Joyce O’Shaughnessy, MD:
We start by discussing 2 interesting studies on preoperative immune checkpoint inhibitor–based regimens in the setting of high-risk estrogen receptor (ER)-positive/HER2-negative early-stage breast cancer (EBC). 

The first study is KEYNOTE 756, a phase III trial comparing neoadjuvant chemotherapy plus either pembrolizumab or placebo followed by adjuvant endocrine therapy plus either pembrolizumab or placebo.^{[Cardoso 2023]} KEYNOTE-756 enrolled 1278 patients with ER-positive/HER2 negative stage II/III invasive ductal breast carcinoma that was centrally confirmed to be grade 3. During the neoadjuvant phase, patients received pembrolizumab or placebo for 4 cycles plus paclitaxel for 12 weeks, followed by pembrolizumab or placebo plus either doxorubicin and cyclophosphamide or epirubicin and cyclophosphamide for 4 cycles. Following surgery, patients received adjuvant pembrolizumab or placebo for 6 months with endocrine therapy given for up to 10 years. The coprimary endpoints are the rate of pathologic complete response (pCR), defined as ypT0/Tis ypN0, and event free survival (EFS).

We should note that KEYNOTE-756 completed enrollment before the availability of adjuvant abemaciclib, which is now standard of care in this setting.^{[NCCN Breast]}

Joyce O’Shaughnessy, MD:
KEYNOTE-756 met the first of its coprimary endpoints, demonstrating a statistically significant absolute improvement in pCR rate of 8.5% (95% CI: 4.2% to 12.8%; P = .00005) with the addition of pembrolizumab vs placebo to neoadjuvant chemotherapy followed by adjuvant endocrine therapy.^{[Cardoso 2023]} The pCR rate was 24.3% with the addition of pembrolizumab vs 15.6% with placebo. Data remain immature for the second coprimary endpoint of EFS. 

A subgroup analysis indicated that all patient subsets experienced pCR improvement with the addition of pembrolizumab. That being said, patients with very low levels of ER expression (<10%), in particular, benefited from the addition of the pembrolizumab vs those with ER expression ≥10%. This is consistent with what we have observed in stage II/III triple negative breast cancer (TNBC), where the pCR rate improves with the addition of preoperative pembrolizumab to neoadjuvant chemotherapy.^{[Schmid 2020]}

Overall, 76% of patients had PD-L1–positive disease, defined as a PD-L1 combined positive score ≥1 per the PD-L1 immunohistochemistry assay with the 22C3 antibody.^{[Cardoso 2023]} Of note, the addition of pembrolizumab was associated with greater improvement in pCR rate for those whose cancers were PD-L1 positive vs negative. 

Regarding safety, there were no new signals in the established immune mediated adverse event (AE) profile for pembrolizumab in this setting. 

Joyce O’Shaughnessy, MD:
There are several key takeaways from KEYNOTE-756. First, this trial observed that patients with low ER expression (1%-9%) had a markedly greater pCR benefit with the addition of pembrolizumab vs those who we would consider to be more “traditionally” ER positive.^{[Cardoso 2023]} The pCR benefit in this KEYNOTE-756 subgroup with low ER expression is very similar to what was reported in patients with early-stage TNBC who received perioperative pembrolizumab plus chemotherapy in the KEYNOTE-522 trial.^{[Schmid 2020]} Many healthcare professionals—including myself—believe that patients with EBC and low ER expression should be treated with the KEYNOTE 522 regimen used for patients with TNBC. Indeed, the 2020 update to the ASCO/CAP guidelines notes that although an ER expression of 1% to 10% is still considered ER positive, there are limited data on the benefits of endocrine therapy in this population.^{[Allison 2020]}

Second, KEYNOTE-756 reported a greater difference in pCR benefit for those with EBC that was PD-L1 positive vs EBC that was PD-L1 negative.^{[Cardoso 2023]} This was also reported for CheckMate 7FL, which we discuss next.

Third, we must wait for EFS data to mature before the KEYNOTE-756 regimen could become a routine standard of care for patients with grade 3 hormone receptor–positive/HER2-negative high-risk EBC. 

