Original CCMTV Oncology Channel
In order to allow mainland clinical oncologists to share world-class scientific research results faster and more conveniently, the "2024 China Clinical Oncology Annual Progress Symposium (BOC) and Best of ASCO 2024 China" co-sponsored by the Chinese Society of Clinical Oncology (CSCO) and Beijing Hesco Clinical Oncology Research Foundation was held in Guangzhou from July 5 to 7, 2024. On the afternoon of July 6, Current Standard Practice after ASCO 2024 was the finale, and Professor Yin Yongmei from Jiangsu Provincial People's Hospital summarized the key developments in the field of breast cancer. The CCMTV Oncology Channel has compiled its content into a text for the benefit of its readers.
HER2-positive breast cancer
HER2+ breast cancer has gone from "no choice" to how to choose between monoclonal antibodies, small molecule TKI drugs, ADC drugs, and new ADC drugs for more than 20 years. The CSCO BC guidelines classify HER2+ breast cancer into two types: tratum treatment sensitivity and tratum treatment failure, and the roadmap shown in the figure can guide our clinical practice at a glance. However, such a roadmap cannot answer all the questions of HER2+ breast cancer.
The first question, is it possible to try new combinations of treatments based on existing drugs?
Previous Phase HER2CLIMB-02III randomized controlled studies have confirmed the feasibility of ADC+TKI. T-DM1+tucatinib significantly improved PFS in patients with treatment-experienced HER2+ MBC (9.5 versus 7.4 months, HR0.76, P = 0.0163). The type of adverse events with combination therapy was consistent with previous reports, with a slight increase in the incidence.
So, is anti-HER2 ADC + pertuzumab feasible? The DB07 study at ASCO this year answers this question. This is a Phase 1b/2, multicenter, open-label cohort study of DS-8201 as a single agent, DS-8021 in combination with immunotherapy, and DS-8201 in combination with pertuzumab. Although this is only a Phase 1b/2 clinical study, it does show that the objective response rate of DS-8201 combined with pertuzumab is higher than that of DS-8201 alone, and at the same time, the safety of 1+1>2 is worthy of our attention.
The incidence of diarrhea and anemia was significantly increased after DS-8201 combined with Patu, and the incidence of grade ≥3 AEs increased by 10% and the incidence of interstitial pneumonia increased by 5% in the combination treatment group.
ADC combined with Patu's Phase III clinical study DB09, which is a clinical study in Germany, Professor Jiang Zefei served as the leading PI in China, trying to answer DS-8201 monotherapy, and the combination of Patu, compared with the current standard first-line treatment of tripa.
The clinical study of SHR-A1811-m-307 is similar to DB09, and Jiangsu Provincial People's Hospital is the team leader. The above two phase III clinical studies can answer the questions of ADC combined with pertuin in terms of efficacy, safety, dominant population, and the arrangement of HER2+ advanced breast cancer in the future.
In addition to the above questions, there are other questions worth pondering. The first-line treatment for HER2+ breast cancer is taxanes + HP, can yew be switched to other chemotherapy agents, such as eribulin?
Eribulin is approved in China and the United States for the treatment of locally recurrent or metastatic breast cancer patients who have received at least two prior chemotherapy regimens, including anthracyclines and taxanes, and in Japan for patients with inoperable or recurrent breast cancer.
At this year's ASCO conference, we saw the exploration of eribulin in this regard, the JBCGR-M06 study led by Japan experts, the head-to-head comparison of first-line eribulin combined with tripazal dual target and standard first-line treatment of taxanes combined with tripa, showed non-inferiority, and the incidence of grade 3 adverse events was smaller than the current standard yew combined with dual target side effects.
In addition, is it possible to go to chemotherapy for HR+/HER2+ advanced breast cancer?
As early as 2021 ASCO, Professor Yuan Zhongyu's SYSUCC-002 study verified the feasibility of chemotherapy for HR+/HER2+ patients. At that time (2013-2019), we didn't have CDK4/6 inhibitors, no dual-target, no ADC drugs, but such a phase III randomized controlled clinical study of chemotherapy plus tractus endocrine plus tract did achieve non-inferior results. In other words, for patients with HR+/HER2+ breast cancer with small tumor burden, endocrine combined targeted anti-HER2 therapy can be used, and the guidelines have also made corresponding recommendations.
So, for HR+/HER2+ breast cancer patients, what is the effect of CDK4/6i+ET+anti-HER2 compared with TPC?
This year's PATRICIA study at ASCO did just that, and found that this "de-chemotherapy" approach resulted in superior results, with mPFS extending from 7.5 months in the control group to 9.1 months. Although the hematologic toxicity associated with CDK4/6 inhibitors is higher, the incidence of pain and vomiting associated with chemotherapy is lower.
