Antibody–drug conjugates: Smart chemotherapy delivery across tumor histologies

Introduction

Cytotoxic chemotherapy constitutes the foundation of traditional anticancer treatment.1 In the past decades, however, knowledge about cancer's molecular and immunologic underpinnings has significantly expanded, and oncology drug development has shifted toward agents that target specific molecular alterations or stimulate the immune response against malignant cells.2, 3 In particular, advances in sequencing technologies have revealed identical molecular targets in multiple tumor histologies, culminating in the concept that tumor biology might better define subpopulations of patients with actionable alterations across cancer types, and ushering in a new era of drug development characterized by the pursuit of tissue-agnostic, biomarker-driven treatments.4 Currently, there are 4 US Food and Drugs Administration (FDA)-approved histology-agnostic indications: larotrectinib and entrectinib for NTRK fusion-positive solid tumors, pembrolizumab and dostarlimab for tumors with high microsatellite instability, and pembrolizumab for tumors with a high tumor mutational burden.5-9 Of note, these biomarker-defined populations identify tumors that share disparate biologic elements: either a driver-targetable gene alteration (NTRK fusions) or, alternatively, common mechanisms leading to higher neoantigen load, T-cell activation, and susceptibility to immune checkpoint blockade (high microsatellite instability and high tumor mutational burden).

In parallel with this new model for drug development, a novel category of medications for the targeted delivery of chemotherapy to solid tumors came of age: namely, antibody–drug conjugates (ADCs).10 The concept of targeted delivery of drugs is not new: in the early 1900s, Paul Ehrlich conceived the magic bullet concept, with the purpose of creating medicines that achieve their intended cell-structural targets directly while remaining inoffensive to normal tissues.11 Biotechnological improvements significantly benefited the clinical activity of ADCs, which are constituted by 3 elements: a monoclonal antibody (MoAb), a linker, and a payload.10, 12 Specifically, innovative linkers and payloads have enhanced drug delivery to tumor cells and improved activity in cancers with heterogenous expression of the targeted antigen. Although a payload can belong to any class of anticancer drugs, to this point, ADC development has mainly explored cytotoxic products. Particularly potent cytotoxic agents that often cause unacceptable toxicities, if unconjugated, have been in the spotlight. In this sense, currently approved ADCs can be seen as targeted chemotherapeutic agents that kill cancer cells by a pharmaceutic Trojan horse mechanism.

The first clinical trials of ADCs in human cancer were designed in the 1980s, achieving disappointing results: high toxicities and no signs of efficacy were observed.13, 14 In 2000, a significant step forward was achieved: the anti-CD33–targeted agent gemtuzumab ozogamicin became the first-ever ADC approved by the FDA.15 About a decade later, in 2011, brentuximab vedotin was approved for the treatment of classical Hodgkin lymphoma and systemic anaplastic large cell lymphoma.16 Shortly thereafter, in 2013, the human epidermal growth factor receptor 2 (HER2)-targeted ADC ado-trastuzumab emtansine (T-DM1) was approved to treat metastatic breast cancer (BC), becoming the first ADC to be approved for the treatment of a solid tumor.17 The momentum of ADC development has since increased, with multiple further approvals in the past 3 years. Moreover, several novel ADCs have demonstrated significant antitumor activity in multiple tumor types that share the expression of the targeted antigen, leading to the hypothesis of a histology-agnostic activity of these compounds (Fig. 1). In this review article, we summarize the current approvals of ADCs by the FDA and discuss the challenges and opportunities posed by the multihistological expansion of ADCs indications.

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Milestones in the Development of Antibody–Drug Conjugates (ADCs) for the Treatment of Solid Tumors. Since the first approval of an ADC for a solid malignancy, significant advancements have been made in this field, with several conjugates demonstrating activity in multiple tumor types and 6 new regulatory approvals for solid tumors in the time frame of the last 3 years. ABC indicates advanced breast cancer; AML, acute myeloid leukemia; ASCO, American Society of Clinical Oncology; BC, breast cancer; CRC, colorectal cancer; EBC, early breast cancer; FDA, US Food and Drug Administration; GC, gastric cancer; HER2+, human epidermal growth factor receptor 2–positive; mGC, metastatic gastric cancer; mTNBC, metastatic triple-negative breast cancer; mUC, metastatic urothelial cancer; NSCLC, nonsmall cell lung cancer; PFS, progression-free survival; R/R, relapsed and/or refractory; T-DCZ, trastuzumab duocarmazine; T-DXd, trastuzumab deruxtecan; TNBC, triple-negative breast cancer. Created with biorender.com.

