CE / CME
Pharmacists: 1.00 contact hour (0.1 CEUs)
Nurses: 1.00 Nursing contact hour
Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™
Released: August 31, 2023
Expiration: August 30, 2024
TNBC Is Responsive to NAC With Outcomes Similar to Non-TNBC
Now we shift our focus to the recent advances in treatment for early-stage TNBC. There are many strategies to improve outcomes in patients with TNBC, including neoadjuvant CT, which can downstage tumors and allow time for germline mutation testing.43 We have known for some time that when patients with TNBC achieve pCR after neoadjuvant CT, they have a better outcome than those who have residual disease.44 Other neoadjuvant approaches may help to increase pCR rates, including ADCs45 and ICIs.46 We also have data that show we can decrease the likelihood of recurrence in patients who have residual disease by giving treatments such as adjuvant capecitabine47 or adjuvant olaparib if they have a BRCA mutation.20
KEYNOTE-522: Study Design
The practice-changing, randomized phase III KEYNOTE-522 trial looked at neoadjuvant carboplatin plus paclitaxel followed by an anthracycline plus cyclophosphamide, with or without pembrolizumab in patients with newly diagnosed TNBC (T1cN1-2 or T2-4N0-2).46 Following surgery, patients were treated with adjuvant pembrolizumab or placebo for 27 weeks. Pembrolizumab was given at 200 mg every 3 weeks IV for 1 year regardless of whether patients had a pCR or not.
The primary endpoints were pCR (ypT0/Tis ypN0) and event-free survival (EFS) by local review, with secondary endpoints including pCR (alternative definitions), OS, and safety. Fifty-two percent of patients had node-positive disease, approximately 25% of patients had stage III disease, and 56% of patients were premenopausal.
KEYNOTE-522: EFS at Interim Analysis 4
With a median follow-up of 39.1 months, there was improvement for pembrolizumab plus CT in 3-year EFS rate (84.5% vs 76.8%; hazard ratio: 0.63; 95% CI: 0.48-0.82; P <.001) and DRFS (87% vs 80.7%; hazard ratio: 0.61; 95% CI: 0.46-0.82) compared with CT alone.46 This is a clinically meaningful result, showing that the addition of immunotherapy to CT is improving outcomes in these patients.
KEYNOTE-522: EFS by pCR
Patients who achieved pCR did better long term, and responders receiving pembrolizumab plus CT had a numerically higher 3-year EFS rate (94.4% vs 92.5%) than responders who received CT alone.46 Of importance, we saw improved EFS in nonresponders who were treated with pembrolizumab plus CT (3-year EFS rate: 67.4% vs 56.8%; hazard ratio: 0.70; 95% CI: 0.52-0.95) compared with nonresponders treated with CT alone. This result further confirms the importance of immunotherapy for patients with TNBC.
KEYNOTE-522: Immune-Mediated AEs
With clinical benefit comes the potential for increased toxicity.46 Across both study phases, patients treated with pembrolizumab plus CT had more AEs (any grade: 43.6% vs 21.9%; grade ≥3: 14.9% vs 2.1%), which led to more treatment discontinuation (10.9% vs 2.6%) compared with patients treated with CT plus placebo.
The most common AE seen with addition of pembrolizumab to CT was thyroid dysfunction (any grade hypothyroidism: 15.1% vs 5.7%; any grade hyperthyroidism: 5.2% vs 1.8%; any grade thyroiditis: 2.0% vs 1.3%). There were a few other rare but serious toxicities seen with addition of pembrolizumab to CT, including adrenal insufficiency (any grade: 2.6% vs 0%), colitis (any grade: 1.7% vs 0.8%), and pneumonitis (any grade: 2.2% vs 1.5%). It is important to keep these toxicities in mind when treating patients.
ICIs in Early-Stage TNBC
Based on the results of KEYNOTE-522, pembrolizumab was approved for the treatment of patients with high-risk, early-stage TNBC in combination with CT as neoadjuvant treatment and then continued as a single agent as adjuvant treatment after surgery.48
This slide highlights the various studies that have been reported using ICI treatment in TNBC. We have seen studies with atezolizumab, durvalumab, and pembrolizumab, some with or without anthracyclines, but currently the only approved ICI therapy is pembrolizumab.
