CME
Physicians: Maximum of 0.75 AMA PRA Category 1 Credit™
Released: August 14, 2024
Expiration: February 13, 2025
I-SPY 2.2: Study Design
Sara Hurvitz, MD:
Next, we will discuss data with the combination of datopotamab deruxtecan (Dato‑DXd) plus durvalumab. Dato‑DXd is a TROP‑2-targeted antibody–drug conjugate (ADC) that is administered once every 3 weeks. We had seen previously in the TROPION‑Breast01 trial that there is benefit with Dato-DXd compared to physician’s choice chemotherapy in ER‑positive metastatic disease,11 though we are still waiting for the FDA approval of Dato-DXd at this time.
At ASCO 2024, we saw data from the I‑SPY 2.2 trial.12 Here, patients with HER2-negative stage II-III high-risk early breast cancer received 4 cycles of neoadjuvant Dato‑DXd plus durvalumab. If they were likely to have achieved a pCR, they could go on to surgery. If not, they continued on to various lines of treatment, but what I am going to discuss here is the data with Dato‑DXd plus durvalumab, so the outcomes after those initial 4 cycles of treatment alone.
Also reported at ASCO 2024 were data from the Dato-DXd monotherapy arm of I‑SPY 2.2.13 For patients who had immune‑positive disease there was an estimated pCR expected rate of approximately 30%, which is not bad with single‑agent ADC.
I-SPY 2.2: Baseline Characteristics
Sara Hurvitz, MD:
Analysis of pathologic response rates among nearly 1000 patients across 10 arms of I-SPY 2.2 yielded a refined classification scheme for breast cancers that was better at predicting treatment response than traditional IHC and molecular subtyping.14 This refined scheme included immunotherapy benefit, DNA damage repair deficiency, hormonal therapy benefit, and HER2 targeting. In the current report, approximately 45% of patients were identified as the immunotherapy response predictive subtype.
I-SPY 2.2: Efficacy of Neoadjuvant Dato-DXd Plus Durvalumab
Sara Hurvitz, MD:
With the combination of Dato-DXd plus durvalumab, we saw that for the HR‑negative population, the modeled pCR rate was 44%. But for the immune‑positive cohort the modeled pCR rate was 65%.12
The combination of Dato‑DXd with durvalumab is moving into a larger phase III study in the early stage setting—TROPION‑Breast04 (NCT06112379)—in patients with TNBC or HR-low/HER2-negative breast cancer. What is interesting about this study is that it shows there may be a subset of patients, those who have immune‑positive disease based upon MammaPrint testing, that seem to potentially respond to Dato-DXd plus durvalumab.
I-SPY 2.2: Safety
Sara Hurvitz, MD:
The side effects from Dato-DXd have been previously described. There were no surprising immunotherapy-related side effects from the addition of durvalumab. When Dato-DXd, hopefully, becomes commercially available, the main thing that we all need to be aware of is the risk of stomatitis and that patients need to use prophylactic steroid rinse and then continue it if they develop stomatitis. That is very important with this particular agent.
Kevin Kalinsky, MD, MS, FASCO:
I agree. Compared with the stomatitis that can be seen with everolimus, the stomatitis with Dato-DXd can be persistent and prophylactic management will be essential. In addition, there is some risk of hematologic toxicities or nausea, and some patients could lose their hair. I think it is also important to be aware of the risk of ocular toxicity that could develop. Per the guidelines in the study, patients were not to wear contacts during the course of the treatment to prevent having any sort of keratitis.
I-SPY 2.2: Clinical Implications
Sara Hurvitz, MD:
At this point, these data are not practice changing but they do set the stage for future studies evaluating this combination.
A-BRAVE: Study Design
Sara Hurvitz, MD:
The A‑BRAVE trial was a phase III open‑label study evaluating whether adjuvant avelumab improved outcomes for patients with high‑risk early-stage TNBC after neoadjuvant or adjuvant chemotherapy.15
Patients had to have received a curative‑intent therapy including an anthracycline and taxane (no neoadjuvant immunotherapy) and have tissue available for PD‑L1 expression assessment. Patients were then stratified by whether they had adjuvant therapy or were treated in the neoadjuvant setting and had residual disease and were randomly assigned to avelumab or observation for 1 year. The coprimary endpoints were disease‑free survival (DFS) and DFS in the patients who were treated in the neoadjuvant setting.