Current Clinical Indications of Approved ADCs for Solid Tumors

Since 2013, the FDA has approved 4 ADCs for 6 indications for the treatment of solid tumors.10 In this section, we provide an overview of the results leading to approvals; data are summarized in Table 1.

TABLE 1. Activity and Toxicity of Antibody-Drug Conjugates Currently Approved for the Treatment of Solid Tumors DRUG NAME DRUG STRUCTURE APPROVED INDICATION STUDY CHARACTERISTIC PRIMARY ENDPOINT SECONDARY ENDPOINTS SAFETY Ado-trastuzumab emtansine (T-DM1) mAb: trastuzumab (anti-HER-2) HER-2+ mBC after trastuzumab and a taxane Phase III randomized (EMILIA) vs lapatinib + capecitabine (n=991) Improved OS (median 30.9 mo vs. 25.1 mo; HR 0.68) Improved PFS (median 9.6 mo vs. 6.4 mo; HR 0.68) Improved ORR (43.6% vs 30.8%) Longer DOR (median 12.6 mo vs 6.5 mo)

T-DM1:

≥ G3 AE 57% - thrombocytopenia (12%), elevated AST (4%) and ALT (3%) Linker: uncleavable Adjuvant therapy of HER-2 + BC with residual invasive disease after neoadjuvant treatment Phase III randomized (KATHERINE) vs trastuzumab (n=1486) Improved iDFS (3y: 88.3% vs 77%; HR 0.50) Decreased distant recurrence as first iDFS event (10.5% vs 15.9%)

T-DM1:

