Review Article
Vol. 2, Issue 2, 2022 · P1-12
Antibody drug conjugates (ADCs): an expanding rational treatment paradigm in breast cancer (CME article)
Fengting Yan, MD, PhD,Lian Sun, B.S.,Aimee Wu,Henry G Kaplan, MD
Submission received: 2022-02-21 / Accepted: 2022-03-14 / Published: 2022-08-05
Abstract
Recent advances in bioengineering and manufacturing have catapulted Antibody–drug conjugates (ADCs) to broader clinical applications. ADCs take advantage of the exquisite specificity of monoclonal antibodies (mAb) to deliver a highly potent cytotoxic agent to a specifically targeted cell expressing a selected antigen. HER2-positive breast cancer has served as a testing ground for ADC development in solid tumors that over-express HER2/ neu by linking trastuzumab to a payload agent. With the current advances, ADCs leverage the selective targeting of monoclonal antibodies to deliver highly potent agents which otherwise have a narrow therapeutic index. Ado-trastuzumab emtansine (T-DM1) was the first ADC approved for patients with HER2-postive metastatic breast cancer (MBC) and fam-trastuzumab deruxtecan-nxki (T-DXd) was recently approved as well. Sacituzumab govitecan-hziy (SG) was approved in 2020 for patients with triple negative breast cancer (TNBC). Studies focusing on utilizing ADCs in earlier stages of breast cancer in the neoadjuvant or adjuvant setting, and central nervous system (CNS) disease are in progress. New ADCs and bispecific antibodies (bAbs) are also in development.
Take home message
- 2 ADCs are approved in HER2-positive breast cancer; 1 ADC approved in triple negative breast cancer
- ADCs have demonstrated activity in the neoadjuvant and adjuvant settings, with one ADC (T-DM1) currently approved as adjuvant therapy
- ADCs have demonstrated potential CNS anti-tumor activity
- ADCs may be active on HER2 mutation and HER2-low expression
1. INTRODUCTION
Despite innovations and improvements in the treatment for early-stage breast cancer, the disease is incurable in the metastatic setting. Antibody-drug conjugates (ADCs) are designed to precisely target specific antigens, and have become a new and advanced class of drugs used for cancer treatment. The initial approval of T-DM1 targeting human epidermal growth factor receptor 2 positive (HER2+) breast cancers produced significant clinical progress, laying a foundation and inspiring the introduction of ADCs in cancer treatment.1
2. ADCS
There are three components of an ADC: the monoclonal antibody (mAb), a highly potent cytotoxic agent or payload, and a linker.2 Even in the context of low antigen expression on tumor cells, a high drug-to-antibody ratio (DAR) maximizes anti-tumoral performance, whereas a low DAR adversely affects efficacy.3 Regarding the payload, there are only select chemotherapy agents appropriately suited as a cytotoxic agent. Two subtypes of linkers are commonly used to bind the mAb to the payload: cleavable and non-cleavable linkers. Cleavable linkers release the cytotoxic agent based on enzymatic proteolysis or pH, whereas non-cleavable linkers undergo lysosomal degradation upon endocytic internalization of the ADC-antigen complex, in order to subsequently release the payload in the cancer cell.4 A cleavable linker increases systemic release, while a non-cleavable linker increases specificity for the target cell.5
Currently, there are three FDA-approved ADCs targeting breast cancer: ado-trastuzumab emtansine (T-DM1), fam-trastuzumab deruxtecan-nxki (T-DXd), and sacituzumab govitecan-hziy (SG). T-DM1 and T-DXd target the HER2 antigen. SG targets the human trophoblast cell-surface antigen 2 (Trop-2) in triple negative breast cancer (TNBC).
This review dives deeper into each of the current ADCs used in breast cancer.
2.1. CURRENT APPROVED ADCS IN BREAST CANCER MANAGEMENT
2.1.1. ADCS IN METASTATIC BREAST CANCER
2.2. ADCS IN EARLIER STAGES OF BREAST CANCER
2.2.1. ADJUVANT THERAPY
The KATHERINE trial compared T-DM1 with trastuzumab in the adjuvant setting. Among HER2+ early breast cancer patients who had residual invasive disease after neoadjuvant therapy, the risk of recurrence of invasive breast cancer or death was 50% lower with adjuvant T-DM1 than with trastuzumab (the estimated percentage of patients who were free of invasive disease at 3 years was 88.3% in the T-DM1 group and 77.0% in the trastuzumab group ),19 which led to the FDA approval of T-DM1 in 2019 in the adjuvant setting for patients with residual disease after neoadjuvant therapy.