Kevin Kalinsky, MD, MS, FASCO:
We had previously seen from the ALEXANDRA/Impassion030 study that there was no benefit for patients with TNBC who went straight to surgery and then received atezolizumab.16 So this study was another randomized phase III trial in patients with TNBC who did not receive neoadjuvant immunotherapy and went to surgery, and the question here is whether there is a benefit of administering immunotherapy in the adjuvant setting only.
A-BRAVE: Baseline Characteristics
Sara Hurvitz, MD:
The majority of patients enrolled in the A-BRAVE trial had HER2 IHC of 0 (64%). Approximately 10% had a germline BRCA mutation and most had a residual cancer burden score that was quite high at 2 (45% overall) or 3 (11% overall). Approximately 20% of the patients in this clinical trial had received adjuvant capecitabine.
A-BRAVE: DFS and OS
Sara Hurvitz, MD:
The 3‑year DFS rate did not look very different between the 2 treatment arms (68.3% with avelumab vs 63.2% with observation), so adjuvant avelumab did not appear to benefit patients. The secondary endpoint of OS, however, was strongly trending towards a benefit with avelumab, with a hazard ratio of 0.66 (P = .035). I found that to be quite interesting. The distant DFS rate also seemed to be improved at 3 years with avelumab (75.4% vs 67.9%).8
Looking at the postneoadjuvant patient population (n = 383), there was a trend toward improvement in the 3‑year DFS rate, approximately a 6.2% difference in favor of avelumab, but that was not statistically significant.
A-BRAVE: Safety
Sara Hurvitz, MD:
The AEs associated with avelumab were as expected, with thyroid dysfunction being the primary type of immune-related AE observed (13.2%), though some patients did have diarrhea/colitis (7.2%) or transaminase elevation (4.7%).
A-BRAVE: Clinical Implications
Sara Hurvitz, MD:
I do not think these data are practice changing. I think they provide early evidence that use of an immune checkpoint inhibitor in patients who did not receive one in the neoadjuvant or adjuvant setting may benefit patients long term, but it did not meet the endpoint of significantly improved DFS. I think these are really interesting data and there are other studies ongoing (NCT02954874; SWOG S1418/BR006) looking at the use of pembrolizumab in patients with TNBC who did not receive it in the neoadjuvant setting and other trials asking similar questions. We will have more data on this strategy in the future.
Kevin Kalinsky, MD, MS, FASCO:
This is technically a negative study where there was no 3-year DFS benefit with 1 year of adjuvant avelumab. Although there was an improvement in OS, the number of events were actually quite small and so in my opinion, this is something that we need to continue to follow. This is a scenario that I encounter in my clinic somewhat regularly, unfortunately, where patients with TNBC have had their surgery first and then they come to medical oncology and the question is whether I should give them adjuvant immunotherapy. At this time with the data available, I would not do that. We await the results of the SWOG S1418/BR006 trial, which randomizes a similar patient population to adjuvant pembrolizumab or observation. In other disease types, such as melanoma, studies have demonstrated a benefit to giving neoadjuvant immunotherapy compared to adjuvant immunotherapy.17 There is something about having the intact tumor and the associated microenvironment that influences the benefit of giving immune checkpoint inhibitors in the neoadjuvant setting. So, again, if I have a patient with TNBC who went to surgery first, I would not give them adjuvant immunotherapy alone. This reiterates the importance that these patients need to be seeing medical oncology before they go to surgery.
NATALEE: Study Design
Sara Hurvitz, MD:
The phase III NATALEE trial evaluated adjuvant ribociclib plus AI vs AI alone in HR-positive/HER2-negative early breast cancer. What was unique about this trial and different from the monarchE study18 of adjuvant abemaciclib, is that NATALEE did allow patients with node‑negative disease, so it included a lower‑risk disease group. Data from the NATALEE trial have been previously published,19 and at ASCO 2024, the subgroup analysis from patients with N0 disease (stage IIA grade 3 or grade 2 and Ki-67 ≥20%, Oncotype DX Breast Recurrence Score ≥26, or high-risk per genomic risk profiling) were presented.20
NATALEE N0 Subgroup Analysis: Baseline Characteristics
Sara Hurvitz, MD:
Approximately three quarters of patients had stage IIA disease.20
NATALEE N0 Subgroup Analysis: Efficacy (iDFS, DDFS, DRFS)
Sara Hurvitz, MD:
The efficacy in terms of invasive DFS, distant DFS, and distant relapse‑free survival all seemed to indicate a similar benefit with adjuvant ribociclib in patients with node-negative disease as seen in the ITT patient population. Of course, this is an exploratory analysis, so statistical significance was unable to be tested, but the hazard ratios for invasive DFS, distant DFS, and distant relapse-free survival in the node‑negative group were 0.723, .703, and .580, respectively.20
Kevin Kalinsky, MD, MS, FASCO:
When we look at distant DFS or distant relapse‑free survival, it’s approximately a 3% difference when you add in 3 years of ribociclib to an AI compared to AI alone. Adjuvant ribociclib is not FDA approved yet, but we will see whether this gets approval in high‑risk patients as well as patients with intermediate‑risk disease, including node‑negative patients.
