8.1. Monoclonal Antibodies
The first groundbreaking trial for anti-HER2 therapy was with trastuzumab and published in 2001 by Dr. Dennis Slamon, although preliminary trial results had previously led to the FDA approval of this drug in 1998. This study evaluated the efficacy and safety of trastuzumab in patients with HER2 positive metastatic breast cancer, who were randomly assigned to receive chemotherapy (CT) alone vs. CT and trastuzumab. The CT backbone was either doxorubicin and cyclophosphamide, or paclitaxel if the patient had previously received anthracycline in the adjuvant setting. The addition of trastuzumab to CT was associated with a longer progression free survival (PFS) (median, 7.4 vs. 4.6 months; P<0.001), a higher rate of objective response (50 percent vs. 32 percent, P<0.001), a longer duration of response (median, 9.1 vs. 6.1 months; P<0.001), a lower rate of death at 1 year (22 percent vs. 33 percent, P=0.008), longer overall survival (OS) (median survival, 25.1 vs. 20.3 months; P=0.046), and a 20 percent reduction in the risk of death. [
11]
Trastuzumab was then FDA approved in 2006 in the adjuvant setting for early stage HER2 positive breast cancer after a joint analysis of two phase 3 trials comparing adjuvant CT with or without 52 weeks of trastuzumab (
NSABP trial B-31 and NCCTG trial N9831). The CT backbone was four cycles of doxorubicin and cyclophosphamide followed by paclitaxel for 12 weeks (AC-T). 2043 patients were enrolled in B-31 and 1633 patients were enrolled in N9831. Out of 394 total events (including cancer recurrence, second primary cancer, and death), only 133 events were observed in the trastuzumab-CT group, while 261 events were observed in the CT only group (HR 0.48, P<0.0001). There was a 33% reduction in the risk of death with the addition of trastuzumab. The risk of cardiac events was 4.1% in the B-31 trial and 2.9% in the N9831 trial. [
77]
After noting the cardiac toxicity of regimens containing both anthracyclines and trastuzumab, efforts were made to develop non-anthracycline regimens. Based on preclinical synergies between trastuzumab and platinums and docetaxel that were not observed with anthracyclines or paclitaxel, the
BCIRG-006 trial chose to study the combination of docetaxel, carboplatin, and trastuzumab (TCH). In this study, 3222 patients with early stage HER2 positive breast cancer were randomized to receive adjuvant CT with doxorubicin and cyclophosphamide followed by docetaxel (AC-T), the same CT regimen plus 52 weeks of trastuzumab (AC-TH), or docetaxel and carboplatin plus 52 weeks of trastuzumab (TCH). The primary end point was disease free survival (DFS) and the secondary end points were overall survival (OS) and safety. The 5-year DFS rates were 75% for AC-T, 84% for AC-TH (HR 0.64; P<0.001), and 81% for TCH (HR 0.75; P=0.04). The 5-year rates of overall survival were 87% for AC-T, 92% for AC-TH (HR 0.63; P<0.001), and 91% for TCH (HR 0.77; P=0.04). In contrast, no significant difference in the rate of disease-free or overall survival was seen between the two trastuzumab-containing regimens, but both combinations showed that trastuzumab improved DFS and OS. In terms of safety, the non-anthracycline regimen was preferred due to lower cardiovascular toxicity and lower risk of leukemia. [
78]
The
HERA trial proved that 1 year of adjuvant therapy with trastuzumab was superior to 6 months, and 2 years had no additional benefit compared to 1 year. [
79] The
PHARE, HORG, and PERSEPHONE trials followed to determine if 6 months were non-inferior to one year. [
79] While the first two trials failed to prove non-inferiority of 6 months compared to one year of trastuzumab, the
PERSEPHONE trial showed that 4-year DFS was 89.8% in the 1 year arm vs. 89.4% in the 6 month arm, and OS was 94.8% vs 93.8% respectively. [
33] However, it was found that the PERSEPHONE trial included a higher than average proportion of low risk node-negative patients (59%) and ER positive patients (69%), and that the majority of these patients (90%) were treated with a historical anthracycline-containing CT regimen, limiting the applicability of this study in the current non-anthracycline CT practices. While the guideline standard of care recommendation remains one year of adjuvant trastuzumab therapy, the results from PERSEPHONE could be considered for patients with limited tolerance to trastuzumab and small (<2cm), node negative, ER positive tumors. [
80].