≥ G3 AE 25% - thrombocytopenia (6%), hypertension (2%) and peripheral neuropathy (1%) Payload: DM1 (microtubule inhibitor) Fam-trastuzumab deruxtecan (T-DXd) mAb: trastuzumab (anti-HER-2) HER-2+ mBC after two or more prior regimens in the metastatic setting Phase II single-arm (DESTINY-Breast01) (n=184) PFS – median 19.4 mo DOR – median 20.8 mo OS - median 24.6 mo ≥ G3 AE 61.4% - decreased neutrophil count (21%), anemia (9%), nausea (8%) Special AE : ILD 15.2% (2.7% G5) Linker: cleavable HER-2+ mGC / mGEJC after prior trastuzumab-based regimen Phase II randomized vs chemotherapy (DESTINY-Gastric01) (n=187) Improved ORR (51% vs 14%) Improved PFS (median 5.6 m x 3.7 mo; HR 0.47) Improved DCR (86% x 62%) Longer DOR (median 11.3 m x 3.9 mo) Improved OS (median 12.5 mo x 8.4 mo; HR 0.59) ≥ G3 AE 51% - decreased anemia (38%), neutropenia (21%), decreased appetite (17%) Special AE: ILD 10% (G1 / 2, 7%; G3 / 4, 7%; G5, 0%) Payload: deruxtecan (topoisomerase I inhibitor) Sacituzumab govitecan mAb: sacituzumab (anti-TROP-2) mTNBC after at least two prior therapies, at least one of which for metastatic disease Phase III randomized vs chemotherapy (ASCENT) (n=468) Improved PFS (median 5.6 mo vs 1.7 mo; HR 0.41) Improved ORR (35% x 5%) Longer DOR (median 6.3 mo x 3.6 mo) Improved OS (median 12.1 mo x 6.7 mo; HR 0.48) ≥ G3 AE 64% - neutropenia (51%), leukopenia (10%), diarrhea (10%) Linker: cleavable mUC after prior platinum-containing chemotherapy and immunotherapy Phase II single-arm (TROPHY-U-01) (n=113) PFS – median 5.4 mo CBR – 37.2% DOR – median 7.2 mo G3 AE NR - neutropenia (35%), leukopenia (18%), anemia (14%) Payload: govitecan (topoisomerase I inhibitor) Enfortumab vedotin mAb: enfortumab (anti-nectin-4) mUC after prior platinum-containing chemotherapy and either PD-1 or PD-L1 mAb Phase III randomized vs chemotherapy (n=608) Improved OS (median, 12.8 mo vs. 8.9 mo; HR 0.70) Improved ORR (41% x 18%) DOR (median 7.3 mo x 8.1 mo ) Improved PFS (median 5.5 mo x 3.7 mo; HR 0.62) ≥ G3 AE 51% - maculopapular rash (7%), fatigue (6%), and decreased neutrophil count (6%) Linker: cleavable Payload: vedotin (microtubule inhibitor) Tisotumab vedotin mAb: antibody-drug conjugate (ADC) directed to tissue factor (TF) Recurrent or metastatic cervical cancer Phase II trial in patients with recurrent or metastatic cervical cancer (n=101) Improved ORR The confirmed objective response rate was 24% (95% CI 16–33), with seven (7%) complete responses and 17 (17%) partial responses. ≥ G3 neutropenia (three [3%] patients), fatigue (two [2%]), ulcerative keratitis (two [2%]), and peripheral neuropathies (two [2%] each with sensory, motor, sensorimotor, and neuropathy peripheral). Linker: cleavable Payload: vedotin (microtubule inhibitor) Abbreviations: AEs, adverse events; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CBR, clinical benefit rate; DCR, disease control rate; DOR, duration of response; G1-G5: grades 1-5; HR, hazard ratio; HER2, human epidermal growth factor receptor 2; iDFS, invasive disease-free survival; ILD, interstitial lung disease; mBC, metastatic breast cancer; mGC, metastatic gastric cancer; mGEJC, metastatic gastroesophageal junction cancer; MoAb, monoclonal antibody; mTNBC, metastatic triple-negative breast cancer; mUC, metastatic urothelial cancer; NR, not reported; ORR, objective response rate; OS, overall survival; PFS, progression-free survival. Trastuzumab Emtansine and Trastuzumab Deruxtecan for HER2-Positive Breast Cancer

HER2-positive BC is an aggressive disease subtype that accounts for 15% to 20% of all BCs.18 In the past 20 years, since the demonstration of improved overall survival (OS) with the combination of trastuzumab plus chemotherapy, there has been a surge in the number and variety of HER2-targeting agents approved for BC treatment.19-21 As of June 2021, there are 8 FDA-approved anti-HER2 drugs, encompassing MoAbs, tyrosine kinase inhibitors, and ADCs.

T-DM1, an ADC consisting of trastuzumab linked through a thioether uncleavable linker to DM1—a cytotoxic microtubule inhibitor—with a drug-to-antibody ratio (DAR) of 3.5:1, was the first drug of its class approved for the treatment of a solid malignancy.17, 22 The first approval, in February 2013, was based on results of the landmark phase 3 EMILIA trial (ClinicalTrials.gov identifier NCT00829166) comparing T-DM1 at a dose of 3.6 mg/kg every 21 days versus lapatinib plus capecitabine in 991 patients who had HER2-positive, advanced BC previously treated with trastuzumab and a taxane.23 Treatment with T-DM1 was associated with improved OS (primary end point; 30.9 vs 25.1 months; hazard ratio [HR], 0.65) and an improved objective response rate (ORR) (43.6% vs 30.8%). Moreover, T-DM1 was associated with fewer grade ≥3 adverse events (AEs) (41% vs 57%); the most common grade ≥3 AEs with T-DM1 were thrombocytopenia (13%), elevated aspartate aminotransferase (4%), elevated alanine aminotransferase (3%), and anemia (3%). At that time, these results firmly established T-DM1 as the standard second-line treatment for patients with metastatic, HER2-positive BC.24 It is essential to note that standard first-line therapy has changed since—now consisting of dual HER2 blockade with trastuzumab and pertuzumab plus a taxane (THP); however, recent analysis suggests meaningful activity of T-DM1, even after progression on first-line THP treatment.25

