A randomized, 3-arm, neoadjuvant, phase 2 study comparing docetaxel + carboplatin + trastuzumab + pertuzumab (TCbHP), TCbHP followed by trastuzumab emtansine and pertuzumab (T-DM1+P), and T-DM1+P in HER2-positive primary breast cancer

Current treatment guidelines recommend the use of multidrug chemotherapy, such as a sequential combination of an anthracycline-containing regimen and taxane or concurrent use of taxane and platinum, in combination with the anti-human epidermal growth factor receptor 2 (HER2) monoclonal antibodies trastuzumab and pertuzumab for the treatment of HER2-positive (HER2+) primary breast cancer [1, 2].

Dual HER2-targeted therapy with lapatinib or pertuzumab in combination with trastuzumab has significantly increased pathological response rates in patients with HER2+ breast cancer. For example, ypT0/is and/or ypN0 rates (pathological complete response [pCR]) showed improvement from 29.5–52.5% to 51.3–65.9% by adding lapatinib [3‐6] and from 22–29% to 45.8–66.2% by adding pertuzumab [7‐10]. Furthermore, attempts have been made to reduce the toxicity of chemotherapy by using dual HER2 blockade alone or trastuzumab emtansine (T-DM1) with or without pertuzumab. Dual HER2 blockade with trastuzumab and pertuzumab alone in the absence of cytotoxic chemotherapy has shown reasonable pathological response rates (16.8%) in patients with locally advanced or inflammatory, operable, HER2+ breast cancer [7]. The response rate was higher (44.4%) with the combination of T-DM1 and pertuzumab (T-DM1+P) in patients with HER2+ early breast cancer [10].

Several studies have investigated HER2 blockade with concurrent hormone therapy (HT) in patients with hormone receptor-positive (HR+) HER2+ breast cancer. A phase 3 study demonstrated reduced disease progression (hazard ratio 0.71; 95% confidence interval [CI] 0.53–0.96; P = 0.019) and significant clinical benefit with the lapatinib–letrozole combination in post-menopausal patients with HR +  HER2+ metastatic breast cancer [11]. A high pathological complete response (pCR, 21%; pathologic response rate, 54%) was also observed with add-on letrozole (+ luteinizing hormone-releasing hormone [LHRH] agonist in pre-menopausal women) to a 12-week trastuzumab–lapatinib combination in patients with estrogen receptor (ER) positive (ER+) HER2+ breast cancer in a phase 2 study [12]. Similarly, the trastuzumab–anastrozole combination showed prolonged progression-free survival (PFS; median, 4.8 months) in patients with HER2+ HR+ metastatic breast cancer in the phase 3 TAnDEM study [13]. In the PERTAIN study, the PFS was 18.9 months/15.8 months in patients with HER2+ HR+ metastatic breast cancer/locally advanced breast cancer who received trastuzumab + aromatase inhibitor (AI) with/without pertuzumab, respectively [14]. A systematic review concluded that treatment with lapatinib/trastuzumab + AI was clinically more effective than AI monotherapy in patients with HR +  HER2+ breast cancer [15]. Thus, concomitant HT is expected to show additional efficacy due to dual action, in ER+ HER2+ breast cancer.

Furthermore, among the common breast cancer subtypes, higher pCR rates were observed in ER-negative (ER−), luminal B HER2-negative (HER2−), nonluminal HER2+, and triple-negative (ER−, progesterone receptor [PgR]-negative, and HER2−) disease [16].

Therefore, the key considerations that remain are improving pCR rates in luminal HER2+ disease, which is less sensitive to the combination of chemotherapy and anti- HER2+ agents, and minimizing treatment-related toxicity without reducing efficacy in terms of pCR rates. This randomized, phase 2, 3-arm study was designed to compare docetaxel + carboplatin + trastuzumab + pertuzumab (TCbHP), TCbHP followed by T-DM1+P, and T-DM1+P for treating HER2+ primary breast cancer patients as a Japan Breast Cancer Research Group (JBCRG) association study-20, Neopeaks. In the T-DM1+P arm, we personalized the treatment after confirming tumor shrinkage and responders continued on the same treatment, whereas nonresponders were switched to a different type of anthracycline-based regimen.