Pertuzumab was first FDA approved for first line metastatic HER2 positive breast cancer in 2012, shortly after results from the groundbreaking
CLEOPATRA phase III trial, which compared treatment with docetaxel and trastuzumab with or without pertuzumab. The trial results met the primary endpoint of progression free survival (PFS). The addition of pertuzumab led to a 6 month improvement in PFS (HR 0.68; 95% CI, 0.58 to 0.80). The updated analysis also showed OS benefit with the group receiving the pertuzumab combination achieving a median OS of 56.5 months compared with 40.8 months in the group receiving the placebo combination (HR 0.68; 95% CI, 0.56 to 0.84; P<0.001), a difference of 15.7 months. [
34]
Pertuzumab was then FDA approved in the neoadjuvant setting in 2013 for early stage HER2 positive breast cancer (T2 and/or N1), after the
NeoSphere phase II trial results. This trial compared 4 groups of neoadjuvant therapy, which was followed by surgery and then further adjuvant anthracycline-based CT with conventional trastuzumab. Neoadjuvant therapy involved 4 cohorts with varying combinations of docetaxel (T) and trastuzumab (H) with or without pertuzumab (P): TH, THP, HP, or TP. The primary endpoint was pathological complete response (pCR) rates, and secondary endpoints were PFS and DFS. The study showed that the addition of pertuzumab to neoadjuvant CT led to a statistically significant and clinically meaningful 16.8% increase in pCR, with THP achieving pCR in 45.8% of patients, compared to TH’s 29.0% pCR rate. These results also supported the association between pCR and improvements in long-term outcomes. Five-year PFS rates were 81% for TH, 86% for THP, 73% for HP, and 73% for TP (HR 0.69 [95% CI 0.34-1.40] for THP vs TH). DFS was 81% for TH, 84% for THP, 80% for HP, and 75% for TP. THP vs TH (HR 0·69 [95% CI 0·34-1·40]).Patients who achieved total pCR (all groups combined) had longer median PFS of 85%, compared with patients who did not achieve pCR with a median PFS of 76% (HR 0·54 [95% CI 0.29-1.00]). [
81]
The
TRYPHAENA phase II trial aimed to assess safety tolerability of combined neoadjuvant anti-HER2 therapy with various CT regimens in the treatment of HER2 positive early breast cancer. This trial had a particular focus on cardiac safety, given the known cardiac toxicity of anti-HER2 mAbs and anthracyclines. There were 3 arms with neoadjuvant CT + HP followed by surgery then completion of one year of trastuzumab monotherapy. Two arms were anthracycline-based CT with HP: 5-fluorouracil + epirubicin + cyclophosphamide (FEC) x 3 followed by THP x 3, or concurrent FEC-HP x 3 followed by THP x 3. There was a third non-anthracycline arm with docetaxel + carboplatin + trastuzumab + pertuzumab (TCHP) x 6 cycles. The trial concluded that the overall combination of CT + HP was safe and tolerable, with low rates of symptomatic left ventricular systolic dysfunction (LVSD) across the study: 5.6% for FEC-HP followed by THP, 4.0% for FEC followed by THP, and 2.6% for TCHP. The pCR rates were also reported, and interestingly the non-anthracycline arm with TCHP had a significant pCR rate of 66.2% (compared to 61.6% and 57.3% for the two anthracycline-based arms), making TCHP one of the clinically preferred neoadjuvant regimens for early stage HER2 positive breast cancer that is at least 2cm or lymph node positive. [
82].
