A Review of Anti-HER2 Targeted Agents in Non-Breast Solid Tumors

Introduction

While HER2–targeted therapies have been utilized primarily in breast cancer for over 25 years, the use of anti-HER2 targeted agents is rapidly changing the treatment landscape for eligible patients in several other solid cancers. HER2 is a tyrosine kinase receptor encoded by the ERBB2 gene on chromosome 17q12. Amplifications of the HER2 oncogene lead to HER2 overexpression and activation of downstream phosphoinositide 3-kinases (PI3Ks) and mitogen-activated protein kinases (MAPKs) signaling cascades, resulting in increased cell proliferation, migration, invasion of local tissues, and improved survival of malignant cells.^1,2 Although the mutations are uncommon and not associated with overexpression, they do lead to increased tyrosine kinase activity, which contributes to greater tumor cell proliferation.³ HER2 amplifications and resultant overexpression have been implicated as a therapeutic target in several solid tumors, including breast, esophageal, gastric, biliary tract, colorectal, non–small cell lung, head and neck, and uterine cancers. Of note, variations in histological and cellular characteristics between solid tumors and their subtypes affect the accuracy and appropriateness of testing methods such as immunohistochemistry (IHC) and in situ hybridization (ISH), which rely on visual characterization methods.^2,4 While IHC and reflex ISH continue to be the gold-standard testing methods used to quantify the extent of HER2 amplification and receptor overexpression, next-generation sequencing (NGS) and polymerase chain reaction offer alternative methodologies for testing and are preferred in the setting of HER2-mutated disease, as is the case with non–small cell lung cancer (NSCLC).^5-10 Table 1 describes the differences in HER2 testing protocols that exist between specific tumor types.^4-19

ASCO, American Society of Clinical Oncology; ASCP, American Society of Consultant Pharmacists; CAP, College of American Pathologists; EGJ, esophagogastric junction; FISH, fluorescence in situ hybridization; IHC, immunohistochemistry; ISH, in situ hybridization; NGS, next-generation sequencing; NSCLC, non–small cell lung cancer; PCR, polymerase chain reaction; SISH, silver in situ hybridization; WT, wild-type.

Historically, anti-HER2 targeted treatment has largely been of interest in the breast cancer setting, which ultimately led to the FDA’s approval of trastuzumab (Herceptin; Genentech) in 1998.²⁰ However, it was not until 2010 that anti-HER2 targeted agents expanded into a non-breast solid tumor setting, with trastuzumab gaining FDA approval in the metastatic gastric cancer setting.^4,21,22 Since then, numerous other anti-HER2 targeted therapies have been developed, including several monoclonal antibodies, antibody-drug conjugates (ADCs), and broad-spectrum small-molecule kinase inhibitors (SMKIs), as summarized in Table 2.^19,21-26 This rapid growth in anti-HER2 development highlights the potential for further lines of therapy in patient populations that may have a limited number of options. This review aims to highlight differences in HER2 testing, summarize the current role of anti-HER2 targeted agents, and describe the outlook of HER2 therapy in non-breast solid cancers.

ADC, antibody-drug conjugate; BTC, biliary tract cancer; CHF, congestive heart failure; CRC, colorectal cancer; DDI, drug-drug interaction; EGJ, esophagogastric junction; IRR, infusion-related reaction; IV, intravenous; LVEF, left ventricular ejection fraction; PN, peripheral neuropathy.

ADC, antibody-drug conjugate; CRC, colorectal cancer; DDI, drug-drug interaction; EGJ, esophagogastric junction; ILD, interstitial lung disease; LVEF, left ventricular ejection fraction; NSCLC, non–small cell lung cancer; PGP, P-glycoprotein; SMKI, small-molecule kinase inhibitor; TKI, tyrosine kinase inhibitor; WT, wild type.

HER2 Testing in Solid Tumors

In breast cancer, HER2 testing by IHC is accomplished via a 3-category scoring system, as illustrated in Table 3.^11,12 HER2 equivocal results require additional testing by ISH, which measures gene amplifications using either a single or a dual probe. Single probes rely on the HER2 copy number (average signal/cell), whereas dual probes measure the ratio of HER2:chromosome 17 (CEP17). In breast cancer, HER2:CEP17 ratio greater than 2.2 and average HER2 copy number of 4 or more is a conclusive positive result.

