CDK4/6 inhibitors compete for early breast cancer: Why did Abesili come first?

Hormone-positive (HR-plus), human skin growth factor-negative (HER2-) is the most common breast cancer subtype, accounting for about 60% to 70% of all breast cancer patients, 5 years relative survival rate of up to 94.1% (SEER 18 2010-2016), the risk of long-term recurrence is significantly higher than triple negative or 2 positive breast cancer, and once there is a distant metastasis, survival rate is often broken.
endocrine therapy (ET) is an important and priority complementary treatment strategy for such patients because of its good efficacy and safety.
However, about 30% of patients with early HR-/HER2-breast cancer will relapse due to ET resistance and progress to incurable metastasis breast cancer, so clinical exploration is gradually under way to improve the patient's long-term prognostics.
For the early HR-/HER2-patient population, the third-generation CDK4/6 inhibitors, Ibersili and Abesili, respectively, conducted Phase III studies code-named PALAS and MonarchE, although the two studies were designed with similar designs and came to very different conclusions.
, Pfizer announced another failure in early-stage breast cancer clinical studies, and the Phase III PENELOPE-B study also failed to reach the primary endpoint of IDFS.
so many, it's thought-provoking - why did the MonarchE and PALAS study come to a different end? What's so special about Abesili? Combined endocrine therapy for HR-/HER2-Advanced Breast Cancer: The three giants are the key proteins that regulate cell cycles, with a difficult cell cycle-dependent kinase 4/6 (CDK4/6).
CDK4/6 inhibitors can block cell cycles in G1, thus acting as a inhibitor of tumor cell proliferation, effectively overcoming or delaying the emergence of endocrine resistance, for patients to strive for a longer survival time.
currently, three CDK4/6 inhibitors have been approved for the market worldwide, including palbociclib, Pfizer, Ribociclib, and Abemaciclib, Lilly.
from the approved adaptive point of view, these three drugs, whether single or combination, whether as second-line therapy or first-line therapy, are suitable for patients with advanced HR-/HER2-patients.
source: Past evidence in the NextPharma database suggests that CDK4/6 inhibitor combination ET can significantly improve PFS in patients with HR/HER2-advanced breast cancer and delay the start of chemotherapy, but whether patients should receive CDK4/6 inhibitor combination ET on the first or second line has not yet been determined.
same time, a small number of patients with limited burden of metastatic diseases and less biologically invasive characteristics were treated with endocrine monodrides, and there are currently no biomarkers to accurately identify such patients.
It should be noted that when combined nonsteroidal aromatase inhibitors (NSAI) were used in first-line therapy, there was little difference in the efficacy data of CDK4/6 inhibitors;
safety, toxic reactions to the blood system associated with the mechanism of action of CDK4/6 inhibitors, such as reduced neutral granulocytes, are common in all three drugs.
the blood system is less toxic and diarrhea is more common and severe than that of erbasili and Riposili.
addition, liver toxicity is common in all three drugs, of which Riposili liver toxicity is most common.
（Spring LM, et al. Lancet. 2020 Mar 7.) Challenging high-risk early breast cancer-assisted treatment: the opposite outcome of Abesili and Erbesili 1. MonarchE Research MonarchE is a randomized, open-label, multi-center Phase III clinical study that included 5,637 lymph node-positive HR-/HER2-high-risk early breast cancer patients.
subjects were randomly assigned to the Abesili Joint Standard Auxiliary ET group, or simply the Standard Auxiliary ET group, on a 1:1 scale.
mid-term analysis presented at the 2020 ESMO conference showed that the study reached the primary endpoint of IDFS, with Abesili significantly reducing the risk of recurrence by up to 25% (HR:0.747; 95% CI:0.598-0.932; p -0.0096) compared to using standard auxiliary ET alone.
source: The NextMed database consistently showed statistically significant benefits in all preset subgroups, with a difference of 3.5 per cent between groups after 2 years of treatment (92.2 per cent in the Abesili group and 88.7 per cent in the control group).
Common adverse events include diarrhea, fatigue and neogenic granulocyte reduction, mostly at levels 1-2;
, according to the monarchE trial, Abesili became the first and only CDK4/6 inhibitor to demonstrate improvement in IDFS in patients with high-risk HR-/HER2-early breast cancer.
is one of the most significant treatment advances for such patients over the past two decades.
has not yet been listed in China, Mr Abesili has attracted a lot of attention.