Subsequently, in May 2019, T-DM1 became the first-ever ADC approved for the adjuvant treatment of a solid malignancy based on results of the KATHERINE trial (ClinicalTrials.gov identifier NCT01772472).26 In that phase 3 study, 1486 patients with HER2-positive, localized/locally advanced BC who had residual invasive disease after neoadjuvant chemotherapy plus HER2-targeted therapy were randomized to receive 14 cycles of adjuvant T-DM1 or trastuzumab. Treatment with T-DM1 led to improved invasive disease-free survival (primary end point: HR, 0.50; 3-year invasive disease-free survival, 88.3% vs 77%), including a 40% reduction in the risk of distant recurrences, after a median follow-up of 41 months.26 Subgroup analysis revealed a consistent benefit of T-DM1 across stratification factors, including among patients who received neoadjuvant dual anti-HER2 blockade (18% of patients), with a safety profile that was consistent with previous reports.27

Fam-trastuzumab–deruxtecan (T-DXd) is an ADC constituted of the anti-HER2 MoAb trastuzumab and a cleavable tetrapeptide-based linker. The payload is an exatecan derivative acting through topoisomerase I inhibition, with a DAR of 8:1. In December 2020, the FDA granted accelerated approval to T-DXd at a dose of 5.4 mg/kg every 21 days for patients with metastatic, HER2-positive BC who received ≥2 prior anti-HER2–based regimens,28 after the compelling efficacy demonstrated in the open-label, phase 2 DESTINY-Breast01 clinical trial (ClinicalTrials.gov identifier NCT03248492).29, 30 That study enrolled 184 patients who had received a median of 6 prior therapies for metastatic disease. All patients enrolled in the trial had received prior T-DM1. The ORR, the primary end point, was 61.4%, with durable responses (the median response duration was 20.8 months). The disease control rate was 97.3%, the median progression-free survival (PFS) was 19.4 months, and the preliminary median OS was 24.6 months after a median follow-up of 20.5 months. During the study, 61% of patients developed grade ≥3 AEs—most commonly decreased neutrophil count, anemia, nausea, and decreased white cell count. Of note, 28 patients (15.2%) developed interstitial lung disease (ILD) related to T-DXd (grade 1, 3.2%; grade 2, 8.8%; grade 3, 0.5%; grade 5, 2.7%).30 The impressive activity of T-DXd after failure of T-DM1 may be attributable to the specific pharmaceutical properties of T-DXd. Key biochemical differences include the increased DAR compared with T-DM1; the mechanism of action of the payload, inhibiting topoisomerase I instead of microtubules; and the potential induction of a bystander killing effect. This phenomenon lies in the ability to provide cytotoxic activity against off-target cancer cells because of diffusion of the free cytotoxic moiety, spreading from the targeted, antigen-positive cells. The bystander killing effect is presumably caused by the membrane-permeable nature of the payload and the properties of the linker.31 This effect is an essential feature of newer ADCs and addresses the antigen heterogeneity often observed in several types of advanced tumors.

It is noteworthy that positive results from the head-to-head DESTINY-Breast03 phase 3 trial (ClinicalTrials.gov identifier NCT03529110) comparing T-DXd versus T-DM1 for HER2-positive, metastatic BC were recently presented at the 2021 European Society for Medical Oncology Annual Meeting,32 representing the first phase 3 study comparing the efficacy of 2 ADCs. That trial randomized 524 patients who had previously been treated with a taxane and trastuzumab; 60% of patients also had received prior pertuzumab. The superiority of T-DXd was demonstrated in terms of PFS (primary end point: median, not reached vs 6.8 months; HR, 0.28) and ORR (79.7% vs 34.2%; complete response rate, 16.1% vs 8.7%), with an initial positive trend in improved OS (12-month OS rate, 94.1% vs 85.9%; HR, 0.56).32 Grade ≥3 AEs occurred in 45.1% of patients in the T-DXd group versus 39.8% in the TDM-1 group. ILD was the most common treatment-emerging AE leading to discontinuation of T-DXd, occurring in 10.5% of patients who were receiving T-DXd (grade 1, 2.7%; grade 2, 7%; grade 3, 0.8%) compared with 1.9% of those who were receiving T-DM1 (grade 1, 1.5%; grade 2, 0.4%).32 The absence of grade 4 and 5 ILD events in this new large study raises questions about whether a less pretreated population and an increased awareness of this toxicity could prevent fatal pulmonary outcomes in patients receiving T-DXd. On the basis of these compelling results, T-DXd is likely to become a standard treatment for patients progressing to THP, raising the challenge of repositioning T-DM1 in the treatment algorithm for HER2-positive BC.

