Expert Discussion: ESMO 2024

Thomssen: Summarizing the results of monarchE and NATALEE (and assuming appropriate approval of both drugs), how would you recommend to integrate CDK4/6 inhibitors into the adjuvant therapy of ER-positive early-stage breast cancer? Do we have a new therapy standard?

Lin: Additional follow-up of both monarchE and NATALEE shows continued separation of the curves over time that has persisted and deepened into the period after completion of the adjuvant CDK4/6 inhibitor. I believe that the consistency in direction of the results between the two studies provides confidence of the benefit of CDK4/6 inhibitors in the adjuvant setting. For patients fulfilling eligibility criteria for monarchE, we have already been incorporating abemaciclib routinely in our treatment standard. For patients who fulfill NATALEE but not monarchE criteria, I do believe the longer follow-up data (and the recent FDA action) now position ribociclib as a standard option as well. For patients who fulfill eligibility for both drugs, I have generally still favored abemaciclib due to shorter overall duration of treatment (2 years vs. 3 years) and less hepatic toxicity. An important question is “how low to go” with ribociclib. NATALEE included patients with stage IIA N0 disease in the case of specific features such as high Ki67 or high genomic risk score. Should all such patients be offered ribociclib, or are there other factors we can use to further refine our risk stratification and estimation of risk-benefit profile?

Banys-Paluchowski: Following the approval of ribociclib in the adjuvant setting, a large number of patients with HR+ HER2- early breast cancer will be eligible for CDK4/6i-based therapy. According to our data from the University Hospital Schleswig-Holstein Campus Lübeck (soon to be published), approx. 33% of these patients are potential candidates for ribociclib, and 25% for abemaciclib. In case of patients with intermediate risk of relapse (i.e., node-negative disease and those with node-positive eBC that do not fulfill monarchE inclusion criteria), only ribociclib can be offered. Peter Fasching showed at the ESMO that ribociclib benefit is not limited to patients with higher tumor burden. Indeed, ribociclib improved 4-year iDFS rates from 87% to 92.1% in patients with node-negative tumors. Therefore, in my opinion, ribociclib should be recommended for this patient group. In case a patient is a candidate for both abemaciclib and ribociclib, individual counseling on potential side effects and duration of therapy will be necessary to guide patient’s decision.

Bidard: The highest risk population, primarily investigated in the monarchE trial, derives a clear benefit of the addition of 2 years of abemaciclib. This benefit is apparently replicated with 3 years of ribociclib. While longer follow-up data should be looked at when they become available, abemaciclib and ribociclib are for me SoC in this population. There is no way to differentiate the two agents in terms of efficacy: in that context, toxicity, tolerability, choice of endocrine therapy backbone, cost, and patient preference should be taken into account to drive the choice between the two drugs.

The 4 y iDFS NATALEE data in stage II (/N0) eBC patients are, in my opinion, maybe the most striking results reported at ESMO: the absolute iDFS gain in this intermediate-risk population made increased to 4–5% at 4 y. This gain is numerically higher than the absolute gain observed (all patients mixed) at 4 y in the EBCTCG meta-analysis that compiled the outcome data for AI vs. TAM. It is interesting to note that this gain in the experimental arm of NATALEE has been obtained despite the use, in both arms, of a maximalist endocrine therapy backbone (i.e., AI+OFS in stage II premenopausal patients). These results have to be balanced with the toxicity of ribociclib, including financial toxicity – but fortunately, ribociclib is much more affordable in our EU countries. The use of adjuvant ribociclib is also opening a venue for chemotherapy de-escalation in this intermediate-risk population, a question that will be investigated in an incoming noninferiority international trial.

Thomssen: Considering the overall survival data of KEYNOTE-522 (KN-522) and the French data on ER low expressors, how would you discuss the future treatment of early-stage triple-negative breast cancer including those with low ER expression (1–9%)? Checkpoint inhibitors for all including T1 and LAR subtype?

Lin: I would generally offer the KN-522 regimen to patients with clinical stage II or III triple-negative breast cancer (ER <1%) but would also offer to patients with low ER expression (1–9%).