For the patients who did not receive neoadjuvant therapy, the phase 3 KAITLIN trial compared adjuvant anthracycline-based chemotherapy followed by T-DM1 plus pertuzumab (AC-KP) to a taxane plus trastuzumab and pertuzumab (AC-THP). Replacing adjuvant taxane and trastuzumab with T-DM1 did not result in a significant improvement in invasive disease-free survival (IDFS) in the node-positive or intent-to-treat population.20 The ATEMPT trial also looked into adjuvant T-DM1 compared to paclitaxel plus trastuzumab (TH) among patients with stage I Her2+ breast cancer, one year of adjuvant T-DM1 was associated with excellent 3-year DFS, but not associated with fewer clinically relevant toxicities compared to TH.21
T-DXd is currently being evaluated in the adjuvant setting compared to T-DM1 in the Destiny-Breast05 trial, NCT04622319.
2.2.2. NEOADJUVANT THERAPY
The KRISTINE trial examined the combination of docetaxel, carboplatin, trastuzumab, and pertuzumab (TCHP) versus T-DM1/P in the neoadjuvant setting for patients with HER2+ disease.22 This trial showed a higher pathologic complete response (pCR) rate with neoadjuvant TCHP (55.7%) over T-DM1/P (44.4%). Importantly, additional chemotherapy was not recommended for patients with residual disease who had received neoadjuvant TCHP, but approximately 9% of the patients assigned to T-DM1/P with residual tumor > 1 cm or nodal disease (> ypN0) received anthracycline-based chemotherapy, and there were 15/223 (7%) locoregional events prior to surgery in the T-DM1/P arm versus 1/221 (<1%) in TCHP arm, suggesting the presence of a subgroup of patients with disease that was primarily refractory to HER2 ADC-based therapy alone due to the inability to internalize the antibody–toxin.23 A three-year follow up of the KRISTINE trial suggested that compared with TCHP, T-DM1/P resulted in a higher risk of an event-free survival (EFS) event owing to locoregional progression events before surgery, a similar risk of an IDFS event, fewer grade 3 or greater AEs during neoadjuvant treatment, and more AEs leading to treatment discontinuation during adjuvant treatment.24 In the recent published I-SPY2, pCR rates were 63%, 72% and 33% for T-DM1/P, paclitaxel, trastuzumab and pertuzumab (THP) and paclitaxel/trastuzumab (TH), respectively.25 Three-year EFS was 88% for T-DM1/P, 92% for THP and 87% for TH. It was found that the degree of HER2 pathway signaling and phosphorylation in pretreatment biopsy specimens were associated with response to T-DM1/P. Overall, the results suggested T-DM1/P is currently not the SOC in the neoadjuvant setting; patients should be carefully selected to consider a chemotherapy–sparing neoadjuvant regimen. More biomarker studies are warranted in this setting.
T-DXd is being studied in the neoadjuvant setting (alone or followed by THP, versus standard treatment AC-THP, NCT05113251).
2.3. CENTRAL NERVOUS SYSTEM (CNS) PENETRATION OF ADCS
The development of CNS disease is associated with debilitating neurological symptoms and poor survival. The efficacy of systemic therapy may be limited by an inability to access the brain, drug efflux pumps that may exclude cytotoxic and ADCs, and acquired resistance to prior treatment regimens.26,27 Accumulating evidence, however, suggests a potential role for ADCs in HER2+ and TNBC MBC patients with brain metastases (BM).28
A subgroup analysis from the phase 3 ASCENT trial29 showed SG led to improvement in response rate and PFS compared to chemotherapy for a patient with metastatic TNBC who had stable BM (5.6 months compared to 1.7 months). The ORR was 35% with SG and 5% with physician's choice of treatment.
Exploratory analysis of KAMILLA trial in patients with HER2+ MBC and BM showed that T-DM1 is active and well-tolerated in this population.30 In 126 patients with measurable BM, the best ORR and CBR were 21.4% and 42.9%. In the 398 patients with baseline BM, mPFS and OS were 5.5 months and 18.9 months, respectively.
However, subgroup analysis of the KATHERINE trial showed that the CNS was more often the site of first recurrence in the T-DM1 arm versus the trastuzumab arm (5.9% vs 4.3%). However, T-DM1 was not associated with a difference in overall risk of CNS recurrence.31 More studies are clearly needed to optimize adjuvant therapy to prevent CNS recurrence.