NATALEE N0 Subgroup Analysis: Safety
Kevin Kalinsky, MD, MS, FASCO:
In terms of toxicities that we can see with ribociclib, liver function test abnormalities or neutropenia occur most commonly and should be monitored for.20
NATALEE N0 Subgroup Analysis: Clinical Implications
Kevin Kalinsky, MD, MS, FASCO:
For patients with high‑risk disease who could receive either adjuvant abemaciclib or adjuvant ribociclib, I would still favor using adjuvant abemaciclib because we have a longer follow-up and because we are still seeing a carryover effect where even from the time that patients have stopped their therapy, there’s a benefit years later. The data with ribociclib are more premature. In addition, the treatment with adjuvant CDK4/6 inhibitors is 2 years of abemaciclib compared to 3 years of ribociclib. If I have a situation where I am worried about a patient’s ability to tolerate abemaciclib or they are actually not tolerating abemaciclib, then I would consider ribociclib. Ribociclib alone could be considered for patients with intermediate‑risk disease; we will have to wait and see whether it gets approved in that setting. Then there also needs to be a conversation with the patient, what does a 3% difference in distant events mean for you? Is it worth 3 years of taking a drug? Those are the kinds of conversations we will have if adjuvant ribociclib is approved.
Sara Hurvitz, MD:
I think these data really underscore that if ribociclib is approved based on the NATALEE trial, this is a therapy we could select for our patients who have higher risk node‑negative disease given that abemaciclib is not indicated in that setting. The NATALEE trial as a whole shows benefit with ribociclib, and I think that if it is approved, it would be a viable option for patients with higher-risk disease as well. When selecting between abemaciclib and ribociclib, it is important to consider the differing lengths of therapy, side effect profiles, and drug–drug interactions with each therapy. In many ways, I agree that it is going to be a patient‑based decision for those who would have qualified for both studies, but for those with node‑negative disease, ribociclib really would be the only choice.
RxPONDER Subset Analysis: Serum AMH and Adjuvant CT for Premenopausal Patients With HR+/HER2- EBC
Sara Hurvitz, MD:
Finally, we will discuss a subset analysis of the RxPONDER trial. This analysis was done to evaluate whether we could select patients who might derive more benefit from chemotherapy utilizing a marker to indicate ovarian reserves.5 So this is a really interesting subgroup analysis that may be practice changing.
To review, RxPONDER enrolled patients with HR‑positive early breast cancer with 1 to 3 positive nodes, and patients were randomized to chemotherapy followed by endocrine therapy or endocrine therapy alone.21
In postmenopausal women with a recurrence score of 0 to 25, there was no benefit with chemotherapy. In premenopausal women, however, there didn’t appear to be a group of patients, based on recurrence score, who did not benefit from chemotherapy. This led to a lot of questions regarding whether the chemotherapy was benefiting these younger women due to its ovarian suppressive effects, and this led investigators to wonder if there was a way to evaluate ovarian reserve as a marker for chemosensitivity.
RxPONDER Subset Analysis: iDFS by Menopausal Status
Sara Hurvitz, MD:
This subset analysis evaluated over 1000 patients who were premenopausal. Dr Kalinsky how was this patient population defined in the RxPONDER study?