Joyce O’Shaughnessy, MD:
At ESMO 2023, Loi and colleagues^{[Loi 2023]} presented the first analysis of the randomized phase III CheckMate 7FL trial in patients with high risk ER-positive/HER2 negative EBC. These patients had clinical stage II/III disease that was either grade 3 with ER expression ≥1% or grade 2 with ER expression of 1% to 10%. In the neoadjuvant phase, the patients received paclitaxel for 4 cycles followed by an anthracycline plus cyclophosphamide for 4 cycles with the addition of nivolumab vs placebo. After surgery, the patients received adjuvant nivolumab or placebo for 7 cycles plus the investigator’s choice of endocrine therapy. 

Following regulatory approval of adjuvant abemaciclib in this setting, the trial was modified in April 2022 because of concerns that a CDK4/6 inhibitor could not be given safely with an anti–PD-1 agent. The primary endpoint was changed to focus only on pCR, defined as ypT0/Tis ypN0, and no further patients were enrolled after 521 participants were randomized. EFS was changed from a primary to an exploratory endpoint and follow-up was reduced to 1 year after surgery. The adjuvant phase was also changed to be open label.

Joyce O’Shaughnessy, MD:
CheckMate 7FL met its primary endpoint, demonstrating a statistically significant absolute improvement in pCR rate of 10.5% (95% CI: 4.0%-16.9%; P = .0021) with the addition of nivolumab vs placebo.^{[Loi 2023]} The pCR rate was 24.5% with the addition of nivolumab vs 13.8% with placebo.

An important secondary endpoint in CheckMate 7FL was the pCR rate in the subgroup with PD L1–positive disease. Approximately 33% of patients had PD-L1–positive disease, defined as ≥1% of tumor-infiltrating immune cells expressing PD-L1 as a percentage of tumor area per the SP142 assay. There was a very large absolute improvement in pCR rate of 24.1% among those with PD-L1–positive disease (odds ratio: 3.11; 95% CI: 1.58-6.11). The pCR rate was 44.3% with the addition of nivolumab vs 20.2% with placebo.

No new safety signals were observed with the combination of nivolumab plus neoadjuvant chemotherapy.

Joyce O’Shaughnessy, MD:
There are 2 key takeaways from CheckMate 7FL. First, this trial met its primary endpoint, demonstrating that the addition of nivolumab to neoadjuvant chemotherapy followed by adjuvant endocrine therapy significantly improved the pCR rate in patients with high-risk ER-positive/HER2-negative EBC. These data further support those reported for the KEYNOTE-756 trial, as both trials demonstrated benefit with the addition of an anti–PD-1 agent to standard preoperative treatment for high-risk ER-positive/HER2-negative disease. 

Second, CheckMate 7FL reported that the greatest benefit from the addition of nivolumab was in patients with PD-L1–positive disease. In KEYNOTE-756, patients with either PD-L1 positive vs negative tumors benefited from preoperative pembrolizumab but PD-L1 positivity predicted for a greater improvement in pCR rate.
 
Unfortunately, we cannot expect the CheckMate 7FL trial to lead to registration of nivolumab in this setting because of changes in the protocol. However, I anticipate that we will see informative biomarker and EFS data from future analyses of this trial.

Joyce O’Shaughnessy, MD:
Turning to early-stage TNBC, Schmid and colleagues^{[Schmid 2023]} presented a 5 year update of the phase III KEYNOTE 522 trial at ESMO 2023. This trial randomized 1174 patients with stage II/III TNBC to neoadjuvant treatment with paclitaxel plus carboplatin for cycles 1-4 followed by doxorubicin and cyclophosphamide or epirubicin and cyclophosphamide for cycles 5-8 plus pembrolizumab vs placebo. After surgery, patients received adjuvant pembrolizumab vs placebo for cycles 1-9. The coprimary endpoints are the rate of pCR, defined as ypT0 ypN0 and ypT0/Tis, and EFS.

Earlier analyses demonstrated that the addition of pembrolizumab significantly increased the pCR rate by 13.6% (P <.001) and, after a median follow-up of 39.1 months, significantly prolonged median EFS (HR: 0.63; 95% CI: 0.48-0.82; P <.001).^{[Schmid 2020; Schmid 2022]} Together, these results led to the FDA approval of pembrolizumab for treatment of patients with high-risk, early-stage TNBC in combination with neoadjuvant chemotherapy and then as a single-agent adjuvant therapy following surgery.^{[Pembrolizumab PI]} The current analysis was performed after a median follow-up of 63.1 months.^{[Schmid 2023]}

Joyce O’Shaughnessy, MD:
The 5 year updated analysis reported a 9% absolute improvement in EFS (HR: 0.63; 95% CI: 0.49-0.81).^{[Schmid 2023]} The pembrolizumab arm demonstrated a 5-year EFS rate of 81.3% vs 72.3% in the placebo arm. 