Results of this study showed that the ypT0/is and ypN0 rate was numerically higher with the TCbHP →  T-DM1+P regimen (71%; group B) than with the standard TCbHP regimen (57%; group A) and the T-DM1+P regimen (57%; group C). As expected, in group C, the rate was higher among responders who continued T-DM1+P (63%; subgroup C1) than in nonresponders who switched to FEC (38%; subgroup C2). Notably, the pCR rate (57.4%) after the initial 4 cycles of T-DM1+P (group C) was equivalent to that with the standard TCbHP regimen (57%). Of note, the pCR rate in the ER+ subgroup of patients was significantly higher in group B (69%) than groups A (43.3%) and C (50.8%), but was comparable in ER– subgroups of patients (66.7–76.2%).

The overall rate of OS was 99.2% and rate of DFS was ≥ 94% in all groups at 3 years in our study, which are reflective of anthracycline-free post-operative therapy in 91.2% of patients in groups A and B. In group C, post-operative anthracyclines were used in approximately 60% of patients, suggesting that even if T-DM1-based pre-operative treatment is administered, anthracyclines can be avoided in 40% of the cases. However, further confirmation of long-term prognosis with anthracycline-free adjuvant therapy is needed.

We observed a remarkably high pCR rate in group B and hypothesize that the HER2+ cancer cells/clones that persisted [19] after the initial 4 cycles of TCbHP treatment may have responded to the subsequent 4 cycles of T-DM1+P. Interestingly, this sequence of TCbHP → T-DM1+P increased the pCR rate compared with the standard regimen of TCbHP, particularly for luminal HER2+ disease.

Although direct comparisons cannot be made with other studies due to differences in study design, region, and treatment regimens, the TRYPHAENA study reported a pCR rate (ypT0-isypN0) of 50.7% with the FEC+H+P×3 → T+H+P×3 regimen, 45.3% with the FEC×3 → T+H+P×3 regimen, and 51.9% with the TCH+P×6 regimen, the only comparable arm, compared with 57% in group A of this study [8]. The pCR rates in the ADAPT study were 41.0% for the T-DM1×4 regimen and 41.5% for the T-DM1+ET×4 regimen in patients with early HER2+ HR+ breast cancer [20]. However, in ADAPT, patients received 4 treatment cycles unlike 6 in our study. In the KRISTINE study, pCR was achieved in 44.4% (HR+, 38.1%; HR−, 54.8%) of patients in the T-DM1+P×6 group compared with 57.4% in group C in this study, and in 55.7% (46.4%, 71.1%) of patients in the TCbH+P×6 group, which was similar to group A of this study (57%) [10]. However, it should be noted that in our study, patients with ER+ breast cancer were treated with concurrent HT along with T-DM1+P, which could have additionally impacted the pCR rates. In an analysis of the I-SPY2 trial in invasive breast cancer in HER2+ subsets, neoadjuvant T-DM1+P×4 followed by doxorubicin + cyclophosphamide × 4 resulted in a pCR rate of 52% (HR+, 46%; HR−, 64%) versus 22% (HR+, 17%; HR−, 33%) with taxane (paclitaxel) + trastuzumab only. The results were similar to the response-guided group C and their ER status for this study [9]. With regard to the DFS and OS outcomes, less than 3 events of recurrence and no events of death were observed at the 3-year follow-up in group C treated with the T-DM1-based regimen. This good outcome is also supported by the results of the KRISTINE trial (T-DM1+P versus TCH + P) [21] and can be expected to spur the development of T-DM1-based pre-operative therapy. Similar to the current study, T-DM1-based regimens demonstrated favorable results in patients with HER2+ metastatic breast cancer in previous studies, including TDM4450g [22] and EMILIA [23]; the efficacy of T-DM1 was more evident in patients with high IHC (3+) [21] or HER2-mRNA [21, 23] expression.