The
APHINITY phase III trial studied the addition of pertuzumab to trastuzumab (HP) in the
adjuvant setting. Eligible patients included those with early stage HER2 positive breast cancer, either node positive or high risk node negative (T1c or greater, grade 3, ER negative, or younger than age 35). After surgery, 4805 patients were randomized to receive standard adjuvant CT with 1 year of trastuzumab, plus or minus pertuzumab. The primary endpoint was invasive disease free survival (IDFS), and a secondary endpoints was OS. The most updated results were presented in 2022, 8 years after the original trial, which proved that there was a benefit with the addition of pertuzumab. IDFS was 88.4% with pertuzumab vs 85.8% without pertuzumab, respectively (HR 0.77; 95% CI=0.66-0.91), amounting to a 2.6% absolute IDFS benefit. While there was a small numerical improvement in OS, it was not statistically significant. The 8-year OS was 92.7% in the pertuzumab group, versus 92.0% in the placebo group, a 0.7% difference (HR 0.83; 95% [CI]=0.68-1.02, P=0.78). The node positive cohort clearly derived the most benefit, with an absolute IDFS benefit of 4.9% [86.1% vs 81.2%] HR 0.72 (95% CI 0.60-0.87), and an absolute benefit of 1.9% for OS. Node-negative patients did not show a benefit, with a IDFS HR of 1.01 and more than 92% of patients being event-free in both arms at 8 years. It was also shown that that both hormone receptor negative and hormone receptor positive patients benefited from the addition of pertuzumab. Hormone receptor negative IDFS had a HR of 0.82 (95% CI 0.64-1.06), and hormone receptor positive IDFS had a HR of 0.75 (95% CI 0.61-0.92). Of note, the benefit in hormone receptor positive patients was not initially seen in the original trial results, highlighting the importance of long-term follow up to observe benefit in hormone receptor positive patients. In general, long term survival was excellent for all groups overall, with more than 92% of all patients still alive as of 2022. [
83]
The larger trials mentioned thus far mostly focused on Stage II and III HER2 positive breast cancer patients. Due to the paucity of data for Stage I HER2 positive patients, who had shown to have more than a minimal risk of recurrence and without any standard treatment recommendation at the time, researchers conducted a single-cohort prospective trial for small HER positive tumors using an abbreviated regimen with paclitaxel and trastuzumab. The
APT trial, originally published in 2015, focused on de-escalation of therapy for patients with lower risk of recurrence (3cm or less, node negative), with weekly paclitaxel and trastuzumab (TH) for 12 weeks, followed by 9 months of trastuzumab monotherapy. It met its primary endpoint of IDFS. The latest update occurred March 2023, showing that 10-year IDFS was 91.3% (95% CI 88.3–94.4), 10-year recurrence-free interval was 96.3% (95% CI 94.3–98.3), 10-year OS was 94.3% (95% CI 91.8–96.8), and 10-year breast cancer-specific survival was 98.8% (95% CI 97.6–100). This trial also included patients with T1a and T1b tumors (<1cm), whom had been largely underrepresented in previous trials. It paved the way for treatment of small HER2 positive tumors with a lower toxicity profile, and is currently endorsed by the NCCN guidelines for T1N0 patients, with consideration for tumors as small as 1mm. [
84]
In 2020 margetuximab, a new anti-HER2 monoclonal antibody, was FDA approved after the findings of the
SOPHIA phase III trial. In this trial, 526 patients with HER2 positive metastatic breast cancer who had previously received at least two lines of anti-HER2 therapy were randomized to receive either margetuximab + CT or trastuzumab + CT. Primary endpoints were PFS and OS. The trial findings showed that median PFS was 5.7 months with margetuximab + CT and 4.4 months with trastuzumab + CT (HR 0.71; 95% CI, 0.58-0.86;
P < .001). OS in the interim also showed some numerical improvement without reaching statistical significance, with median OS of 21.6 months in the margetuximab group versus 19.8 months in the trastuzumab group (HR, 0.89; 95% CI, 0.69-1.13;