A subgroup analysis of the DESTINY-Breast01 trial investigated T-DXd in 24 patients with HER2+ MBC with BM.32 The ORR, mPFS, and mDOR with T-DXd were 58.3%, 18.1 months, and 16.9 months, respectively. Most recently, the phase 3 DESTINY-Breast03 trial (NCT03529110) was reported at SABCS 2021. The study compared T-DXd and T-DM1 in patients with HER2-positive unresectable and/ or metastatic breast cancer previously treated with trastuzumab and a taxane. In patients with stable brain metastases at baseline, treatment with T-DXd resulted in higher PFS compared to T-DM1 (HR 0.25; 95% confidence interval [CI] 0.13-0.45). T-DXd improved PFS to a median of 15 months versus 3 months for T-DM1.
There is currently an ongoing, open-label, multicenter study assessing the efficacy and safety of T-DXd in HER2+ MBC participants with or without BMs who have had progression of disease on trastuzumab, pertuzumab, or T-DM1 (DESTINY-B12, NCT04739761).
2.4. ADCS ON HER2 MUTATION AND HER2-LOW EXPRESSION
Studies of Her2-targeted ADCs has expanded to patients with negative HER2 expression, as well as patients with Her2 mutation and those with low expression level of HER2. Recent genome sequencing projects revealed that HER2 mutations also exist in breast cancer.33 There is recent case report of a patient with de novo MBC who harbored both HER2 amplification and the L755S mutation; the lesion responded to T-DM1 and after progression on T-DM1 to T-DXd after initially exhibiting clinical resistance to trastuzumab- and lapatinib-based therapies.34 A recent study using isogenic cell lines stably expressing wild-type or mutant (S310F and L755S) HER2 demonstrated that HER2 mutations enhance the internalization of T-DM1.35 There are also promising findings in patients with HER2-mutated lung cancer, showed that HER2 ubiquitination and internalization, rather than overexpression, are key mechanisms promoting endocytosis and efficacy of both T-DM1 and T-DXd. They also found that T-DXd was active in T-DM1 resistant tumors.36 These findings support the hypothesis that HER2 mutations do not compromise the activity of HER2-directed ADCs such as T-DM1 and T-DXd.
Recent studies suggest antitumor activity by T-DXd even in HER2-low expressing tumors, possibly due to its cleavable linker allowing the payload to promote a bystander killing effect.37 In an open-label, phase Ib clinical trial, 54 heavily pretreated patients with HER2–low MBC were treated with T-DXd at two dose levels. ORR was 37%, mDOR was 10.4 months. Notably, three patients in the cohort receiving the higher dose died of effects deemed to be due to study treatment, two of pneumonitis and one of ILD. Due to the greater potential for AEs with the higher dose, the lower dose was (5.4 mg/kg) recommended for further study.12
A phase 3, randomized study of T-DXd versus investigator's choice chemotherapy in HER2-Low, hormone receptor (HR) positive MBC is currently recruiting (DESTINY-Breast06, NCT04494425).
2.5. COMBINATION OF ADCS WITH OTHER THERAPIES
Patients with HER2+ MBC are often treated with a multitude of therapies, additional strategies to improve responses to anti-HER2 therapies are needed. There have been studies combining T-DM1 with capecitabine and with paclitaxel but these regimens proved quite toxic without improvement of clinical outcomes.38,39
2.5.1. COMBINATION OF T-DM1 AND TUCATINIB
There is evidence that dual targeting of HER2, either through the combination of 2 different HER2-targeted antibodies or through an antibody-based therapy and a tyrosine kinase inhibitor (TKI), can lead to further improvements in efficacy.40
A recent phase 1b study investigated the maximum tolerated dosage (MTD) of tucatinib combined with T-DM1. The ORR was 48%; mPFS was 8.2 months. The results compare favorably with those of retrospective trials suggesting a mPFS of 6 months with T-DM1 in a similar population.41 HER2CLIMB-02 is a randomized, double-blind, phase 3 study designed to evaluate the efficacy and safety of tucatinib in combination with T-DM1 in those patients who have had prior treatment with a taxane and trastuzumab (NCT03975647).
The phase 3 CompassHER2 RD trial compares T-DM1 and tucatinib with T-DM1 alone in preventing relapses in people with high risk HER2+ breast cancer in the adjuvant setting (NCT04457596).
T-DXd is also being studied in combination with tucatinib (Her2Climb04, NCT 04539938).