IHC, immunohistochemistry; ISH, in situ hybridization.

Additionally, a fluorescence ISH result of more than 6 HER2 gene copies per nucleus is also considered positive. In breast cancer, IHC and ISH testing are considered equally predictive, while in gastric cancer, IHC testing has greater predictive value than ISH testing.^4,12 The degree of membranous staining may be reduced in cancers with a high degree of histological heterogeneity, as is the case with gastric cancer.4 As such, IHC and ISH must be thoroughly investigated in each cancer type to validate accuracy in identifying HER2-positive (HER2+) patients. While some non-breast solid tumors continue to follow the testing algorithm for breast cancer, new testing methods are emerging for many other non-breast solid tumors to improve detection and increase patient access to targeted therapies.^4,7-9,12 As cancer-specific guidance emerges in the realm of HER2 testing, a challenge for clinicians will be evaluating inclusion criteria in clinical trials used to identify HER2+ cohorts. Recommended algorithms for HER2 testing in non-breast cancers compared with breast cancer are summarized above in Table 1.^4-19

Esophegeal, Esophagogastric Junction, and Gastric Cancer

The reported rates of HER2 positivity in patients with gastric cancer range from 7% to 34%, varying by histological subtype.^4,5,13 In the last several years, HER2 expression has become increasingly important for the treatment of esophageal/esophagogastric junction (EGJ) and gastric cancers, leading to the approval of several anti-HER2 targeted agents in the advanced or metastatic setting. To date, several studies have evaluated the safety and efficacy of trastuzumab and fam-trastuzumab deruxtecan-nxki (T-DXd) in advanced esophageal/EGJ and gastric cancers.

The ToGA trial (NCT01041404) was a randomized prospective phase 3 trial that evaluated the efficacy of trastuzumab in combination with chemotherapy in patients with HER2+ advanced gastric (81.5%) and EGJ cancers (18.5%).²⁰ The trial demonstrated a significant improvement in the primary outcome of median overall survival (OS) of 13.8 months vs 11.0 months (HR, 0.74; P = .0046), with the addition of trastuzumab in patients with HER2+ disease. Additionally, there was a more pronounced benefit in patients with HER2 positivity defined as IHC 2+ and ISH+ or IHC 3+ (n = 446; OS, 16 months vs 11.8 months; HR, 0.65; 95% CI, 0.51-0.83). Based on the efficacy data from the ToGA trial, trastuzumab in combination with fluoropyrimidine and oxaliplatin or cisplatin is the preferred first-line treatment for HER2-overexpressing metastatic gastric or EGJ adenocarcinoma.^5,20

Several studies following the ToGA trial have added to the body of evidence supporting the use of trastuzumab in addition to standard-of-care (SOC) chemotherapy in patients with advanced HER2+ gastroesophageal cancers. 28,29 This includes the phase 3 KEYNOTE-811 study (NCT03615326), which evaluated the efficacy of SOC chemotherapy with trastuzumab combined with pembrolizumab in treatment-naive patients with HER2+ advanced EGJ and gastric tumors.30 Interestingly, trastuzumab has been shown in preclinical studies to upregulate the expression of PD-1 and PD-L1. The coadministration of immune checkpoint inhibitors (ICIs) and trastuzumab is thought to enhance HER2-specific T-cell responses, leading to the expansion of the peripheral memory T-cell pool. The addition of ICIs to trastuzumab-based therapy may be used as a strategy to combat resistance to anti-HER2 targeted agents.³⁰

Updated results from the third interim analysis of the KEYNOTE-811 study demonstrated an improvement in the dual primary end points of median progression-free survival (PFS) (10 months vs 8.1 months; HR, 0.73; 95% CI, 0.61-0.87) and OS (20 months vs 16.8 months; HR, 0.84; 95% CI, 0.70-1.01) with the addition of pembrolizumab to SOC chemotherapy and trastuzumab. In the subgroup of patients with a PD-L1 combined positive score of 1 or more, there were also numerical differences in median PFS of 10.9 months vs 7.3 months (HR, 0.71; 95% CI, 0.59-0.86) and OS of 20 months vs 15.7 months (HR, 0.81; 95% CI, 0.67-0.98). Although there was a benefit observed for both primary assessments, these outcomes were not yet significant for the entire cohort and the trial will continue to its final analysis.³¹