The efficacy of T-DM1 is also supported by the KATHERINE study, where the interim analysis shows that the invasive DFS was significantly higher in the T-DM1 group than the trastuzumab alone group among patients with HER2+ early breast cancer with residual invasive disease after completion of neoadjuvant therapy [24].

In pre-menopausal women with ER+, ovarian suppression is often engaged using HT. In the ADAPT study, pCR rates were 41.5% and 15.1% in patients with HER2+ HR+ breast cancer receiving concomitant HT with 12-week T-DM1 and trastuzumab, respectively [20], suggesting improved efficacy of anti-HER2 therapy without any detrimental effects with concomitant HT. In the Neo-LaTH study [25], patients receiving anti-HER2 therapy (with/without HT) before chemotherapy for longer duration (18 versus 6 weeks) tended to show more tumor shrinkage. In our study as well, pCR was the highest (69%) in patients with ER+ in group B that received T-DM1 with concurrent HT, which was preceded by 4 cycles of TCbHP. Thus, de-escalation strategies using an antibody–drug conjugate regimen along with concomitant HT to enhance treatment efficacy warrant further investigation.

This approach of imaging-based and biopsy-incorporated treatment personalization may be useful for both maintaining pCR rates and minimizing toxicity. Further evaluation is required to support the initiation of the T-DM1+P with or without HT regimen, which may be useful in a selected group of HER2+ patients based on lack of feasibility.

As anticipated, patients with strong HER2 expression (IHC3+) had higher pCR rates than those with mild HER2 expression (IHC2+ and DISH+) in group C and subgroup C1, suggesting that the effect of T-DM1 might depend on membrane HER2 expression levels.

Breast conservation was achieved in approximately half (51–54%) of the patients, except in subgroup C2 (38%). Also, among those who underwent BCS instead of planned mastectomy, breast conservation success rate was higher in all patients (32–39%), except subgroup C2 (14%). These findings may be useful for considering surgical approaches for each individual. As anticipated, compared to the T-DM1 backbone only arm (group C), the incidence of AEs was highest in the taxane backbone arm (group A) followed by the taxane + T-DM1 backbone arm (group B). The T-DM1 backbone arm also reported better quality of life in the Swedish PREDIX HER2 trial (T-DM1 versus DTP) [26] and the KRISTINE trial (T-DM1+P versus TCH+P) [21]. Of special mention are drug-related alopecia and febrile neutropenia, which were less frequent in subgroup C1 (5.0%, 0%) versus group A (94.1%, 21.6%), group B (86.5%, 15.4%), or subgroup C2 (81%, 33.3%). This suggests that tailoring the T-DM1 backbone into the neoadjuvant therapy regimens is beneficial from a safety perspective and the treatment of HER2+ breast cancer can be modified with a more personalized approach. Study limitations include the fact that the pharmacoeconomic efficiency of the regimens and impact of the pCR rate of the T-DM1 regimen on long-term survival and quality of life were not evaluated.

Overall, the pCR rate was not statistically different among the treatment groups. However, compared with the standard TCbHP and response-guided T-DM1+P regimens, the pCR rate with the TCbHP →  T-DM1+P regimen was numerically higher in the neoadjuvant setting. Exploratory analyses showed that the pCR rate was significantly higher with the TCbHP →  T-DM1+P regimen than with the standard TCbHP and T-DM1+P regimens in patients with ER+, but was comparable in ER− patients. ER status might be an indicator to personalize dual HER2-targeted therapy. T-DM1+P was generally safe and well tolerated, with the fewest AEs throughout the study. No significant differences in safety were observed between patients who received TCbHP alone and TCbHP → T-DM1+P. Given the patient numbers, the personalization of treatment showed that the efficacy among T-DM1+P regimen responders was better than that of the TCbHP regimen alone and could thus serve as a reasonable approach to minimize toxicity while maintaining efficacy.