and it’s presumed that their inhibition leads to the breakdown of the DNA machinery involved in DSB repair that cannot take place in BRCA1/2 deficient cells, a concept referred to as synthetic lethality.
Within the past two years, three PARP inhibitors gained regulatory approval for the treatment of advanced ovarian cancer – Lynparza® (olaparib, AstraZeneca), Rubraca® (rucaparib, Clovis Oncology), and Zejula™ (niraparib, Tesaro). Additionally, four PARP inhibitors – Lynparza, talazoparib (Pfizer / Medivation), veliparib (ABT-888, AbbVie), and Zejula – are in Phase III development for locally advanced or metastatic BRCA1/2 mutated breast cancer, starting a race to see which agent will be first to market in this indication.
AstraZeneca, as an output of its 2005 acquisition of the British biotechnology company KuDOS, became the first pharmaceutical company to launch a PARP inhibitor, with Lynparza obtaining accelerated approved as a monotherapy for the treatment of gBRCA ovarian cancer patients previously treated with three or more lines of chemotherapy. Following this initial launch, AstraZeneca has an extensive life-cycle management development plan in-place for Lynparza, with its eyes on breast cancer as the next indication for approval.
In the Plenary session at the 2017 ASCO conference, the first randomized results to support its development in breast cancer were presented1,2. The Phase III OLYMPIAD trial (NCT02000622) evaluated Lynparza in comparison to “physician’s choice” chemotherapy (capecitabine, vinorelbine, eribulin) in 302 metastatic HER2- breast cancer patients with deleterious or suspected gBRCA mutations.
Patients could have had up to two prior lines of chemotherapy and must have received prior anthracycline and taxane, and hormone receptor-positive patients must have received at least one prior line of hormone therapy unless considered unsuitable; ultimately, one-third of enrolled patients were treated on-study as first-line therapy for metastatic disease, one-quarter as third-line, and the remainder as second-line.
Late breaking results for this trial presented at ASCO demonstrated for the first time positive data for a PARP inhibitor in metastatic breast cancer with a statistically-significant improvement in progression-free survival (PFS) compared to standard chemotherapy and a meaningful improvement in health-related quality of life (HRQoL) in these patients.
The data showed a statistically significant PFS gain of nearly 3 months in patients treated with Lynparza (300 mg BID; n=205) versus chemotherapy (n=97) (7.0 vs 4.2 months, respectively; HR 0.58; p=0.0009). Although immature, overall survival (OS) was not statistically different between the two arms (19.3 versus 19.6 months, HR 0.90; p=0.5665). The ORR in the two arms was 60% versus 29%, respectively, with more complete responses in patients treated with Lynparza (9%) versus chemotherapy (2%). Although exploratory, data suggest similar level of benefit regardless of patient’s prior exposure to platinum or other chemotherapy, but suggest greater benefit in patients with triple-negative breast cancer (PFS HR 0.43) than in patients with hormone receptor-positive disease (PFS HR 0.82).
Fewer patients in the Lynparza arm than in the chemotherapy arm experienced Grade 3/4 adverse events (AE; 36.6% vs. 50.5%) and slightly fewer AE-related treatment discontinuations (4.9% vs. 7.7%). The most common Grade 3/4 adverse events in the Lynparza and chemotherapy arms were anemia (16% vs. 4%) and neutropenia (9% vs. 26%). As a secondary endpoint, the results showed that Lynparza led to a modest but clinically meaningful improvement in HRQOL compared to chemotherapy (estimated difference in EORTC QLQ-C30 global HRQOL score of 7.5 points, p=0.0035) and significantly longer time to deterioration of HRQOL (median not reached vs. 15.3 months; HR 0.44, p=0.0043).
These results represent the first positive Phase III trial for a PARP inhibitor in breast cancer and the discussant, Dr. Allison Kurian, had an overall positive outlook stating that these results” are practice-changing.” However, the magnitude of the benefit (3 months difference) and lack of OS benefit could raise questions by others in the field about the clinical meaningfulness of these results.
It is encouraging that the incidence of adverse events was lower, fewer treatment discontinuations were needed, and HRQOL was improved with Lynparza, but the magnitude of each of these improvements seems to run on the edge of meaningful from the a clinical perspective. When the clinical benefits run along that edge, commercial considerations have a greater likelihood of taking hold, and some physicians (and payers) may question whether the benefit with Lynparza compared to generic chemotherapy justifies the costs. Despite these concerns, Lynparza stands a good chance of gaining regulatory approval, so these debates may ultimately play out in the clinic and everyday practice.
While it may launch as a monotherapy, ultimately the greater movement forward with PARP inhibitors lies in alternative development strategies. Correlative biomarkers for PARP inhibition (beyond gBRCA1/2) may help to further identify patients that will benefit the most from Lynparza. Additionally, the double-hit approach of single-agent PARP inhibitors in gBRCA mutated disease may not be robust enough, and we could ultimately find more effective strategies with a targeted combination approach – this includes combinations with chemotherapy or radiotherapy (which can induce DSBs)or with other mechanisms of action.