Trastuzumab Deruxtecan for HER2-Positive Gastric Cancer

Approximately 20% of metastatic gastric cancers (GCs) have overexpression or amplification of HER2 (HER2 immunohistochemistry [IHC] 3+ or IHC 2+ and positive fluorescence in situ hybridization [FISH]), with this molecular feature mainly detected in intestinal-type and gastroesophageal junction tumors.33 Similar to HER2-positive BC, the addition of trastuzumab to chemotherapy improves survival in the first-line metastatic setting.34 Contrary to BC, however, dual HER2 blockade has not demonstrated an added benefit,35 and there has been no survival benefit to this point of adding anti-HER2 agents in the (neo)adjuvant setting.36

Until recently, there was a lack of meaningful activity of HER2-targeted agents in subsequent lines of therapy.37 However, the results of the open-label, randomized, phase 2 DESTINY-Gastric01 trial (ClinicalTrials.gov identifier NCT03329690) brought about a paradigm shift. T-DXd at a dose of 6.4 mg/kg every 21 days demonstrated improved efficacy compared with standard therapies in patients with HER2-positive gastric cancer (GC) who had received ≥2 prior treatment regimens.38 Among 182 enrolled patients, the ORR (the primary end point) was 51% with T-DXd and 14% with standard therapies (irinotecan or paclitaxel); the median duration of response also favored T-DXd (11.3 vs 3.9 months); and the median OS was significantly longer in the T-DXd group than in the physician's choice (TPC) group (12.5 vs 8.4 months; HR, 0.59) after a median follow-up of 12 months. Interestingly, the ORR was higher among patients who had an HER2 IHC score of 3+ compared with those who had an IHC score of 2+ and positive FISH results (58% vs 29%). The most common grade ≥3 AEs with T-DXd were anemia (38%), decreased white cell count (21%), and decreased appetite (17%); 12 patients (9.6%) developed drug-related ILD or pneumonitis, which was primarily low-grade, with no deaths related to this AE (grade 1, 2.4%; grade 2, 4.8%; grade 3, 1.6%; grade 4, 0.8%). On the basis of these data, in January 2021, the FDA approved T-DXd for patients who had locally advanced or metastatic, HER2-positive GC with prior receipt of a trastuzumab-based regimen.39 After additional follow-up (median, 18 months), the final OS results were presented at the 2021 American Society of Clinical Oncology Annual Meeting, and the benefit of T-DXd was maintained (median OS, 12.5 vs 8.9 months; HR, 0.60).40 It is relevant to highlight that the DESTINY-Gastric01 trial also included patients with low levels of HER2 expression (an IHC score 1+ or 2+ and negative FISH results) in 2 separate exploratory cohorts; the results in these cohorts are discussed further below.

Sacituzumab Govitecan for Triple-Negative Breast Cancer

Patients with pretreated, metastatic, triple-negative BC (TNBC) have a poor prognosis, and cytotoxic chemotherapy remains the mainstay for the systemic treatment of this subtype.41 Sacituzumab govitecan is an ADC built of an antitrophoblast cell-surface antigen 2 (Trop-2) antibody linked to the cytotoxic agent SN-38, which is the active metabolite of the topoisomerase I inhibitor irinotecan.42 Trop-2 is a transmembrane calcium signal transducer highly expressed in multiple tumor types, including BC (>90%).43 Upregulation of Trop-2 has been shown to stimulate tumor growth in several cell lines,44 and retrospective studies have linked Trop-2 membrane expression to a worse prognosis in BC.45 Similar to T-DXd, sacituzumab govitecan carries a membrane-permeable payload that elicits a bystander effect and has a hydrolyzable linker, which allows for the release of the warhead in the tumor microenvironment.46