The phase 2 DESTINY-Gastric01 trial (NCT03329690) evaluated the safety and efficacy of T-DXd compared with physician’s choice of chemotherapy in patients with advanced or metastatic HER2+ EGJ or gastric adenocarcinoma. 32 This trial included patients from Japan and South Korea who had progressed on 2 or more lines of prior therapies, including trastuzumab. The dosing for T-DXd in this trial differed from the dosing used in breast indications, with patients receiving 6.4 mg/kg once every 3 weeks instead of 5.4 mg/kg. A significantly better objective response rate (ORR) was observed with patients in the T-DXd arm (51% vs 14%; P < .001), with 11% of patients deemed as complete responses (CRs) and 50% as partial responses (PRs). The T-DXd arm also demonstrated significant improvement in OS, a secondary end point studied, a difference of 12.5 months vs 8.4 months (HR, 0.59; P = .01). However, the T-DXd arm had an observable increase in grade 3 to 4 adverse events (AEs), treatment interruptions, and discontinuations. Most notable differences included a 9.6% incidence of interstitial lung disease (ILD) or pneumonitis and higher rates of cytopenias, including a 51% incidence of grade 3 neutropenia.³²

The DESTINY-Gastric02 trial (NCT04014075) was a follow-up to the DESTINY-Gastric01 trial in which efficacy and safety of T-DXd 6.4 mg/kg were evaluated in patients with metastatic or unresectable HER2+ EGJ or gastric cancer in the United States and Europe who had progressed on first-line therapy with a trastuzumab-containing regimen.^32,33 At the median follow-up of 10.2 months, the primary outcome of ORR was 42% (95% CI, 30.8%-53.4%), including 5% CR and 37% PR.33 Secondary end points demonstrated a median OS of 12.1 months (95% CI, 9.4-15.4) with a median duration of response (DOR) of 8.1 months (95% CI; 5.9-not estimable [NE]). ILD rates were similar between the DESTINY-Gastric02 and DESTINY-Gastric01, with a single grade 5 AE reported in DESTINY-Gastric02.^32,33 Following the DESTINY-Gastric01 trial, T-DXd received FDA approval at the 6.4 mg/kg dose for adult patients with locally advanced or metastatic HER2+ EGJ or gastric adenocarcinoma who have received a prior trastuzumab-based regimen.^5,32 T-DXd is currently listed as a preferred second-line treatment option for advanced disease in the National Comprehensive Cancer Network (NCCN) guidelines.^5,15

Biliary Tract Cancer

HER2 is estimated to be overexpressed or amplified in 5% to 20% of cholangiocarcinomas and 15% to 30% of gallbladder cancers.^6,22 While early studies of anti-HER2 targeted agents have shown mixed results, the current use of these therapies in biliary tract cancer (BTC) is primarily a result of 2 large multiple basket trials, MyPathway (NCT02091141) and SUMMIT (NCT01953926).^34,35 The efficacy of trastuzumab and pertuzumab (Perjeta; Genentech) in MyPathway and neratinib (Nerlynx; Puma) in SUMMIT were evaluated in BTC, colorectal, non–small cell lung, uterine, urothelial, salivary gland, ovarian, pancreatic, and several other non-breast solid cancers. The MyPathway study excluded breast, EGJ, and gastric cancers, which at the time were the only solid tumors for which trastuzumab and pertuzumab had received FDA approval.³⁴

The MyPathway trial and SUMMIT trial included small cohorts of patients with advanced HER2+ BTC (n = 39, MyPathway; n = 25, SUMMIT).34,35 The trials demonstrated similar ORRs of 23% (95% CI, 11%-39%) and 16%, (95% CI, 4.5%-36.1%) respectively. Secondary outcomes include median OS of 10.9 months (95% CI, 5.2-15.6) in the MyPathway study and 5.4 months (95% CI, 3.7-11.7) in the SUMMIT study. Currently, no anti-HER2 targeted agents are FDA approved for BTC.^11,13,18 However, trastuzumab in combination with pertuzumab is listed in the NCCN guidelines as an option for subsequent-line therapy for HER2+ BTC following the response observed in the MyPathway study.^6,34