Banys-Paluchowski: Regarding patients fulfilling KN-522 inclusion criteria but expressing ER at a low level (1–9%), I would recommend neoadjuvant treatment as for patients with triple-negative disease (i.e., chemotherapy with pembrolizumab) and continue pembrolizumab after the surgery for 9 cycles. The PROMENADE study confirms this strategy as very effective in terms of pCR for this patient group. However, based on the data presented by Choong et al. from the Mayo Clinic at the ASCO 2024, I would discuss adjuvant endocrine therapy as well.

Bidard: The retrospective pooled analysis on ER-low TNBC is another layer of evidence that the European definition of TNBC is more appropriate than the definition used for registration by FDA. Within the stage II–III tumors, more research is needed to understand exactly which patients do not benefit from the addition of pembrolizumab and I consider it is too early to de-escalate outside clinical trials. These trials are mostly focusing on the post-surgery pembrolizumab tail, which is the most trivial and less risky de-escalation to address. Outcome data for stage I do not suggest a strong unmet need that would justify the use of pembrolizumab.

Thomssen: Retrospective data from the French database demonstrated that nonadherence to adjuvant endocrine therapy may be detrimental, at least in younger ages. How would you integrate these data with the general conception that drug holidays may be possible in distinct situations as for long-term aromatase inhibitors (SOLE), or for desire to have children (POSITIVE)?

Lin: My interpretation of these data is that deliberate drug holidays in the specific circumstances of POSITIVE and SOLE are not detrimental, but that chronic underdosing/nonadherence/permanent early discontinuation of endocrine therapy is detrimental. In SOLE, patients were enrolled only after several years of traditionally dosed endocrine therapy and so is asking whether deliberate drug holidays in the late adjuvant setting is reasonable. In POSITIVE, while patients discontinued endocrine therapy to try to conceive, they re-initiated later in time. I think of endocrine therapy as a marathon and not a sprint.

Banys-Paluchowski: Motivating patients to increase therapy adherence seems crucial in the context of these new data. On the other hand, respecting patient individual wishes, e.g., regarding family planning, needs to be considered as well. In case of patients wishing to interrupt adjuvant endocrine therapy in order to conceive, I would strongly recommend maximal therapy adherence as long as the therapy is administered (i.e., at least 18 months), the use of assisted reproductive techniques if spontaneous pregnancy could not be achieved within 6 months, and restart of endocrine therapy soon after giving birth. Regarding “drug holiday,” we need to keep in mind that studies exploring the oncological safety of this strategy, such as the SOLE trial, included patients who already completed 4–6 years of endocrine therapy. These results should not be uncritically extrapolated to patients in the first years of adjuvant treatment.

Bidard: There are fundamental differences in the study design that explain these apparently discrepant results. First, the size of the French study is much larger (100x) than in SOLE and POSITIVE and therefore allows to detect small trends that were missed by prior studies. I think that the linear impact observed (i.e., the magnitude of the detrimental effect of nonadherence being proportional to the length of nonadherence) really advocates in favor of the reality of the observation reported in the French study.

Second, clinical trials investigating drug holidays and registries focusing on pregnancy are enriched in women at lower risk of relapse.

Third, these drug holidays/pregnancies also occurred after an initial adherence to therapy (often several years), while the French retrospective cohort results also include immediate “quitters.” Results reported at ESMO did not show the impact of when the discontinuation is happening.

My opinion is that any discontinuation of endocrine therapy is associated with a decreased benefit of endocrine therapy, but this impact may be clinically marginal. What POSITIVE showed is that endocrine stimulation (during the pregnancy) is not associated with a dramatic increase of relapses.

Thomssen: With regard to radiotherapy (HypoG-01), would you consider mild hypofractionation (40 fractions à 2.67 Gy) as the new standard for adjuvant therapy of the breast, the thoracic wall, and the regional lymph node? Is there any place left for conventional fractionation (25 fractions à 2.0 Gy)? Will these short-term therapies have an impact on the timing of radiotherapy and chemotherapy?

Lin: The data certainly looked very encouraging. I would like to defer on committing to an answer to this question and solicit feedback of radiation oncology colleagues!

Banys-Paluchowski: After the hypofractionation became standard of care for radiotherapy of the breast, the optimal fractionation in case of nodal irradiation remained a matter of debate. The HypoG-01 trial confirms noninferiority of hypofractionation and is a practice-changing study. From now on, all patients are candidates for mild hypofractionation.