Kevin Kalinsky, MD, MS, FASCO:
We used 55 as the age cutoff because most patients had undergone menopause by that age. In this analysis, premenopausal was defined as last menstrual period within 6 months or age younger than 50 years with no last menstrual period for more than 12 months and no bilateral salpingo-oophorectomy.22
RxPONDER Subset Analysis: Serum AMH in Premenopausal Women <55 Yr of Age
Kevin Kalinsky, MD, MS, FASCO:
Estradiol, progesterone, LH, FSH, and inhibin B were evaluable. None of those were found to be predictive of chemotherapy benefit. AMH is a measure of ovarian function, which is a marker that our reproductive endocrinologists are utilizing for fertility. Based upon the ELISA assay, if serum AMH is low, meaning less than 10 pg/mL, patients are defined as being at their final menstrual period or later. Here, when we look at women who are younger than 45 years old, very few had a low AMH; it was approximately 3%. It was approximately 15% for patients age 45 to 49, but if women were aged 50 to 54, around 50% of patients had a low AMH level.22
RxPONDER Subset Analysis: Serum Hormone Levels and CT Benefit in Premenopausal Women <55 Yr of Age
Kevin Kalinsky, MD, MS, FASCO:
A multivariable analysis looked at age younger than 55 and found that AMH was the only statistically significant predictor for chemotherapy benefit in this population. There was a trend towards inhibin B, but inhibin and AMH were strongly associated and AMH was a stronger predictor of benefit.22
RxPONDER Subset Analysis: Serum AMH Level and iDFS in Premenopausal Women <55 Yr of Age
Kevin Kalinsky, MD, MS, FASCO:
The key points are that if a patient was younger than 55, had been defined as premenopausal per the study, and had a low AMH, there was no benefit for chemotherapy in terms of invasive DFS. If patients had a medium or high serum AMH, the benefit with chemotherapy was 8% with a hazard ratio of 0.48. And there was a significant interaction P value of .019.22
RxPONDER Subset Analysis: Serum AMH Level and DRFS in Premenopausal Women <55 Yr of Age
Kevin Kalinsky, MD, MS, FASCO:
The same trend was found when evaluating 5-year distant relapse‑free survival. For patients with low AMH, no benefit; for medium or high serum AMH, there was a 4.4% improvement in distant relapse‑free survival with chemotherapy.22
RxPONDER Subset Analysis: Clinical Implications
Sara Hurvitz, MD:
It is important to note that testing for AMH is a commercially available assay that can be ordered and done in clinic. I think these data are actually quite interesting, because prior to this, for a woman who was premenopausal, there was really no indication to order OncotypeDX if they had 1 to 3 positive nodes. Now we may have an assay to help us identify perimenopausal patients who may not need chemotherapy.
Kevin Kalinsky, MD, MS, FASCO:
AMH testing may not be available at every institution. It may be a send-out test. It is important to know which assay is being used as well as the lower limit of detection for that particular assay.
Serum AMH was also assessed by race and ethnicity and notable differences between ethnic groups were not identified, though I will also say some of the underrepresented groups are underrepresented in RxPONDER. It is important to realize that compared to FSH and estradiol, for instance, serum AMH is more reliable and not dependent on where a woman is in their menstrual cycle. Furthermore, AMH declines earlier than what we see with FSH, for example FSH rise when a woman is about to go into menopause. So this is a more reliable indicator of ovarian reserve than what we have with our currently tested hormone levels.
So, in which patients would I test serum AMH? I would not test women younger than age 45, as the rate of low AMH was less than 3% in this group, unless a patient really underwent premature ovarian failure. This is something I would consider in a patient whose menopausal status is unclear; for example, perhaps a woman who has not menstruated regularly within the last year, or somebody who has undergone a hysterectomy but still has her ovaries. These findings will be validated in an RxPONDER cohort of French patients.
Of importance, the rate of GnRH analog use or patients removing their ovaries was less than 20% among the one third of premenopausal patients enrolled in RxPONDER. That has been the major controversy from this study, specifically for those premenopausal patients, the question has become: If we optimally utilize ovarian function suppression, is there really a benefit with chemotherapy? From the RxPONDER study, we are not going to be able to answer the question of whether patients get the same benefit from ovarian function suppression as they would from chemotherapy. That is the purpose of the OFSET trial (NCT05879926), which is an ongoing study in a genomically defined population including the RxPONDER cohort, where patients are randomly assigned to ovarian function suppression plus endocrine therapy with or without chemotherapy. We will have to wait for the results of this study to answer this question.
Concluding Remarks
Sara Hurvitz, MD:
It is a very exciting time as we are not only seeing clinical outcome results from studies, but the correlative and biomarker work being done in the context of these trials promises to help us identify subgroups of patients most likely to benefit from a particular strategy.
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