In April 2020, the FDA granted accelerated approval to sacituzumab govitecan for patients with metastatic TNBC who have received ≥2 prior therapies for metastatic disease, based on an encouraging ORR of 33.3% observed in a phase 1/2 study enrolling patients who received a median of 3 previous therapies.47 Subsequently, in April 2021, the FDA granted regular approval to sacituzumab govitecan in patients who received ≥2 prior systemic therapies (with at least one in the metastatic setting), based on positive results of the confirmatory phase 3 ASCENT study (ClinicalTrials.gov identifier NCT02574455).47 The ASCENT clinical trial was a global, open-label, randomized, phase 3 trial evaluating the efficacy of sacituzumab govitecan at a dose of 10 mg/kg on days 1 and 8 every 21 days versus TPC—consisting of single-agent eribulin, vinorelbine, capecitabine, or gemcitabine—in 468 patients who had relapsed or refractory, metastatic TNBC after ≥2 prior regimens. No biomarker selection was required for enrollment, and Trop-2 expression was only assessed for correlative analyses. The patients who received sacituzumab govitecan achieved improved ORR (35% vs 5%), a longer duration of response (median, 6.3 vs 3.6 months), longer PFS among those without brain metastasis (the primary end point; median PFS, 5.6 vs 1.7 months; HR, 0.41), and a doubling of OS (median, 12.1 vs 6.7 months; HR, 0.48) compared with those who received chemotherapy. The most common grade ≥3 treatment-related AEs with sacituzumab govitecan were neutropenia (51%), leukopenia (10%), diarrhea (10%), anemia (8%), and febrile neutropenia (6%).48

Sacituzumab Govitecan and Enfortumab Vedotin for Urothelial Carcinoma and Tisotumab Vedotin for Cervical Cancer

The standard treatments for metastatic urothelial carcinoma (mUC) in the first-line, second-line, and maintenance settings include platinum-based chemotherapy and anti–PD-1/anti–PD-L1 inhibitors.49 In addition, 2 ADCs have recently been approved for patients with mUC: enfortumab vedotin and sacituzumab govitecan.50, 51

Enfortumab vedotin is an ADC directed against nectin-4, a cell-adhesion molecule that is highly expressed in mUC, combined through a protease-cleavable linker to monomethyl auristatin E, an antimicrotubule agent.52 In analogy with T-DXd and sacituzumab govitecan, preclinical observations have suggested that enfortumab vedotin may be able to elicit bystander killing of antigen-negative cells.53 In December 2019, the FDA granted accelerated approval to enfortumab vedotin based on encouraging preliminary efficacy data observed in a phase 2 study.51 Subsequently, an application has been submitted to the FDA to convert the accelerated approval into a regular approval, succeeding positive results of the confirmatory EV-301 study (ClinicalTrials.gov identifier NCT03474107).54 In the phase 3 EV-301 study, 608 patients who had mUC after progression on platinum-containing chemotherapy and immune checkpoint inhibitors were randomized to receive either enfortumab vedotin or chemotherapy (single-agent docetaxel, paclitaxel, or vinflunine). Treatment with enfortumab vedotin led to improved ORR (40.6% vs 17.9%), longer PFS (median, 5.5 vs 3.7 months; HR, 0.62), and longer OS (the primary end point; median, 12.8 vs 8.9 months; HR, 0.70) compared with chemotherapy.54 Grade ≥3 treatment-related AEs occurred in 51% of those receiving enfortumab vedotin, most commonly maculopapular rash (7%), fatigue (6%), and decreased neutrophil count (6%). On the basis of these data, the prospective basket phase 2 EV-202 study (ClinicalTrials.gov identifier NCT04225117) was initiated to investigate the activity of this conjugate in other diseases known to express nectin-4, including breast, lung, head and neck, and gastroesophageal cancers.55