Colorectal Cancer

HER2 is rarely amplified/overexpressed in colorectal cancer (CRC; 3%), however, there is a higher prevalence reported in patients who have KRAS/BRAF–wild type (WT) tumors, approximately 5% to 14%.^7,8 Additionally, while HER2 identification in CRC does not demonstrate a prognostic role, HER2 status may help predict resistance to EGFR-targeting monoclonal antibodies.^7,8,36 Several anti-HER2 targeted agents are currently approved for use in CRC, with the most recent accelerated approval by the FDA for tucatinib (Tukysa; Seagen) combined with trastuzumab earlier this year. This approval stems from the MOUNTAINEER study (NCT03043313), a phase 2 trial evaluating trastuzumab with or without tucatinib for chemotherapy-refractory, HER2+, KRAS-WT metastatic CRC.³⁷ In this study, the primary outcome of ORR was 38.1% (95% CI, 27.7%-49.3%). Of the secondary end points, median PFS was 8.2 months (95% CI, 4.2-10.3) and OS was 24.1 months (95% CI, 20.3-36.7).³⁷

Prior to the MOUNTAINEER study, 2 large basket trials, MyPathway and TAPUR (NCT02693535), included small cohorts of patients with HER2+ CRC.^38,39 The MyPathway study included 57 patients with treatment-refractory, HER2-amplified, advanced CRC.38 Patients were treated with a combination of trastuzumab and pertuzumab. After a median follow-up of 7.3 months, 32% of patients in the MyPathway study had an objective response (95% CI, 20%-45%). Secondary outcomes included a median DOR of 5.9 months (95% CI, 2.8-11.1), with 22% of patients demonstrating a prolonged response of 12 months. Additionally, the median PFS reported was 2.9 months (95% CI, 1.4-5.3) and OS was 11.5 months (95% CI, 7.7-NE). The TAPUR trial also demonstrated positive results for a cohort of patients with HER2 amplification (n = 28) or HER2/3 mutation (n = 10) who had no remaining standard treatment options.39 Following treatment with trastuzumab and pertuzumab, disease control was observed in 54% of patients with HER2 amplification (95% CI, 37%-67%), whereas objective response was seen in 25% (95% CI, 11%-45%). Of the reported secondary outcomes, median PFS was 17.2 weeks (95% CI, 11.1-27.4) and OS was 60 weeks (95% CI, 32.1-102.3) in the HER2 amplification cohort. Thus, both MyPathway and TAPUR demonstrated the utility of trastuzumab and pertuzumab in patients with advanced HER2+ CRC who are refractory to previous treatments.^38,39

Lastly, for HER2-targeted monoclonal antibodies and SMKIs in CRC, the HERACLES trial (NCT03225937) was a phase 2 trial evaluating weekly trastuzumab and oral lapatinib (Tykerb; Novartis) in 27 patients with HER2+, KRAS-WT advanced CRC.⁴⁰ After a median follow-up of 94 weeks, objective responses were achieved in 30% of patients (95% CI, 14%-50%), with 1 CR. Based on the results of the MOUNTAINEER, MyPathway, and HERACLES studies, trastuzumab given in combination with tucatinib, pertuzumab, or lapatinib are all recommended regimens in the NCCN guidelines in pretreated patients with advanced CRC.^7,8 These treatment options offer a promising alternative to available second-line treatments, such as trifluridine-tipiracil (Lonsurf; Taiho Oncology) and regorafenib (Stivarga; Bayer), which are poorly tolerated and have limited response rates in patients with HER2+, KRAS/BRAF-WT tumors.^7,8 Therefore, in addition to improved efficacy, anti-HER2 targeted agents also offer favorable safety profiles compared with other late-line options inadvanced CRC.