The closest drug taking this approach is veliparib, which is being studied in the Phase III BROCADE 3 trial (NCT02163694), which is enrolling HER2- breast cancer patients harboring deleterious BRCA1/2 or gBRCA1/2 mutations with less than two lines of prior therapy, who will be randomized to treatment with carboplatin and paclitaxel in combination with veliparib or placebo. Other PARP inhibitors in development in breast cancer are being developed as monotherapies – talazoparib in the Phase III EMBRACA trial (NCT01945775 and Zejula in the Phase III BRAVO trial (NCT01905592). The OlympiAD results, Lynparza is now officially ahead of the competition and could emerge as a potential agent of change in gBRCA breast cancer management, creating a new standard of care for the gBRCA1/2-mutated patient population. With so many competitors hot on its heels, it will be critical for Lynparza to get a solid push off of the starting block in order to put as much distance between itself and the others in this Olympic race in the breast cancer market.
By Megan Epperson, PhD, and Arnold DuBell, PhD, MBA
For HR+/HER2- advanced breast cancer patients, endocrine therapy has proved to be an effective and well-tolerated treatment option. In order to delay the initiation of more cytotoxic therapies, physicians will typically utilize hormone therapy as long as possible in these patients, although the majority will become resistant to hormone therapy. In recent years, pairing hormone therapy with targeted therapies has become a popular strategy. This strategy began in 2011 with the data from BOLERO 2, which found that addition of Afinitor® (everolimus, Novartis) to exemestane could help re-sensitize patients to hormone therapy regimens1. Even more recently, physicians are combining hormone therapy with cell cycle inhibitors targeting the cyclin-dependent kinases 4 and 6 (CDK4/6). First to lay claim to this concept was Ibrance® (palbociclib, Pfizer), which was first approved in 2015 by the U.S. FDA as first-line therapy in combination with letrozole (later loosened to include all aromatase inhibitors,) based on the PALOMA-1 trial2. Further, after the results of the PALOMA-2, and -3 trials were presented, the FDA and the EMA approved Ibrance as first-line therapy in combination with aromatase inhibitor or as a second-line option in combination with either an aromatase inhibitor or Faslodex® (fulvestrant, AstraZeneca)3,4. There are now two more players in addition to Ibrance targeting CDK4/6 for inhibition in breast cancer: Kisqali® (ribociclib, Novartis), and abemaciclib (Eli Lilly and Company). Kisqali was approved by the FDA in March 2017 for use in the first-line setting in combination with an aromatase inhibitor based on positive data from MONALEESA-25. As targeting of this pathway has proven to yield effective results in breast cancer, many trials have been initiated utilizing this class of inhibitors in breast cancer. Currently, there are 60 active trials involving these three inhibitors in breast cancer (Kantar Health’s CancerLandscapeTM, accessed June 2, 2017). Lilly is also interested in this space for their CDK4/6 inhibitor abemaciclib, having initiated two global Phase III trials (MONARCH 2 and MONARCH 3) in HR+/HER2- metastatic breast cancer.
Top-line results were presented from MONARCH 2 today at the American Society for Clinical Oncology (ASCO) annual meeting. This trial randomized 669 patients to abemaciclib (150 mg or 200 mg, po, BID) in combination with Faslodex (150 mg or 200 mg, po, BID) or placebo plus Faslodex in HR+/HER2- advanced breast cancer patients as either a first- or second-line treatment option6. Patients enrolled in MONARCH 2 were allowed to have progressed on neoadjuvant, adjuvant, or first-line endocrine therapy. Notably, MONARCH 2 differed from PALOMA 3 in that the use of prior chemotherapy was an exclusion criterion. The addition of abemaciclib significantly improved progression-free survival (PFS; 16.4 months versus 9.3 months, HR 0.553, p<0.0000001). MONARCH 2 also met its secondary endpoint of overall response rate (ORR in the intent-to-treat population; 35.2% versus 16.1%, p<0.001). Although not significant, the rate of complete responses was also improved with the addition of abemaciclib (3.5% versus 0%).
Toxicity may be an issue for abemaciclib. Of specific concern, the incidence of diarrhea was increased with abemaciclib (all grades, 86.4% versus 24.7%; Grade 3-4, 13.4% versus 0.4%). Due to discontinuations related to this adverse event, the dose of abemaciclib was reduced from 200 mg to 150 mg after enrollment of 178 patients. The discontinuation rate before the dose reduction was 24%, and post-reduction discontinuations dropped to 13%. The presenter noted in his summary, however, that diarrhea was manageable with use of loperamide. Other grade 3-4 toxicities of note included neutropenia (26.5% versus 1.7%), leucopenia (8.8% versus 0%) and anemia (7.2% versus 0.9%). As the trial met its PFS primary endpoint, Lilly announced that it intends to file for approval of abemaciclib in Q3 2017 (Press Release, March 20, 2017).
With Ibrance’s 2015 approval and the recent approval of Kisqali, abemaciclib will be third-to-market in the HR+/HER2- advanced breast cancer setting. All three inhibitors appear to provide benefit to patients as all showed significant improvements in PFS. While both Ibrance and Kisqali have similar toxicity profiles, abemaciclib alone appeared to struggle with higher incidences of diarrhea. While it is not completely clear why abemaciclib differs in its toxicity profile in this way, it may be related to the fact that abemaciclib is more potent against CDK4/cyclin D1 than CDK6/cyclin D3 in enzymatic assays; the reverse is true for Ibrance and Kisqali. The dosing strategy for abemaciclib also differs from Ibrance and Kisqali in that it is administered via continuous dosing, while the other two inhibitors are administered for 21 days, with a 7 day treatment holiday per cycle. Given the hurdles, these data are only “semi-sweet”: good enough for regulatory approval, but the toxicities seen in MONARCH 2, and abemaciclib’s eventual third-to-market introduction might cause physicians to question when to offer the agent.