In April 2021, mUC became the second solid malignancy with 2 approved ADCs because the FDA granted accelerated approval to sacituzumab govitecan for this disease.56 Similar to BC45 and several other tumor types,57-59 mUC significantly overexpresses Trop-2 compared with normal tissues, and increased expression is associated with disease severity,60 making Trop-2 an appealing target for this disease. The single-arm phase 2 TROPHY-U-01 trial (ClinicalTrials.gov identifier NCT03547973) enrolled 113 Trop-2–unselected patients who had mUC after progression on platinum-based chemotherapy and anti–PD-1/anti–PD-L1 treatment. Treatment consisted of sacituzumab govitecan at a dose of 10 mg/kg on days 1 and 8 every 21 days. The ORR was 27%, and the median duration of response was 7.2 months. Moreover, 77% of patients had a decrease in the sum of target lesions, with a median PFS of 5.4 months, at a median follow-up of 9.1 months.56 The safety profile was consistent with that observed in other trials, with the most common grade ≥3 treatment-related AEs being neutropenia (35%), leukopenia (18%), anemia (14%), and diarrhea (10%)56. In September 2021 the FDA granted accelerated approval to tisotumab vedotin, a tissue factor directed antibody and microtubule inhibitor conjugate, for patients with recurrent or metastatic cervical cancer progressive on or after chemotherapy. The main efficacy outcome measures were objective response rate and duration of response (DOR). The ORR was 24% (95% CI: 15.9%, 33.3%) with a median duration of response of 8.3 months (95% CI: 4.2, not reached). The most common adverse reactions were fatigue, nausea, peripheral neuropathy, conjunctival adverse reactions with dry eye.56, 61

The Broad Spectrum of Activity of ADCs

Added to the indications mentioned above, the 4 ADCs currently approved for solid tumors, among others, have also demonstrated activity across other histologic subtypes, as discussed below and summarized in Figure 2.29, 38, 48, 56, 62-65 Indeed, expression of HER2,66 Trop-2,43 nectin-4,67 and multiple other antigens has been described in a wide variety of cancer types, raising the hypothesis that ADCs targeting such antigens could achieve a broad spectrum of activity across solid malignancies (Fig. 2).

image Emerging Activity of Selected Novel Antibody–Drug Conjugates (ADCs) on Multiple Cancer Types. The activity—in terms of the objective response rate (ORR)—of selected ADCs is illustrated in patients with advanced cancer according to the histologic subtype of the tumor. The ORR was defined as the percentage of patients achieving a partial or complete response to the ADC within a prospective clinical trial (any phase). The reported rate refers to the highest rate observed in a cohort of patients with the same cancer histology. Activity was determined not applicable (NA) if no published or presented data were available in that histologic context or if 29; Shitara et al, 2020 (gastric cancer)38; Siena et al, 2021 (colorectal cancer)62; and Li et al, 2021 (lung cancer).63 References for sacituzumab govitecan: Bardia et al, 2021 (breast cancer)48; Tagawa et al, 2021 (urothelial cancer)56; and Bardia et al, 2021 (lung cancer, endometrial cancer, colorectal cancer).64 References for trastuzumab duocarmazine: Banerji et al, 2019 (breast cancer, endometrial cancer, urothelial cancer, gastric cancer).65 Created with biorender.com. Targeting HER2 Across Histologies With ADCs Trastuzumab emtansine

After its FDA approval for the treatment of BC, T-DM1 has been evaluated in multiple other HER2-positive solid tumors, with mostly disappointing results to date. The GATSBY adaptive phase 2/3 study trial, for instance (ClinicalTrials.gov identifier NCT01641939), randomized patients who had HER2-positive GC after progression on first-line therapy to receive either single-agent taxane chemotherapy or T-DM1. Although T-DM1 demonstrated meaningful clinical activity (ORR, 20.6%), it was not superior to taxanes in terms of PFS or OS (the primary end point).68 Later, the efficacy of T-DM1 in HER2-amplified solid tumors, other than BC and GC, was evaluated in subprotocol Q of the basket trial NCI-MATCH (ClinicalTrials.gov identifier NCT02465060). Thirty-eight patients who had HER2 amplification and received no prior anti-HER2 therapies were enrolled across more than 10 histologies—most commonly gynecologic malignancies (n = 14) and lower gastrointestinal cancers (n = 11).69 This trial did not achieve the prespecified end point of ORR because only 2 patients (5.6%) achieved an objective response, both of whom had parotid gland tumors.70 Moreover, T-DM1 was tested in combination with pertuzumab to treat patients with HER2-positive, advanced colorectal cancer (CRC) and achieved an unsatisfactory ORR of 9.7% and a median PFS of 4.1 months.71 Of note, however, T-DM1 showed encouraging preliminary activity (ORR, 44%) for the treatment of advanced nonsmall cell lung cancer (NSCLC) harboring HER2-mutations in a phase 2 trial,72 leading to the current category 2A recommendation granted by the National Comprehensive Cancer Network for this indication.