The DESTINY-CRC01 trial (NCT03384940) was a phase 2 study evaluating the safety and efficacy of T-DXd 6.4 mg/kg in patients with HER2+ metastatic CRC who had progressed on 2 or more previous regimens.⁴¹ After a median follow-up of 27.1 weeks, the ORR was 45.3% (95% CI, 31.6%-59.6%). Median OS observed was 15.5 months (95% CI, 8.8-20.8) with a median PFS of 6.9 months (95% CI, 4.1-8.7).⁴¹ Subsequently, the DESTINY-CRC02 trial (NCT04744831) compared the efficacy of 5.4 mg/kg to 6.4 mg/kg dosing of T-DXd in patients with previously treated, HER2+ advanced CRC.⁴² Overall response rates were similar in both arms, 37.8% of patients in the 5.4 mg/kg group (95% CI, 27.3%-49.2%) vs 27.5% in the 6.4 mg/kg group (95% CI, 14.6%-43.9%). Additionally, both groups demonstrated a parallel median DOR of 5.5 months (95% CI, 4.2-8.1 in the 5.4-mg/kg group; 95% CI, 3.7-NE in the 6.4-mg/kg group). Overall, the DESTINY-CRC02 trial demonstrated that at reduced doses, T-DXd retained antitumor activity with decreased rates of AEs, including a 4.4% reduction in ILD and a 6.7% reduction in serious AEs.^41,42 Based on the results of the DESTINY-CRC01 trial, T-DXd is recommended in the NCCN guidelines for HER2-amplified and KRAS/BRAF-WT patients with advanced CRC as a subsequent line regimen,^7,8,41 although T-DXd has yet to gain approval in the CRC setting.¹⁵

Non-Small Cell Lung Cancer

While HER2 overexpression/amplification has proven prognostic significance and infers anti-HER2 therapy treatment benefit in other cancers such as breast and gastric, NSCLC differs in that treatment response was observed in patients with HER2 mutations.⁹ HER2 genomic alterations including insertion/duplication events in exon 20 and gene amplification result in the activation of cell growth and division pathways in NSCLC. HER2 exon 20 mutations occur in approximately 3% of patients with advanced nonsquamous NSCLC. Because HER2 mutations drive oncogenic potential in this specific population, NGS testing is recommended.⁹

Trastuzumab, in addition to both of the available trastuzumab-based ADCs, T-DXd and ado-trastuzumab emtansine (T-DM1, Kadcyla; Genentech), and several SMKIs have been studied in the setting of HER2-mutated NSCLC.⁹ However, early trials of trastuzumab-based regimens have failed to demonstrate significant response or survival benefits in the NSCLC setting. Limited data described a positive response rate (83%) in a subset of 6 patients who were HER2+ (IHC 3+) when treated with chemotherapy combined with trastuzumab; however, the small sample size makes it difficult to draw conclusions.⁴³ These disappointing outcomes may also be attributed to challenges in selecting appropriate HER2 testing methodologies in NSCLC.⁴⁴ In later studies, T-DM1 and SMKIs demonstrated improved efficacy compared with previous trials with trastuzumab in patients with HER2-mutant NSCLC (HER2/ERBB2-activating mutations) with response rates of 0% to 30% and up to 44%, respectively.^45-47 More recently, the TAPUR basket trial included a cohort of 28 patients with NSCLC harboring a HER2 mutation (n = 15), HER2 amplification (n = 12), or both (n = 1).⁴⁴ Results demonstrated modest disease activity with the combination of trastuzumab and pertuzumab in heavily pretreated patients, with the best results in patients with a HER2 mutation. Mixed results from previous studies with various anti-HER2 targeted agents spurred interest in T-DXd activity in HER2+ NSCLC as a potent and efficacious ADC.^17,48 The DESTINY-Lung01 trial (NCT03505710) was a single-arm, phase 2 study that investigated T-DXd dosed at 6.4 mg/kg in 91 patients with metastatic HER2-mutated NSCLC that was refractory to standard treatment.⁴⁸ The ORR with T-DXd far exceeded results with previous anti-HER2 targeted agents at 55% (95% CI 44-65), as well as median DOR and OS of 9.3 months (95% CI 5.7 to 14.7) and 17.8 months (95% CI, 13.8%-22.1%), respectively. However, there was a high incidence of ILD (26%), resulting in 2 treatment-related deaths, high rates of discontinuation, and interruption of treatment.⁴⁸ Overall, after the DESTINY-Lung01 trial, T-DXd gained a breakthrough therapy designation in patients with unresectable or metastatic NSCLC whose tumors have activating HER2 mutations after prior systemic therapy.^9,15