2. PALLAS Research PALAS is a randomized, forward-looking, open-label international multi-center Phase III clinical trial conducted at more than 400 centers in 21 countries around the world, with a total of 5,760 patients with early infrastructural (Phase II-III) HR-/HER2-breast cancer.
grouped at 1:1, one group of patients will receive a two-year combined standard assisted ET treatment, followed by a standard auxiliary ET until the fifth year, and the other group will receive a separate five-year standard assisted ET.
three-year iDFS or no distant re-occurrence period (DRFS) were observed in both groups at 23.7 months of medium follow-up.
common adverse events include blood system toxicity, fatigue, upper respiratory tract infections, nausea/diarrhea, and hair loss.
source: NextMed Database 3. PENELOPE-B Research On October 9, Pfizer announced that the Phase III PENELOPE-B study for the treatment of patients with HR-HER2-early breast cancer had not reached the primary endpoint of IDFS, and that these patients still had residual leaching disease after completing new complementary chemotherapy.
PENELOPE-B study was a randomized, double-blind, placebo-controlled Phase III clinical trial that included 1,250 patients and was designed to compare the efficacy and safety of the combined endocrine standard therapy with the placebo combined endocrine standard.
these patients had a clinical pathology stage-estrogen/grade (CPS-EG) score of 3 or higher (or 2 points if there was lymph node metastasis during surgery).
no new safety signals were observed in the study.
detailed trial data will be presented at a later medical conference.
why did the MonarchE and PALAS study come to a different end? Now let's compare the results of the monarchE and PALAS study.
PALLAS study included 5,760 patients with HR-/HER2-Early Immersion (Stage II-III) breast cancer, allowing lymph node-negative patients to be included in the group, and the MonarchE study included 5,637 lymph node-positive ≥4, or 1-3 high-risk early breast cancer patients with other high-risk factors.
The former's overall trial results did not indicate benefits, nor did they indicate any clinical subsets that might benefit, including a high-risk subset (approximately 59% of patients);
source: Why do two drugs that are so similar in metastasis background produce such different results in the auxiliary background? There are many potential reasons: it's all accidental.
any study, no matter how many P-values have 0s, may only happen by accident.
both negative and positive studies.
may be a research design error.
CDK4/6 inhibitors are a class of drugs that are thought to reverse endocrine resistance and prolong benefits.
, however, the above study obtained early follow-up results, while early recurrence of tumors was usually more affected by chemotherapy and less affected by endocrine therapy.
may have been mis-designed.
may be differences in the mechanisms of drug action.
although abesili and erbesili are both designed to inhibit CDK4/6, their relative potency is significantly different from other activities.
Abesili is also active against a variety of kinases that are not inhibited or only slightly inhibited by pypsyri or riposili, and can also block the G1 and G2 stages of the cell cycle, still have inhibitory effects on pRB defective cells, and have a higher selectivity to CDK4, so the hematological toxicity is small while the strong inhibition of tumor cell proliferation.
in metastasis background, this does not appear to affect effectiveness, but significantly affects toxicity characteristics.
may indeed lead to differences in efficacy in complementary therapy.
may also be a problem with medication patterns.
can be taken continuously without interruption because of the weak hematological toxicity of Abesili.
, in contrast, erpene is a three-week suspension of the drug after a week of intermittent dosing.
the rate of adverse events occurred, the rate of drug suspension also varied.
16.6 percent of patients in the MonarchE study had treatment interruptions, while the PALLAS study had more treatment interruptions (42.2 percent).
there is no standard answer to why the two trials are different, and more data and longer time to understand.
The Abersilli and MONARCH series later studied drug action mechanisms that were more unique, blood system toxicity was less common, and Abersili, which seemed to be better through the blood-brain barrier, was a "strong" dark horse, despite the FDA's latest approval.
based on public information on the U.S. Clinical Trials Registry website, we combed through the MONARCH series of studies conducted by Abesili at all stages of breast cancer to get a full picture.
The basics of combing according to the start time of the study are as shown following for the late-stage HR-/HER2-breast cancer population 1/2/3; green: for early-stage HR-/HER2-breast cancer population; red: for non-HR-/HER2-breast cancer populations; another perspective, re-grooming according to disease stage and type of therapy: In a word, Abesili is in the highest trial stage of new assisted treatment for early breast cancer II Period, currently only neoMONARCH results announced, Abesili combined anazole can significantly reduce the expression of tumor tissue Ki-67, in the early stage of breast cancer-assisted treatment in the highest trial phase III, monarchE phase analysis published in ESMO2020, reached the main endpoint IDFS, only a few patients due to diarrhea suspension, joint standard ET or will become a high-risk early breast cancer recommendation program; Second-line therapy combined with fluovirs has become the standard therapy, and Abesili monotherapy has also been shown to be effective.
recommendations for the NCCN Breast Cancer Guidelines for Abesili Source: NextMed Database Resources: 1 s Opposing Trial Results on CDK ResOrs Means Good Science. Medscape October 07, 2020.