Trastuzumab deruxtecan

Contrary to T-DM1, T-DXd has demonstrated encouraging efficacy in HER2-positive tumors other than BC and GC and in some HER2 low-expressing cancers. In the open-label, phase 2 DESTINY-CRC01 study (ClinicalTrials.gov identifier NCT03384940), 78 patients with HER2-expressing, metastatic CRC received T-DXd at a dose of 6.4 mg/kg every 21 days in 3 cohorts: cohort A enrolled those who had HER2-positive CRC with an IHC score of 2+ or 3+ and positive FISH results, cohort B enrolled those who had an IHC score of 2+ and negative FISH results, and cohort C enrolled those who had an IHC score of 1+.62 The primary end point was the ORR. For the 53 patients enrolled in cohort A, the ORR was 45% and was not influenced by prior HER2-targeted treatment (received by 30% of patients). Interestingly, however, the ORR was lower (7.7%) in 13 patients who had cancers with IHC scores of 2+ and positive FISH results.62 No responses were seen in cohorts B (n = 15) or C (n = 18). ILD occurred in 8 patients (9.3%; grade 2, 4.7%; grade 3, 1.2%; grade 5, 3.5%).

T-DXd at a dose of 6.4 mg/kg every 21 days has also demonstrated antitumor activity in HER2-mutated and, to a lesser degree, HER2-overexpressing NSCLC in the open-label, phase 2 DESTINY-Lung01 trial (ClinicalTrials.gov identifier NCT03505710). In patients with HER2-mutant NSCLC (n = 91), the ORR was 55%, and the disease control rate was 92%.63 Efficacy was consistent across subgroups, and the median PFS was 8.2 months after a median follow-up of 13.1 months.63 Encouraging, albeit less robust, activity was also observed among patients who had HER2-overexpressing NSCLC (IHC score, 2+ or 3+; n = 49), with an ORR 24.5%, a disease control rate of 69%, and a median PFS of 5.4 months.73 The ORR was not affected by HER2 IHC expression (ORR, 20% in patients with IHC 3+ expression vs 25.6% in those with IHC2+expression). The safety profile was consistent with prior reports. In the HER2-mutant cohort, 26.4% of patients presented with ILD (grade 1, 3.3%; grade 2, 16.5%; grade 3, 4.4%; grade 5, 2.2%); whereas, in the HER2-overexpressing cohort, ILD occurred in 8 patients (16.3%; grade 1, 4.1%; grade 2, 6.1%; grade 5, 6.1%).

Intriguingly, T-DXd demonstrated variable activity in HER2-low cancers (solid tumors expressing HER2 with an IHC score of 1+ or 2+ with a negative FISH assay). Indeed, activity of the conjugate was substantial among 54 patients who had HER2-low BC, with an observed ORR of 37%, a median duration of response of 10.4 months, and a median PFS of 11.1 months.74, 75 After these encouraging results, 2 large phase 3 trials were initiated to confirm the activity of T-DXd in patients who had advanced HER2-low (and even ultra-low [IHC score, 0]) BC. If confirmed, these results could potentially revolutionize HER2 testing paradigms in BC.

Nonetheless, the efficacy of T-DXd was far less convincing in HER2-low gastrointestinal malignancies. Forty-four patients who had HER2-low, advanced GC were treated with T-DXd within an exploratory cohort of the phase 2 DESTINY-Gastric01 trial, obtaining an ORR of 17.5% (n = 7 of 40 patients) and a median PFS of 2.8 to 4.4 months, depending on HER2 expression (longer for tumors with an IHC score of 2+).

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