Phase II NeoPACT study
An important question has been whether it is necessary to give an anthracycline to our patients with TNBC, given the robust benefit seen with the addition of pembrolizumab. To address this, the single-arm phase II NeoPACT trial evaluated neoadjuvant pembrolizumab plus carboplatin and docetaxel in 115 patients with stage I-III TNBC.49
The patients did quite well, with good pCR (58%) and residual cancer burden 0+1 (69%) rates, and the 2-year EFS rate was 89% overall (98% in responders). These are intriguing data and something to consider for patients with TNBC who are not able to receive an anthracycline.
ICIs in EBC: Select Clinical Trials
There are several ongoing studies of ICIs in EBC that we are awaiting the results on, including two in the TNBC setting.
The proposed phase III SCARLET (SWOG 2212) study will compare the KEYNOTE-522 regimen (neoadjuvant pembrolizumab plus carboplatin and paclitaxel followed by an anthracycline plus cyclophosphamide) vs the NeoPACT regimen (neoadjuvant pembrolizumab plus carboplatin and docetaxel) in patients with TNBC who have high tumor-infiltrating lymphocytes. These are patients who tend to have a greater response to neoadjuvant therapy, which may allow them to de-escalate or opt out of certain therapies. This could potentially be a practice-changing study, and the primary endpoint will be EFS.
As I mentioned earlier, patients in the KEYNOTE-522 trial who achieved a pCR had better outcomes, but it was not clear whether they needed to continue a full year of pembrolizumab treatment. To address this question, the randomized phase III OptimICE-PCR study (NCT05812807) is evaluating adjuvant pembrolizumab vs observation in patients with TNBC who have achieved pCR on neoadjuvant pembrolizumab plus CT.
General Guidelines for Management of Immune-Related AEs
This slide shows general guidelines for management of immune-related AEs.50-52 For the more serious AEs, we need to give steroids sooner rather than later, and if the disease is steroid refractory, we must consider other immunosuppression such as infliximab or mycophenolate. Always think about incorporating other specialists like endocrine or rheumatology. Immune-related endocrinopathies such as thyroid dysfunction are usually treated with hormone replacement and not steroids.
Also, some immune-related AEs can start early and some can be later. If patients do not have AEs within the first 3 months, it is still possible for them to develop one over time.
CREATE-X: Study Design
One last treatment option that does not fit in any of the categories already covered is capecitabine. The randomized phase III CREATE-X study compared adjuvant capecitabine plus SoC vs SoC in patients with HER2-negative EBC who had residual disease following neoadjuvant CT and surgery.47 It is worth noting that the capecitabine dose in this study (1250 mg/m2 twice daily on Days 1-14 every 3 weeks for 6-8 weeks) is higher than that I typically find patients can tolerate. When I use capecitabine in the adjuvant setting, I generally give a maximum of 1000 mg/m2 twice daily.
The primary endpoint was DFS, with secondary endpoints including OS, time to recurrence or death, and safety.
In total, 887 patients with stage I-IIIB, HER2-negative EBC were included in the full analysis set, 32% of whom had TNBC. Thirty-nine percent of patients had node-negative disease, 38% had 1-3 positive lymph nodes, and 23% had ≥4 positive lymph nodes.
CREATE-X: DFS and OS
The addition of capecitabine to SoC significantly improved 5-year DFS (74.1% vs 67.6%; hazard ratio: 0.70; 95% CI: 0.53-0.92; P = .01) and 5-year OS (89.2% vs 83.6%; hazard ratio: 0.59; 95% CI: 0.39-0.90; P = .01) compared with SoC alone in patients with HER2-negative EBC.47
CREATE-X: DFS by Subgroup
The subgroup analysis showed that adjuvant capecitabine improved DFS particularly in the patients with TNBC (hazard ratio: 0.58; 95% CI: 0.39-0.87), whereas the DFS benefit to the HR-positive cohort was not significant (hazard ratio: 0.81; 95% CI: 0.55-1.17).47
Considerations in the Treatment of Early-Stage TNBC
This slide summarizes considerations for the treatment of early-stage TNBC.
