Potential and Competition: Viewing the Landscape of New Breast Cancer Drugs from the SABCS 2021 Conference

In the last month of 2021, the SABCS 2021 meeting ends
.

This conference also witnessed new breakthroughs in the treatment of new breast cancer drugs in the HER2+ and HR+ populations

1.
HER2+ breast cancer ADC gradually enters early treatment

1.
HER2+ breast cancer ADC gradually enters early treatment

About 15-20% of breast cancers are HER2 positive
.

The current HER2+ breast cancer treatment drug market is still dominated by Roche

▲Roche's HER2 assets accounted for about half of its revenue in the first three quarters of 2021

The HER2+ ADC drug Enhertu jointly developed by Daiichi Sankyo and AZ has sales of US$293 million in global markets outside of Japan in the first three quarters of this year.
The only approved indication in the field of breast cancer is HER2+ advanced breast cancer third-line or above treatment, based on Destiny -The results of the Breast 01 study received accelerated approval
.

The Destiny-Breast 03 study published on ESMO this year has made Enhertu the focus of attention in the field of HER2+ breast cancer treatment.

▲Destiny-Breast 03 shows that Enhertu's PFS is significantly better than Kadcyla

Interestingly, at the SABCS 2021 conference, Enhertu also announced a phase II biomarker study called DAISY, which included three groups of patients with advanced breast cancer, namely, patients with high, low, and no expression of HER2.
The results showed that HER2 was high.
The response rate was 69% (47/68) in the expression group, 33% (24/72) in the low expression group, 31% (11/36) in the no expression group, and 11.
1, 6.
7, and 4.
2 months for the three PFS groups, respectively
.

Enhertu has an effect on people with low and no HER2 expression.

Enhertu's Destiny-Breast series of trials are still exploring more front-line treatments, from the end-line treatment to the front-line.
Other current researches using the new load Her2 ADC are also adopting this strategy, including Byondis’ trastuzumab duocarmazine, which is developing the end-line Research, and Rongchang Bio's disitamab vedotin, are used in the research of HER2+ breast cancer with liver metastasis
.

In addition to the progress of ADC, although PD-(L)1 inhibitors have not shown an effect on HER2+ breast cancer, there are currently many attempts to combine with HER2+ targeted drugs, including Roche is developing Trastuzumab Emtansine and Atezolizumab or placebo It is also used in HER2+ and PD-L1 positive advanced breast cancer
.

Corning Jerry announced the preliminary results of KN026 (anti-HER2 bispecific antibody) combined with KN046 (PD-L1/CTLA-4 bispecific antibody) in the treatment of metastatic HER2+ breast cancer patients at the SABCS 2021 meeting, and 36 cases were enrolled in the trial Most of the patients have received HER2 targeted therapy above the 3rd line.

2.
The worries and joys of front-line exploration of CDK4/6 inhibitors

2.
The worries and joys of front-line exploration of CDK4/6 inhibitors

CDK4/6 inhibitors are also exploring frontline treatment
.

Among the three major CDK4/6 inhibitors currently on the market, Pfizer has become a leader in the HR+/HER2- field with the listing of the CDK4/6 inhibitor Ibrance.

Lilly's CDK4/6 inhibitor Abemaciclib was approved on October 13, 2021 for the adjuvant treatment of breast cancer with positive HR, negative Her2, positive lymph nodes, high risk of recurrence, and a Ki-67 score of at least 20%.
Patients, regardless of Ki-67 scores, have shown iDFS advantages in patients with high recurrence risk, but the efficacy is more significant in Ki-67 ≥ 20%, so this population restriction is added to the approval, which is the first An FDA-approved CDK4/6 inhibitor for adjuvant treatment of breast cancer
.

The 2-year and 3-year DRFS (survival without distant metastasis) updated at this year's ESMO meeting also proved the effectiveness of Abemaciclib for adjuvant treatment of high-risk HR-positive people

▲Long-term follow-up proves the effectiveness of Abemaciclib as an adjuvant treatment

Another also hitting the adjuvant therapy market is Novartis’s Ribociclib.
Its ongoing NATALEE trial will release the results at the end of next year.
Unlike the MonarchE study, NATALEE includes intermediate-risk and high-risk patient populations.
According to the successful results of MonarchE, the efficacy is more clear for high-risk groups, so the success of the Natalee trial may also be related to the proportion of patients with different risk levels
.

3.
The rise of SERD

3.
The rise of SERD

Fulvestrant is a selective estrogen receptor degrading agent (SERD), the only drug approved for the treatment of breast cancer, and can be used as an ER downregulator
.

With the expiration of the patent, AZ is also looking for a successor to this former blockbuster drug, Camizestrant, which is an oral selective ER degrading agent (ngSERD), but whether its SERENA-2 is used for second-line treatment, or SERENA-4 is the first-line target Trials in the treatment population will not have preliminary results until after 2022

▲The effectiveness and safety of the main SERD currently in the clinic are compared

Competition for the next generation of oral SERD inhibitors is also fierce
.
Sanofi announced the study of SERD amcenestrant named AMEERA-1: amcenestrant combined with the targeted anticancer drug CDK4/6 inhibitor Ibrance (palbociclib) in HR+/HER2- postmenopausal women with breast cancer, the results showed that ORR was 34%, CBR It is 74%
.
This is an important step for Sanofi to restructure its oncology business
.
The key phase III of AMEERA-3 for the second-line treatment population needs to be postponed until next year to have results
.

The first to announce the results of the Phase III trial will be Radius’ Elacestrant.
The EMERALD trial requires that CDK4/6 inhibitors have been used.
This is also the biggest difference between this trial and other second-line treatment trials of ER degradants.
The primary endpoint includes the entire population.
PFS and PFS in ESR1 mutant populations
.
The mutation rate of ESR1 in primary breast cancer is very low, less than 5%, but the proportion can increase to about 30% in patients who have undergone endocrine therapy
.
The results at the SABCS 2021 meeting showed that the PFS of fulvestrant was improved in all populations
.

▲EMERALD test results

In addition, Pfizer cooperated with Arvinas to obtain PROTAC SERD ARV-471, which believes that the ER protein can be degraded for multiple rounds to make it more effective
.
SABCS 2021 also reported preliminary results.
Among HR+/HER2- breast cancer patients, as of June 6, 2021, 50 patients received single-drug escalation therapy
.
The maximum tolerated dose was not reached and no dose limiting toxicity (DLT) was observed
.
The most common (≥10%) treatment-related adverse events (TRAE) were nausea (24%), fatigue (12%), and vomiting (10%), where clinical benefit can be assessed (confirm complete remission, partial remission, or stable disease) Among 34 patients ≥24 weeks), the CBR was 41%
.
And it has shown encouraging clinical activity (41% CBR) in patients who have received CDK 4/6 inhibitor therapy
.
ARV-471 is currently under VERITAC Phase II single-drug study, 200 mg and 500 mg once a day
.