P = .33). Margetuximab also had an acceptable safety profile that was very similar to trastuzumab, with most common adverse events including fatigue, nausea, diarrhea and neutropenia in both groups with more vomiting in the margetuximab group and more anemia in the trastuzumab group. [
85]
8.2. Antibody Drug Conjugates
The
EMILIA phase III trial led to the first FDA approval of trastuzumab emtansine (T-DM1) in breast cancer in 2013. It studied women with HER2 positive metastatic breast cancer previously treated with trastuzumab and a taxane, and randomized them to receive T-DM1 or lapatinib plus capecitabine. The primary end points were PFS, OS and safety. T-DM1 drastically improved PFS and OS with less toxicity than lapatinib plus capecitabine. The median PFS was 9.6 months with T-DM1 versus 6.4 months with lapatinib plus capecitabine (HR 0.65; 95% CI 0.55 to 0.77; P<0.001), and median OS at the second interim analysis crossed the stopping boundary for efficacy (30.9 months vs. 25.1 months; HR 0.68; 95% CI 0.55 to 0.85; P<0.001). Rates of adverse events of grade 3 or above were higher with lapatinib plus capecitabine than with T-DM1 (57% vs. 41%). The incidences of thrombocytopenia and increased serum aminotransferase levels were higher with T-DM1, whereas the incidences of diarrhea, nausea, vomiting, and palmar–plantar erythrodysesthesia were higher with lapatinib plus capecitabine. [
75]
The
KATHERINE phase III trial was initiated because we know that HER2 positive early breast cancer patients who receive neoadjuvant HER2-based chemotherapy and have residual invasive disease on surgical pathology have a worse prognosis than those who achieve a pathologic complete response [
12]. This trial aimed to determine if adjuvant T-DM1 would provide benefit when there is pathological residual disease. HER2 positive early breast cancer patients with residual invasive disease in the breast or axilla at surgery after receiving neoadjuvant therapy containing a taxane (with or without anthracycline) and trastuzumab were randomly assigned to receive adjuvant T-DM1 or trastuzumab for 14 cycles. The primary end point was IDFS at 3 years, which was significantly higher in the T-DM1 group at 88.3% compared to the trastuzumab group at 77.0% (HR 0.50; 95% CI 0.39 to 0.64; P<0.001). Adjuvant T-DM1 is now the standard of care for HER2 positive patients with residual disease on pathology. [
86]
Fam-trastuzumab-deruxtecan-nxki (T-DXd) first received accelerated approval by the FDA in 2019 after results from the
DESTINY-Breast01 phase II trial, which showed T-DXd achieved an overall response rate of 60.9% and a median PFS of 16.4 months in a single cohort of patients with HER2 positive metastatic breast cancer who had previously received at least two anti-HER2 regimens. This PFS exceeded that of any anti-HER2 therapy existing at the time, and paved the way for a head to head comparison of T-DXd with T-DM1. In the subsequent
DESTINY-Breast03 phase III trial, a total of 524 patients with HER2 positive unresectable or metastatic breast cancer previously treated with trastuzumab and a taxane were randomly assigned to T-DXd or T-DM1 as second line therapy or beyond. The primary endpoint was 12 month PFS, which was 75.8% with T-DXd and 34.1% with T-DM1 (HR 0.28; 95% CI, 0.22 to 0.37; P<0.001). A secondary endpoint was 12 month OS, which was 94.1% with T-DXd and 85.9% with T-DM1 (HR 0.55; 95% CI, 0.36 to 0.86; prespecified significance boundary not reached). The incidence of adverse events of any grade was 98.1% with T-DXd and 86.6% with T-DM1. The most common adverse events with T-DXd were bone marrow suppression, transaminitis, nausea, diarrhea, alopecia, fatigue. An important adverse event of T-DXd was interstitial lung disease or pneumonitis, which occurred in 10.5% of the patients; none of these events were of grade 4 or 5. Overall, a manageable safety profile of T-DXd was confirmed with longer treatment duration. [
76] T-DXd is currently the second line standard of care treatment for metastatic HER2 positive breast cancer, after THP.