If I have patients with T1a/b, N0 tumors, I have them go straight to surgery. But for patients with T1b tumors, we discuss the advantages and disadvantages.
If patients have T1c, N0 disease, I consider giving them neoadjuvant treatment.
If patients have residual disease and a germline BRCA mutation, you can consider giving them olaparib.
I want to emphasize that I give adjuvant pembrolizumab only to those patients who have T2 or node-positive disease and have received neoadjuvant pembrolizumab and not those with T1c disease.
For patients with a tumor that is ≥2 cm or those with any node-positive disease, we give them neoadjuvant therapy, often the KEYNOTE-522 regimen. I often continue with a full year of pembrolizumab whether they achieve a pCR or not, although the question of whether this is necessary is being addressed by the OptimICE-PCR study, as I mentioned. If these patients have residual disease, I often give them adjuvant capecitabine and then add in pembrolizumab. It is worth highlighting that in the KEYNOTE-522 trial, patients did not receive adjuvant capecitabine, which has led to differences in practice patterns across various sites.
For patients with BRCA mutations, although the combination of PARP inhibitor plus pembrolizumab was not permitted in OlympiA or KEYNOTE-522, there are phase I data with ICIs in combination with PARP inhibitors in metastatic cancer, including breast and ovarian cancers.53-55
Next, we discuss the role of ADCs in EBC, including some ongoing trials that are looking at their use in the setting of residual disease.
TROP-2–Targeted ADC: Sacituzumab Govitecan-hziy
ADCs have been practice-changing for our patients with metastatic breast cancer. Sacituzumab govitecan-hziy is a TROP-2–directed ADC comprising a humanized IgG1 antibody connected to SN-38, the active metabolite of irinotecan (topoisomerase I inhibitor), via a pH-sensitive linker.56 The target protein, TROP-2, is a stem cell marker that is commonly expressed in metastatic TNBC tumors.57,58
In the randomized phase III ASCENT trial, single-agent sacituzumab govitecan-hziy showed improved median progression-free survival (5.6 vs 1.7 months; hazard ratio: 0.41; 95% CI: 0.32-0.52; P <.001) and median OS (12.1 vs 6.7 months; hazard ratio: 0.48; 95% CI: 0.38-0.59; P <.001) compared with physician’s choice of CT in patients with relapsed or refractory metastatic TNBC.59 In the randomized phase III TROPiCS-02 trial, single-agent sacituzumab govitecan-hziy resulted in improved median PFS (5.5 vs 4.0 months; hazard ratio: 0.66; 95% CI: 0.53-0.83; P = .0003) compared with physician’s choice of CT in patients with heavily pretreated, unresectable, HR-positive/HER2-negative, locally advanced or metastatic breast cancer.60
Based on the results of these trials, sacituzumab govitecan-hziy was approved for treatment of adult patients with metastatic TNBC who have received ≥2 prior systemic therapies, including ≥1 for metastatic disease, and for treatment of adult patients with unresectable locally advanced or metastatic HR-positive/HER2-negative breast cancer who have received ET and ≥2 additional systemic therapies in the metastatic setting.61
ADCs in EBC: Select Clinical Trials
Numerous studies are looking at the role of ADCs in the adjuvant setting for patients with EBC who have residual disease after neoadjuvant CT.
The phase III SASCIA trial (NCT04595565) in Germany is looking at the role of sacituzumab govitecan-hziy vs physician’s choice (CT or observation) in patients with HER2-negative EBC and residual disease after neoadjuvant CT.
The randomized phase III ASCENT-05 trial (NCT05633654) is looking at combination sacituzumab govitecan-hziy plus pembrolizumab vs physician’s choice treatment (pembrolizumab with or without capecitabine) in patients with TNBC and residual disease after neoadjuvant CT.
Finally, the randomized, 3-arm phase III TROPION-Breast03 trial (NCT05629585) is looking at a different TROP-2–directed ADC, datopotamab deruxtecan, with or without durvalumab vs physician’s choice of treatment (pembrolizumab and capecitabine, alone or in combination as indicated). The regimen of datopotamab deruxtecan, which is given once every 3 weeks, is different from sacituzumab govitecan-hziy, which is given 2 weeks on and 1 week off.
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