Bidard: There are debates as to whether one toxicity (lymphedema) was the most appropriate endpoint for the Hypo-G1 trial (presented first at ESTRO and represented at ESMO). However, my understanding is mild hypofractionation is becoming SoC, since hypofractionation is more convenient and survival curves look somehow the same. At a higher level, my only (and unsubstantiated) concern is that many de-escalations in local therapy have been investigated separately but are now being implemented at the same time in our eBC patients.

Thomssen: Considering the results of DESTINY-Breast12, what is the future of treating brain metastases? Can we treat brain metastases first line without administering local therapy (no irradiation, no surgery)? Is there any role left for tyrosine kinase inhibitors?

Lin: I think that the response rates and PFS were sufficiently high in DB-12 to make treating brain metastases systemically with trastuzumab deruxtecan (T-DXd) and deferring radiation a generally safe and reasonable option for patients. As always, the specific patient scenario matters. For a patient on HP maintenance with excellent systemic control and a first presentation of a limited number of brain metastases amenable to SRS, I think that SRS and continuation of HP remains the best option for most patients, as both HP and SRS are generally very well tolerated. For patients with too many brain metastases for SRS (i.e., WBRT is being considered), or for patients who have a high brain metastasis velocity after SRS, or progression in SRS-treated sites, trying T-DXd in lieu of local therapy seems very reasonable given results of DB-12. There is still a role for HER2-targeted TKIs – in particular, most patients will still progress eventually on T-DXd and there is a need for CNS-active therapies in the post-T-DXd setting. Some patients may prefer the toxicity profile of the HER2CLIMB regimen over T-DXd and elect to lead with tucatinib first. Finally, there are a number of studies combining various HER2-targeted ADCs with HER2-targeted TKIs and it is possible a combination approach will be superior with either approach alone.

Banys-Paluchowski: In my opinion, this study does not answer the question on the optimal form of therapy (surgery vs. local irradiation vs. systemic therapy) but confirms T-DXd as an effective systemic therapy regimen, independent of the type of brain metastasis (active vs. stable). DESTINY-Breast12 is a single-arm study, and one might argue that the level of evidence for T-DXd remains lower than in case of tucatinib-based therapy (randomized HER2-CLIMB study). Both regimens are valid options in patients with active brain metastases, and the choice of therapy should be based on patient preferences and toxicity profile.

Bidard: DB-12 could have been a typical French trial, where we demonstrate in theory what we already knew from the practice: T-DXd is an efficient therapy for brain mets, including active ones. As discussed by C Saura at ESMO, TKIs will likely be used after T-DXd in patients with brain mets. However, DB-12 does not demonstrate that active brain mets should not be treated by stereotactic radiosurgery whenever and as soon as possible.

Thomssen: With regard to new therapeutic options and concepts that were presented at ESMO 2024, what are the most promising “new kids on the block”?

Lin: There continue to be a large number of ADCs in clinical development – additional HER2- and Trop2-targeted ADCs including IBI354, ESG401, but other targets and payloads as well. In addition, there were data presented in metastatic TNBC for bispecific VEGF-PD1/PDL1 antibodies such as ivonescimab and PM8002/BNT327 that were encouraging. Finally, we saw a novel design of preoperative combination immunotherapy without chemotherapy in patients with TNBC and high TILs showing pCR rate of 47% with nivo/rela and 33% with nipi/ivo – the rate of IO toxicity was higher than we would like to see in a curative intent setting, but the concept of tuning immunotherapy to maximize benefit by leveraging a neoadjuvant model was notable.

Banys-Paluchowski: I would recommend to look closely at three strategies: (1) the combination of durvalumab and datopotamab deruxtecan showed high pCR rates in patients with specific subtypes (I-SPY 2.2), (2) stereotactic body radiation therapy applied to the primary tumor during neoadjuvant chemo- and immune therapy resulted in high pCR rates (NeoCheck Ray), and (3) structured exercise interventions are the focus of several completed (OptiTrain, eMOUVOIR-1902) and upcoming trials (NeoACT; https://www.eubreast.org/neo-act-trial).

Bidard: ESMO 2024 was more on gaining confidence with recently or soon-to-be-approved drugs (KN-522, DB-12, NATALEE…). The multitude of new ADCs and bi-specific mAbs presented at ESMO shows the dynamism of biotech companies, especially from China. There is apparently a strong shift toward early drug development taking place in China, which is likely to precede the emergence of big pharmaceutical Chinese companies.