Due to the potent bystander effect of drugs like T-DXd, which delivers its cytotoxic payload not only intracellularly but also to neighboring cells, efforts were made to explore drug efficacy in breast tumors with lower levels of HER2 expression (“HER2-low”). These cancers would not traditionally be considered to be HER2 positive based on current criteria, that is, they are either hormone receptor positive or triple negative breast cancers. The
DESTINY-Breast04 phase III trial studied patients with HER2-low metastatic breast cancer who had previously received at least one line of chemotherapy in the metastatic setting or who developed disease recurrence within six months of completing adjuvant chemotherapy. A total of 88.7% of all the patients were hormone receptor positive (a proportion that is representative of such disease in the HER2-low population), and they must have also received at least one line of endocrine therapy. HER2-low status was defined as a score of 1+ on IHC or as an IHC score of 2+ and negative results on FISH. A total of 557 patients were randomly assigned in a 2:1 ratio to receive T-DXd or chemotherapy (physician’s choice). The primary end point was PFS in the hormone receptor positive cohort. Secondary endpoints were PFS among all patients and OS in the hormone receptor positive group. There was significantly longer PFS and OS with T-DXd compared to chemotherapy. In the hormone receptor positive cohort, the median PFS was 10.1 months in the T-DXd group and 5.4 months in the chemotherapy group (HR 0.51; P<0.001), and OS was 23.9 months and 17.5 months, respectively (HR 0.64; P=0.003). Among all patients, the median PFS was 9.9 months in the T-DXd group and 5.1 months in the chemotherapy group (HR 0.50; P<0.001), and overall survival was 23.4 months and 16.8 months, respectively (HR 0.64; P=0.001). [
76,
87] The FDA approved T-DXd in 2022 for patients with HER2-low metastatic breast cancer after having received at least one line of chemotherapy in the metastatic setting or with recurrence within six months of adjuvant chemotherapy.
8.3. Tyrosine Kinase Inhibitors
The first anti-HER2 TKI that was discovered was lapatinib (reversible). In 2006 a phase III trial randomly assigned 324 women with HER2 positive metastatic breast cancer previously treated with trastuzumab to treatment with lapatinib plus capecitabine versus capecitabine alone. The primary endpoint was median time to progression, which was 8.4 months in the combination-therapy group as compared with 4.4 months in the monotherapy group (HR 0.49 (95% CI 0.34 to 0.71; P<0.001). There were no symptomatic cardiac events and most adverse events were manageable and included diarrhea and hand-foot syndrome. [
88]
Lapatinib was FDA approved in 2007 for previously treated metastatic HER2 positive cancer.
Neratinib, a pan-HER2 irreversible TKI, was first studied at large scale as extended adjuvant therapy in the
ExteNET trial. This phase III trial studied neratinib in patients with early stage HER2 positive breast cancer; while initially all patients with stages 1-3 were eligible, a protocol amendment 7 months into the study restricted eligibility to higher risk patients with stage 2-3, and patients who completed neoadjuvant chemotherapy were only eligible if there was pathological residual invasive disease at the time of surgery. After completion of neoadjuvant or adjuvant CT with one year of trastuzumab, a total of 2840 patients were randomized to receive neratinib or placebo for one year. The primary endpoint was IDFS, which was indeed significantly improved, particularly in the HER2 positive/hormone receptor positive (HR+) population. Overall, the IDFS at 5 years was 90.2% in the neratinib group and 87.7% in the placebo group, with 116 versus 163 IDFS events, respectively (HR 0.73, 95% CI 0.57-0.92, P= 0.0083). There was lower benefit in T1 (2cm or less) or node negative tumors. [
89] A consistent finding in the first two interim analyses was that the benefit was more profound in two predefined subgroups: patients who initiated neratinib within one year of trastuzumab completion (versus greater than one year), and patients with HER2 positive/hormone receptor positive (HR+) disease (versus hormone negative). There were 1334 patients who were HER2+/HR+ and initiated neratinib within the one year window, and for them the absolute IDFS benefit at 5 years was 5.1% (HR 0.58; 95% CI 0.41-0.82). Within this HR+ cohort initiating therapy within one year, an even deeper benefit of was seen in the 295 patients who had residual invasive disease: there was a 7.4% IDFS benefit at 5 years (HR 0.60; 95% CI 0.33-1.07, P=0.086) and a 9.1% absolute OS benefit at 8 years (HR 0.47; CI 0.23-0.92, P=0.03). [
90] The additional benefit in the HR positive population (most of whom received concomitant endocrine therapy) is thought to be from inhibition of reciprocal crosstalk between the signaling pathways of the HER2 and estrogen receptors, a known mechanism of resistance for these tumors. A final analysis for OS revealed that in the overall HER2+/HR+ cohort, 8-year overall survival rates were 93.2% in the neratinib group and 90.4% in the placebo group (HR 0.65; 95% CI 0.41–1.03). On the other hand, OS at 8 years was comparable in the intention to treat population with 90.1% in the neratinib group and 90.2% in the placebo group (HR 0.95; 95% CI 0.75–1.21; P= 0.69) [
47]
While diarrhea was the most prominent side effect, with grade 3 diarrhea occurring in up to 40% of patients, it was found that either dose escalation or prophylaxis with loperamide/ colestipol can significantly improve tolerability [
91]. The FDA first approved neratinib in 2017 as extended adjuvant therapy following completion of one year of trastuzumab for early stage HER2 positive breast cancer based on the trial’s intention to treat population, whereas the European Medicines Agency approved it only for HER2 positive early stage breast cancer that is also HR+ and when it is started within 1 year of trastuzumab completion.