Of note, there were very few recurrences after Year 4 in the pembrolizumab-treated patients. The EFS curve flattened out by Year 4, suggesting that the immune activation induced by pembrolizumab is curing these patients earlier than in the placebo arm. In the placebo arm, most EFS events had occurred by Year 5, but a small percentage of patients continued to recur after Year 5. 

Another important finding involved the large subgroup of approximately 60% of patients who achieved a pCR across both arms.^{[Schmid 2020]} In this subgroup, there was a 4% absolute improvement in the 5-year EFS rate with pembrolizumab vs chemotherapy (HR: 0.65; 95% CI: 0.39-1.08).^{[Schmid 2023]} Among patients who achieved pCR, the 5-year EFS rate was 92.2% with the addition of pembrolizumab vs 88.2% with placebo.

There was also a highly significant improvement in distant progression–free survival or distant recurrence–free survival at Year 5 (HR: 0.64; 95% CI: 0.49-0.84), with very few events after Year 5 among patients receiving pembrolizumab. The 5-year rate was 84.4% with the addition of pembrolizumab vs 76.8% with placebo.

Joyce O’Shaughnessy, MD:
The 5-year update to KEYNOTE 522 is very important for several reasons. First, these data show that among patients who received only preoperative chemotherapy for stage II/III TNBC, 27.7% experienced recurrence or death by Year 5.^{[Schmid 2023]} By contrast, among those who received the addition of pembrolizumab to preoperative chemotherapy, only 18.5% experienced recurrence or death—representing an absolute benefit close to 10%. This is a major step forward in the standard treatment of high risk, early-stage TNBC. 

Second, recall that in the subgroup achieving pCR, there was a notable 4% absolute improvement in the 5-year EFS rate with the addition of pembrolizumab vs placebo. These data suggest that the pCR achieved with pembrolizumab is associated with a greater likelihood that subclinical metastatic disease was eradicated than the pCR achieved with chemotherapy alone.

Joyce O’Shaughnessy, MD:
The updated data from monarchE continue to support use of adjuvant abemaciclib in the cohort 1 population.^{[Harbeck 2023]} As a reminder, the labeling has changed, and we do not have to consider the Ki 67 score in identifying patients eligible for adjuvant abemaciclib. 

Joyce O’Shaughnessy, MD:
In addition to the 5-year update, my colleagues and I^{[O’Shaughnessy 2023]} presented an analysis of how abemaciclib dose reduction affected efficacy using data from an earlier OS interim analysis with a median follow-up of approximately 42 months.

In monarchE, 43.6% of patients had an abemaciclib dose reduction. When we compared outcomes across 3 equally sized subgroups categorized by relative dose intensity—where patients with dose reductions had a lower relative dose intensity—we observed comparable 4-year iDFS rates ranging from 83.7% to 87.1%. Similar efficacy was observed when we considered the timing of abemaciclib dose reductions in a time-dependent Cox proportional hazard model.

This analysis indicates that dose reductions were not associated with any diminution in the efficacy of abemaciclib, even among those who needed a second dose reduction. Because dose reduction does not decrease the clinical benefit that patients receive, we should dose reduce for patients who need it so that patients are able to continue on abemaciclib.

Joyce O’Shaughnessy, MD:
An exploratory analysis of monarchE was presented by Goetz and colleagues^{[Goetz 2023]} evaluating the prognostic and predictive roles of ER, progesterone receptor (PgR), and Ki 67. The relationship between iDFS and these biomarkers as continuous variables was assessed using “subpopulation treatment effect pattern plot” (STEPP) statistical analyses in the ITT and cohort 1 populations. 