Summary of HER2-positive breast cancer
Optimal first-line treatment:
- THPy and THP parties remain the preferred referral schemes. Eribulin may be considered in patients who have failed taxane therapy; First-line treatment studies of T-DXd and A1811 are ongoing;
- Whether the "ADC+" regimen can be moved forward requires more data to optimize the deployment plan and reasonably assess the treatment benefit, drug toxicity and patient-reported outcomes.
Intensive endocrine dechemotherapy regimen is suitable for:
- PAM50 and others may be considered to screen patients who have benefited from endocrine therapy;
- The PATINA study is ongoing, exploring the effectiveness of the maintenance therapy phase + CDK4/6i after 6-8 cycles of first-line therapy.
HR-positive breast cancer
For the adjuvant treatment of HR+EBC, in the 2024 CSCO BC guidelines, for patients with a high risk of recurrence (4 positive lymph nodes≥ or 1-3 positives with G3, T≥5cm, Ki67≥20%), based on the MonarchE study, the guidelines will recommend AI+abeciclib as the first level.
So, can node-negative patients benefit from CDK4/6i treatment? The MonarchE study was unable to answer this question because it did not enroll N0 patients.
The NATALEE study, which enrolled 28% of N0 patients, reported iDFS in the N0 subgroup at this year's ASCO Congress, and the benefit of rebociclib in the N0 subgroup was consistent with the total population. However, we can also see that the number of events is relatively low due to the relatively low risk of N0 patients. Rebociclib's 3-year iDFS has only brought less than 3% benefit, so based on the NATALEE study, should node-negative patients be given intensive adjuvant with CDK4/6 inhibitors?
In this regard, the ASCO panel concluded that the risks of rebociclib treatment may outweigh the benefits of rebociclib for low-risk patients included in the NATALEE trial, particularly those with node-negative breast cancer. There is currently insufficient evidence to determine which subgroups must not require treatment, and the benefits, risks, costs, and preferences of each patient should be considered.
The 2024 CSCO BC guidelines for HR+MBC divide advanced breast cancer into 5 stratifications, namely: no endocrine therapy, TAM treatment failure, NSAI treatment failure, SAI treatment failure, and CDK4/6i failure. However, the guidelines for the diagnosis and treatment of ABC5 advanced breast cancer in foreign countries are different, and the stratification of HR+MBC is as follows: primary endocrine resistance, secondary endocrine resistance, and non-endocrine resistance.
For the treatment strategy of HR+MBC, the first question is whether it is necessary to stratify the treatment according to the endocrine resistance after the failure of adjuvant endocrine therapy?
2023年SABCS，INAVO120研究在辅助内分泌治疗原发及继发耐药伴PIK3CA突变患者中探索Inavolisib+哌柏西利+氟维司群的疗效与安全性，三药联合PFS较对照组显著获益（15 vs. 7.3mo, HR:0.43）。
INAVO120 PFS2 results were disclosed at ASCO 2024. Inavolisib in combination with palbociclib + fulvestrant was associated with sustained benefit after disease progression, showing a delay in the need for subsequent anti-tumor therapy (8.9 months delay), including chemotherapy (NEvS. 15.0 months), supporting the clinical benefit of inavolisib-based regimens.
The second question is, the real-world data of the application of 4 CDK4/6i in China?
At present, four late-stage CDK4/6i have been approved, and the efficacy is similar. Under the premise of patient-centered and quality of life improvement, the reported outcome performance of CDK4/6i is worthy of attention.
The first cross-sectional study of CDK4/6i in China, led by Prof. Jiong Wu, focused on the safety and patient-reported outcomes of palbociclib, abeciclib, and darsilib. The results of the patient questionnaire showed that the incidence of fatigue, hair loss, hot flashes, insomnia, arthralgia, nausea, vomiting, diarrhea, and anorexia was the lowest in the dalsili group.
In addition to this, the question we need to answer is, what is the treatment option after CDK4/6i progression?
The 2022 ASCO, Phase II. MAINTAIN study explored the feasibility of continuing CDK4/6 inhibitor maintenance therapy in patients who failed CDK4/6 inhibitor therapy (N=120). PFS was longer in the reboxiclib group than in the placebo group (5.29 versus 2.76 m).
The 2024 ASCO: Phase III postMONARCH study enrolled patients with advanced CDK4/6i treatment failure and no other treatment regimens, and found a 27% lower risk of PFS events in the abeciclib group compared with placebo.
In addition, for patients with low HR+/HER2 expression, based on the outstanding performance of DS-8201 in the DB04 study in HER2-low expression population, we changed the previous dichotomy of HER2+ and HER2- and proposed the concept of HER2 low expression.
The data of the DB06 study at ASCO this year were announced, and the DB04 and DB06 studies included people with low expression of HR+/HER2, and the differences between DB06 and DB04 are: 1. The number of lines is moved forward: DB04 is enrolled in patients who have received first- to second-line chemotherapy, and some of DB06 are patients who have progressed within 6 months of first-line CDK4/6i combined with endocrine therapy; 2. The DB06 study included patients with ultra-low expression: defined as weak cell membrane staining (IHC>0<1+) of ≤10% invasive cancer cells.