2.5.2. COMBINATION OF T-DM1 AND CDK4/6 INHIBITORS
Combinations involving targets downstream of the HER2 pathway, particularly cyclin D and cyclin-dependent kinases (CDK) 4/6, could potentially enhance therapeutic efficacy in HER2+ MBC. While CDK 4/6 inhibitors have been FDA approved for the treatment of HR+ MBC, the activity has been attributed in part to the proven pathogenesis of these tumors in promoting cyclin D1 expression and CDK 4/6 activity. This activity also occurs downstream of HER2, thus making it an appealing partner with anti-HER2 therapy.42
A phase 1b study combined ribociclib and T-DM1 in patients with HER2+ MBC previously treated with trastuzumab and a taxane.43 Based on the pharmacokinetic analysis, AEs, and dose reductions, 400 mg was determined to be the recommended phase II dose (RP2D) for ribociclib given with T-DM1.
There is also a multi-center, randomized, phase 2 study of T-DM1 with palbociclib in HER2+ MBC (NCT03530696).
2.6. ADVERSE EVENTS OF SPECIAL INTEREST WITH ADCS
2.6.1. THROMBOCYTOPENIA
The most frequently occurring all-grade AEs in patients receiving T-DM1 include fatigue (46%), nausea (43%), thrombocytopenia (32%), headache (29%), and constipation (26%).44,45 Thrombocytopenia is a common AE in patients receiving T-DM1. In EMILIA trial, grade 3-4 thrombocytopenia incidence was 12%. Almost all patients receiving T-DM1 experience a transient decline of platelet count, nadir at day 8, with subsequent recovery at day 15.46 Experimental studies evaluating the mechanism of thrombocytopenia suggested an uptake of T-DM1 by megakaryocytes through a non-target-mediated mechanism (e.g. pinocytosis), whereas the intracellular generation of the active catabolite results in the disruption of microtubules and inhibition of pro-platelet production.47,48
Grade 3-4 thrombocytopenia typically occurs during the first 2 treatment cycles. Most patients are able to continue T-DM1 with dose modification or treatment delays. Guidelines suggest treatment interruption in case of grade 3 thrombocytopenia until the platelet count recovers to grade ≤ 1. In the case of a grade 4 thrombocytopenia, T-DM1 treatment should be re-initiated at a lower dose level after recovery.
2.6.2. INTERSTITIAL LUNG DISEASE (ILD)
Drug-induced ILD has been reported among patients with HER2+ MBC receiving anti-HER2 therapies, including trastuzumab, lapatinib, T-DM1, T-DXd, and trastuzumab duocarmazine. A recent review49 selected 18 articles and assessed 9,886 patients who received trastuzumab, lapatinib, T-DM1, or T-DXd. The overall incidence of all-grade ILD was 2.4%, with 66.7% occurring as grade 1–2 events, 0.5% grade 3–4, and 0.2% grade 5. The studies indicated that ILD events were managed via dose interruption, dose reduction, or treatment discontinuation.
T-DXd is of special interest given the phase 1 study13 reported ILD incidence of 17.4% (20 patients) of 115 patients. The phase 2 study14 assessed 184 patients, 25 patients (13.6%) had a treatment-related ILD event, most of which were grade 1–2 (n=20, 10.9%). In a phase 2 clinical trial of T-DXd, Modi et al.12 recommend T-DXd dose interruption and possible systemic steroids for grade 1 events, and permanent T-DXd discontinuation with prompt initiation of systemic steroids for grade 2, 3, or 4 events; hospitalization is required for grade 3 or 4 events.
ILD remains an important identified risk with T-DXd. A recent analysis50 used data from 245 patients with HER2+ MBC treated with T-DXd monotherapy at 5.4 mg/kg every 3 weeks from August 2015 to June 2020; of these 61 patients participated in two phase I studies (NCT02564900, NCT03383692) and 184 patients were in the phase II DESTINY-Breast01 study (NCT03248492). During treatment, 38 (15.5%) patients experienced an ILD event that was adjudicated as drug related. Of patients with ILD, most (79%) experienced Grade 1 or 2 events. Thirty patients (12.2%) were Grade 1 or 2 events. Grade 3 and Grade 4 ILD events were reported in one (0.4%) patient each. Six (2.4%) patients died due to a Grade 5 ILD event. Most of the ILD events occurred within the first 12 months of treatment. The median time to first ILD event was 5.6 (range, 1.1 to 20.8) months, with 97% of patients experiencing the first onset of ILD prior to 12 months.
The incidence of ILD seems to be lower when T-DXd is used in the second-line setting in DESTINY-Breast03.15 As mentioned, 524 patients with unresectable or metastatic HER2-positive breast cancer previously treated with trastuzumab and a taxane were randomly assigned 1:1 to receive T-DXd or T-DM1. Adjudicated drug-related ILD or pneumonitis was reported in 27 patients (10.5%) treated with T-DXd and five patients (1.9%) treated with T-DM1 overall, with no Grade 4 or 5 events. The data suggested that patients who were heavily pre-treated might be at higher risk to develop grade 4 or 5 ILD while receiving T-DXd.