The exploratory analysis observed a consistent iDFS benefit across all ranges of ER, PgR, and Ki-67 expression. Of note, this analysis also found that adjuvant abemaciclib had a more pronounced absolute improvement in iDFS of 11.5% for patients with ER-positive/PgR-negative disease compared with 5.2% for those with ER-positive/PgR-positive disease. When treated with endocrine therapy alone, the prognosis for the ER-positive/PgR-negative subgroup was worse than that of the ER-positive/PgR-positive subgroup, with 4-year iDFS rates of 68.5% and 81.5%, respectively. Patients with early recurrence often manifest resistance to chemotherapy and to optimal endocrine therapy.^{[Riggio 2020]} Thus, it was gratifying that patients at a higher risk for early recurrence also had positive outcomes with the addition of adjuvant abemaciclib.

Joyce O’Shaughnessy, MD:
Continuing with our discussion of adjuvant CDK4/6 inhibitors, Bardia and colleagues^{[Bardia 2023a]} presented a subgroup analysis of the phase III NATALEE trial at ESMO 2023. NATALEE enrolled patients with hormone receptor–positive/HER2-negative EBC that was high risk and node positive similar to monarchE, along with patients with high risk, node negative disease or intermediate risk, node positive disease. The trial randomized 5101 patients to receive either adjuvant ribociclib at a daily dose of 400 mg (3 weeks on/1 week off) for 3 years in combination with a nonsteroidal aromatase inhibitor (NSAI) for ≥5 years vs NSAI only. Premenopausal women and men also received goserelin. 

The primary endpoint of this analysis is iDFS using “standard definitions for efficacy end points in adjuvant breast cancer trials” (STEEP) criteria.

Joyce O’Shaughnessy, MD:
Earlier in 2023, Slamon and colleagues^{[Slamon 2023]} presented data showing that NATALEE met its primary endpoint. In the ITT population, there was a statistically significant 3.3% absolute improvement in the 3 year iDFS rate (HR: 0.748; 95% CI: 0.618-0.906; P = .0014), which was 90.4% in the ribociclib plus NSAI arm vs 87.1% in the NSAI arm. The current subgroup analysis was prespecified and is based on the same data cutoff as that iDFS analysis, with a median follow-up of 27.7 months.^{[Bardia 2023a]}

The investigators reported a consistent iDFS benefit with the addition of ribociclib to NSAI across the subgroups examined, which were defined by menopausal status, anatomic stage, nodal status, age (<65 vs ≥65 years), and Ki-67 score (≤20% vs >20%). 

The data for 2 subgroups are of particular interest. First, patients with Ki 67 expression >20% had a 5% absolute improvement in iDFS with the addition of ribociclib (HR: 0.75; 95% CI: 0.56-1.00), whereas patients with Ki 67 ≤20% had only a 2% absolute improvement (HR: 0.80; 95% CI: 0.59-1.08). Second, among the 12% of patients who had node negative disease confirmed pathologically, there was an absolute improvement in 3 year iDFS rate of 5% (HR: 0.63; 95% CI: 0.34-1.17). By comparison, those with node positive disease had a 3% improvement (HR: 0.77; 95% CI: 0.63-0.94).

Joyce O’Shaughnessy, MD:
These are early subgroup analyses, but still very interesting, as all the subgroups benefited from the addition of adjuvant ribociclib.^{[Bardia 2023a]} Patients with higher Ki-67 scores are at risk for earlier recurrence, and this analysis observed that they are experiencing a greater benefit from the use of adjuvant ribociclib, consistent with data from monarchE.^{[Harbeck 2023]} 

We will see more data from NATALEE at the 2023 SABCS. I look forward to further follow-up and potentially FDA approval of this agent for our patients.

Joyce O’Shaughnessy, MD:
It is good to see data for imlunestrant monotherapy in patients with pretreated aBC, with a clinical benefit rate of 42%.^{[Jhaveri 2023]} Imlunestrant is being evaluated across the disease continuum. In the advanced setting, the phase III EMBER 3 trial (NCT04975308) is evaluating single agent imlunestrant and imlunestrant combined with abemaciclib, after progression on a CDK4/6 inhibitor in patients with ER-positive/HER2-negative aBC. If EMBER-3 is positive, we hope that will lead to the approval of single agent imlunestrant, as well as imlunestrant plus abemaciclib. In the adjuvant setting, the phase III EMBER 4 trial (NCT05514054) is comparing imlunestrant vs standard endocrine therapy in patients with ER-positive/HER2-negative EBC at an increased risk for recurrence. The patients will have previously received 2-5 years of adjuvant endocrine therapy and are permitted to have received (neo)adjuvant treatment with chemotherapy and/or a CDK4/6 or PARP inhibitor. The patients are randomized to continue their same endocrine therapy or to switch to imlunestrant.