DB06 showed that in the HER2-low population, the median PFS was 13.2 months in the T-DXd group, which was 5.1 months longer than that in the TPC group, and the risk of disease progression or death was reduced by 38% (HR=0.62, 95% Cl: 0.51-0.74). The improvement in PFS in the HER2 ultra-low expression population was consistent with the benefit in the HER2-low expression population.
DB-06 indicates that T-DXd is a new option for patients with low and ultra-low HR+HER2 expression ≥ 1L endocrine therapy. However, whether the applicable population of T-DXd can be extended to "ultra-low expression" is challenged by pathological detection standards. In 2022, when the FDA approved the low expression of DB04 HER2, it also approved the HER2 protein detection antibody. It shows that the consistency of pathological testing is a consideration for the approval of indications. It remains to be seen whether the ultra-low expression population in DB06 can be recognized by the regulatory authorities.
Summary of HR-positive mastochropathy
Early CDK4/6 inhibitors are suitable for:
- Adjuvant CDK4/6 inhibitors are recommended for patients at high risk of recurrence; Node-negative patients should be cautiously considered in light of the disease.
Early adjuvant endocrine therapy resistance (ABC5: primary, secondary) population:
- After endocrine therapy failure, patients with PIK3CA mutations can consider a three-drug combination regimen of PI3K inhibitor + CDK4/6 inhibitor + ET
After failure of advanced CDK4/6 inhibitor therapy:
- From the perspective of research data, the T-DXd scheme achieved excellent mPFS; However, it remains to be seen whether it can be extended to "ultra-low expression".
- From the perspective of drug accessibility, switching to CDK4/6 inhibitor cross-line therapy is an option.
- From a biomarker perspective: NGS testing can be considered for targeted therapy of the PAM signaling pathway.
Triple negative breast cancer
For triple-negative breast cancer (TNBC), there are many questions that need to be answered, but few that can be answered.
The first question is, does the order of early TNBC immunotherapy matter?
Keynote 522 study, with positive results from pembrolizumab in both neoadjuvant and adjuvant phases. Therefore, the 2024 CSCO BC guidelines also include them in neoadjuvant immunotherapy and neoadjuvant postadjuvant therapy for early TNBC.
However, the Impassion 030 study, in which atezolizumab was used in the adjuvant phase, failed. At ASCO 2024, the A-BRAVE study targeted adjuvant immunotherapy in high-risk populations, and although the DFS value was improved, no statistical difference was obtained.
Why is immunotherapy positive in the neoadjuvant and late treatment phases of TNBC but negative in the adjuvant phase?
This may be due to changes in the tumor microenvironment after surgery, leading to immunotherapy failure in the adjuvant phase.
New ADC drugs and new combinations
This year, there are the following ADC new drug studies at ASCO that deserve our attention:
First of all, in the phase III clinical study of the domestic HER2-ADC ARX788 of which Professor Hu Xichun served as the leading PI, ARX788 showed a statistically significant PFS improvement compared with lapatinib combined with capecitabine, and the OS was not yet mature, but showed a trend of benefit. At the same time, we should pay attention to the occurrence of ARX788 ocular toxicity and interstitial pneumonia.
The second is the domestic Trop-2 ADC drug, which we are accustomed to calling SKB264, and the OptiTROP-Breast01 clinical study is mTNBC for advanced stage ≥2L anti-tumor therapy, and Academician Xu Binghe and I jointly serve as the leading PI. SKB264 achieved statistically significant and clinically meaningful improvements in both PFS and OS compared to chemotherapy. Regardless of the clinical benefit of TROP2 expression, patients with high TROP2 expression tended to have better PFS.
In terms of safety, the data for SKB264 and gosatuzumab (SG) in the Chinese population are similar. We look forward to the launch of this domestic TROP2 ADC in China as soon as possible."
So, can this TROP2 ADC be combined with immunotherapy in the future? Whether "synergy" is "synergistic" or not yet needs to be verified by clinical studies.
The existing treatment of HR+HER2-mBC ≥ 1 L of gosatuzumab in combination with pembrolizumab, and the neoadjuvant treatment of HER2-EBC with dato-TXd in combination with durvalumab, showed only numerical improvement, but not a statistically significant difference.
We expect the ongoing TROPION-Breast 04 (Phase III, Dato-Dxd + durvalumab, early TNBC), TroFUSE-010 (Phase III, SKB264 + pembrolizumab, HR+HER2-late), and TroFUSE-012 (Phase III, SKB264+ pembrolizumab, early TNBC) to answer this question.
These are the changes that the latest research from ASCO 2024 has brought to our clinical practice.