The
NALA phase III trial studied 621 patients with metastatic HER2 positive breast cancer who received more than two previous HER2-directed therapies, and randomized them to treatment with neratinib plus capecitabine (N+C) versus lapatinib with capecitabine (L+C). The study included patients with stable, asymptomatic CNS disease. Co-primary endpoints were PFS and OS, and the study was considered positive if at least one endpoint was met. Some secondary endpoints were time to intervention for CNS disease, overall response rate (ORR), and duration of response. The results showed that N+C significantly improved PFS and reduced the number of interventions needed for CNS disease compared to L+C. Median PFS was 8.8 months with N+C and 6.6 months with L+C (HR 0.76; 95% CI 0.63 to 0.93; P =.0.0059). The median OS was 24.0 months with N+C and 22.2 months with L+C (HR 0.88 (95% CI, 0.72 to 1.07; P = 0.2098). The cumulative number of interventions for CNS disease was 22.8% with N+C versus 29.2% with L+C (P = 0.043). The ORR was 32.8% with N+C and 26.7% with L+C (P = 0.1201), with a median duration of response 8.5 versus 5.6 months, respectively (HR 0.50; 95% CI 0.33 to 0.74; P = 0.0004). [
92] ] The FDA approved neratinib in combination with capecitabine in 2020 for HER2 positive metastatic breast cancer patients previously treated with at least two anti-HER2 based regimens in the metastatic setting.
The
HER2CLIMB trial investigated tucatinib, a highly selective anti-HER2 TKI. A total of 612 patients who were previously treated with trastuzumab, pertuzumab and T-DM1 were randomly assigned to receive either tucatinib or placebo in combination with trastuzumab and capecitabine. Notably, patients with brain metastases were also included. The primary endpoint was PFS, and secondary endpoints included OS, PFS among patients with brain metastases, and safety. The study met its primary and secondary endpoints. It was especially found to be helpful in the setting of patients with brain metastatic disease. PFS at 1 year was 33.1% in the tucatinib-combination group and 12.3% in the placebo-combination group (HR 0.54; 95% CI, 0.42 to 0.71; P<0.001), and the median PFS was 7.8 months and 5.6 months, respectively. OS at 2 years was 44.9% in the tucatinib-combination group and 26.6% in the placebo-combination group (HR 0.66; 95% CI, 0.50 to 0.88; P=0.005), and the median OS was 21.9 months and 17.4 months, respectively. Among the patients with brain metastases, PFS at 1 year was 24.9% in the tucatinib-combination group and 0% in the placebo-combination group (HR 0.48; 95% CI, 0.34 to 0.69; P<0.001), and the median CNS PFS was 7.6 months and 5.4 months, respectively. In terms of adverse effects, there was an increased risk of diarrhea and transaminitis in the tucatinib combination when compared to the placebo combination. [
93]
The COMPASS-HER2 trial (NCT04266249) is currently studying adjuvant T-DM1 in combination with tucatinib versus placebo for early stage, high risk HER2 positive breast cancer patients with residual disease after neoadjuvant HER2-directed therapy. The primary objective of this ongoing phase III trial will be IDFS, and secondary objectives will be breast cancer free survival, distant recurrence free survival, brain metastases free survival, and overall survival.