That being said, current data indicate that we will need to use oral SERDs in combination with other agents to meaningfully improve PFS. As we see in EMBER, the combination with alpelisib is challenged by toxicities and dose discontinuations, although there is no doubt that some patients do very well even with the full dose.^{[Jhaveri 2023]} Others do well with a dose reduction, but this combination is more challenging to administer than imlunestrant plus everolimus, which is quite well tolerated. I am particularly interested in the combination of imlunestrant with everolimus and look forward to potentially seeing that regimen evaluated in larger trials.

Joyce O’Shaughnessy, MD:
The data from TROPION-Breast01 are very encouraging.^{[Bardia 2023c]} I look forward to further follow-up that will provide us with mature OS data. Currently, we prioritize use of the TROP-2–directed ADC sacituzumab govitecan in patients with pretreated hormone receptor–positive/HER2-negative metastatic breast cancer because this agent demonstrated significantly prolonged OS vs single agent chemotherapy in the TROPiCS-02 trial.^{[NCCN Breast; Tolaney 2023]} It will be interesting and important to see whether Dato-DXd, which also targets TROP-2, significantly improves OS.

Regarding safety, I would consider Dato-DXd to be a well-tolerated agent. It was good to see that Dato-DXd had such limited myelosuppression because that means that patients should need fewer dose interruptions and modifications and, therefore, can have greater exposure and more potential benefit.^{[Bardia 2023c]} As for the oral mucositis/stomatitis, the investigators have found that using a steroid mouth rinse prophylactically for at least a few months on Dato-DXd helps a great deal in preventing this complication. Lubricating eye drops also help with the dry eye, which is typically low grade and only led to 1 treatment discontinuation in TROPION-Breast01. The nausea was consistent with studies of another deruxtecan-based ADC, trastuzumab deruxtecan (T-DXd), and can be ameliorated with olanzapine at a dose of 2.5 mg taken at bedtime.^{[Rugo 2022]}

In terms of ILD, this trial reported much lower rates of ILD than what we have seen with T-DXd.^{[D’Arienzo 2023]} These results suggest that the HER2-directed antibody drives the higher rate of ILD with T-DXd, whereas ADCs with TROP-2–directed antibodies—such as Dato-DXd and sacituzumab govitecan—cause markedly less ILD.

Joyce O’Shaughnessy, MD:
A key clinical implication of this study is that T DXd is active in patients with untreated, active brain metastases and those with treated, stable brain metastases.^{[Hurvitz 2023]} We currently use T-DXd in the second line setting, and these data mean that patients with asymptomatic untreated brain metastases may not have to undergo radiotherapy prior to beginning T-DXd, as is currently the case with the tucatinib, capecitabine, trastuzumab for patient with active brain metastases. Given the high rate and durability of intracranial objective responses achieved with T-DXd, it is reasonable to treat this population with T-DXd and follow them very closely. 

That being said, in patients with brain predominant metastases, I consider the data with tucatinib, trastuzumab, and capecitabine from the phase III HER2CLIMB trial to be more compelling because this regimen demonstrated significant improvement in OS.^{[Lin 2023]} This pooled analysis did not address OS.^{[Hurvitz 2023]} Nonetheless, if patients have extensive extracranial and some intracranial disease, then T-DXd is a very reasonable option. We would then recommend tucatinib, trastuzumab, and capecitabine as their next line of therapy. 

Ultimately, this analysis bolsters the use of T-DXd in patients who have brain metastases and systemic disease in need of control in the second line setting.

Joyce O’Shaughnessy, MD:
ESMO 2023 was an important conference for breast cancer. Many important studies were presented; of note, longer-term follow-up from monarchE continues to support the use of adjuvant abemaciclib. The first data from KEYNOTE-756 and longer follow-up data from KEYNOTE-522 support the use of preoperative pembrolizumab in different patient populations. We also saw important data from CheckMate 7FL and TROPION-Breast01 as well as the first data for imlunestrant in combination with targeted therapy. Altogether, these trials provided data that are very pertinent to clinical practice.