2.6.3. NEUTROPENIA
Neutropenia is one of the most common treatment-related adverse events. In the ASCENT trial, 63% of patients receiving SG had any grade of neutropenia, 51% with grade 3 or higher neutropenia. The incidence of grade 3 and 4 febrile neutropenia was 5% and 1%, respectively, with SG. Neutropenia was managed with dose reduction, dose delay, or both and with growth-factor support after day 1 of cycle 1. Concomitant growth-factor support was given to 49% of the patients treated with SG.
T-DXd had lower incidence of neutropenia compared to SG. In the DESTINY-Breast01 trial, incidence of grade 3 or higher neutropenia was 20.7%. Incidence of grade 3 or higher neutropenia from T-DXd was 19.1% in the second-line setting in DESTINY-Breast03.
2.6.4. CARDIOVASCULAR TOXICITIES
Cardiotoxicity was an unusual finding among patients treated with T-DM1 after anthracycline-based chemotherapy.43,44 Verma et al.8 reported that 97% of patients receiving T-DM1 maintained an LVEF of ≥ 45%. This is consistent with the results of other landmark studies reporting that very few patients discontinue treatment due to cardiotoxicity. The current recommendation includes cardiac function evaluation prior to the therapy initiation and at regular intervals throughout treatment.
2.6.5. ALOPECIA
Interestingly the incidence of alopecia can be different depending on the ADCs but most commonly grade 1 or grade 2. Alopecia is common in patients receiving SG (46% of any grade alopecia in ASCENT trial, no grade 3 or grade 4 alopecia) or T-DXd (48.4% of any grade alopecia in DESTINY-Breast01 and 0.5% grade 3, no grade 4 alopecia). Given the incidence, patients should be informed of the incidence and severity of alopecia.
2.7. ADCS IN LOW RESOURCE COUNTRIES AND COST-EFFECTIVENESS
Unfortunately, T-DM1, T-DXd, or SG are not available in every country. Earlier studies suggested that T-DM1 is not cost-effective when compared to the lapatinib plus capecitabine combination therapy.51–53 However, by combining the cost of drugs with OS, T-DM1 is cost-effective for the treatment of pretreated HER2+ MBC.54 A recent analysis55,56 showed that compared to trastuzumab, T-DM1 in the adjuvant setting yielded lower lifetime costs (−$40,271), and higher life-years (2.980) and quality-adjusted life-years (2.336). The patent expiration date for T-DM1 in Europe was June 2020. The patent is set to expire in September 2026 in the US. We are anticipating biosimilar products will be more widely available in the next few years.
3. FUTURE DIRECTIONS
There is ongoing research to develop second-generation ADCs (Table 1), by identifying new targets and modifying the linker and/or payload. Currently, (Vic-)Trastuzumab Duocarmazine (SYD985) is being investigated in the phase 3 TULIP trial. It was reported at ESMO 2021 that treatment with SYD985 significantly improved PFS in comparison with standard physician's choice chemotherapy and may provide a new treatment option for patients with pretreated locally advanced or metastatic HER2+ MBC (PFS of 7.0 months vs 4.9 months). ARX788 (Her2 antibody-MMAF) and Zilovertamab Vedotin (UC961-MMAE, MK-2140, VLS-101) are being investigated in phase 2 studies. There are multiple other ADCs in phase 1 studies.
Bispecific mAbs currently under development for the treatment of breast cancer target two different epitopes on HER2, HER3, B7H4, and/or an epitope on T cells. ZW25, Zenocutuzumab, PRS-343 and PF-07260437 are currently undergoing clinical trials.
Future attention must be paid to ADC resistance mechanisms to engineer new ADCs to bypass/overcome resistance pathways; clinical use of ADCs in combination with other treatment modalities and integration with immune-acting agents.
The general theorem of ADC action is that these drugs remain chemotherapeutics at their core. The development of "chemo-free" bispecific antibodies seems to be the future direction of personalized treatment of breast cancer.
Table 1. Ongoing clinical trials on ADCs
4. CONCLUSION
ADCs are a revolutionary and unique approach where mABs and chemotherapy agents are linked to deliver payloads to targeted cancer cells to improve treatment specificity and reduce systemic toxicity. Clinical trials and research are exploring the possibilities of engineering newer ADCs to bind to additional targets and deliver more effective payloads. In general, this new realm of ADCs showcases encouraging treatment options for breast cancer.
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