Due to the high rates of ILD noted in the DESTINY-Lung01 trial, the DESTINY-Lung02 trial (NCT04644237) assessed the safety and efficacy of reduced-dose T-DXd at 5.4 mg/kg once every 3 weeks.^48,49 The results confirmed the efficacy of T-DXd in this population with an ORR of 49% in the 5.4 mg/kg arm (95% CI, 39.0%-59.1%) vs 56% in the 6.4 mg/kg arm (95% CI, 41.3%-70.0%).49 Median DOR was 16.8 months in the 5.4 mg/kg cohort (95% CI, 6.4-NE) and not estimable in the 6.4 mg/kg cohort (95% CI, 8.3-NE). Notably, rates of ILD were significantly lower in the 5.4 mg/kg group (12.9%) compared with the 6.4 mg/kg group (28%).⁴⁹ In the DESTINY-Gastric trials, rates of ILD were much lower overall compared with those observed in NSCLC patients, at 9.5% in the DESTINY-Gastric01 trial and 7.6% in the DESTINY-Gastric02 trial.^32,33 There are many factors that increase the risk of ILD in the NSCLC population, including HER2 overexpression in the lung tissue in patients with NSCLC and, consequentially, increased delivery of cytotoxic payload to the lungs.^9,15 T-DXd may also cause direct tissue destruction and inflammation, leading to the release of the intracellular contents of lysed cells, initiating a cascade of cytokine release and immune cell activation, further promoting inflammation and tissue destruction that are characteristic of ILD.^9,15,50 Factors identified that may have also contributed to the increased rates of drug-related ILD in the DESTINY-Lung trials include preexisting disease–related pneumonitis, smoking, and prior chest/lung radiotherapy.^48,49 In this setting, vigilant monitoring by patients and clinical teams is crucial in the early detection and management of ILD.

Currently, NCCN guideline recommendations include T-DXd as the preferred subsequent therapy option for patients with HER2-mutated NSCLC. Following the DESTINY-Lung02 trial, T-DXd received accelerated FDA approval in the aforementioned population, at a dose of 5.4 mg/kg.^15,49 The positive benefit seen with T-DXd in NSCLC spurred interest in evaluation of another ADC, T-DM1 in this population. In a phase 2 basket trial, Li et al reported that patients with NSCLC who were positive for HER2-mutations received T-DM1.⁴⁷ Results demonstrated a positive primary outcome with an ORR of 44% (95% CI, 22%-69%) and limited toxicities.⁴⁷ T-DM1 has since been incorporated in the NCCN guidelines as an alternative subsequent therapy option, with a preference for T-DXd over T-DM1.⁹

Salivary Gland Cancer

The true incidence of HER2 positivity in salivary gland cancers (SGCs) is unknown owing to a highly heterogeneous cancer with 21 currently identified histologic subtypes and low annual incidence of SGC.^10,23,51 A systematic review and meta-analysis that assessed the prevalence of HER2 positivity in various histological subtypes of SGCs found that prevalence ranged from 0% to 43%, with the highest rates noted in salivary duct carcinoma (SDC) at 43%.²³

Trastuzumab has been studied as monotherapy and in combination with chemotherapy and pertuzumab for HER2+ salivary cancers, with promising efficacy. Published data prior to the MyPathway trial included case reports and small single-arm studies.^52,53 A single-arm study evaluated the efficacy of trastuzumab and docetaxel in HER2+ patients with SDC.53 The ORR was 70.2% (95% CI, 56.6%-81.6%), with a median PFS of 8.9 months (95% CI, 7.8-9.9) and OS of 39.7 months (95% CI, not reached [NR]-NR). Not long after these results, dual-HER2 inhibition with trastuzumab and pertuzumab was also studied in 15 patients enrolled in the MyPathway study.⁵⁴ Of the 15 patients with HER2 amplification/overexpression, 60% of the cohort had an objective response (95% CI, 32%-84%) with 1 CR and 8 PRs. The median PFS was 8.6 months (95% CI, 2.3-NE) and OS was 20.4 months (95% CI, 8.2-NE) in patients with advanced HER2+ SGC.⁵⁴

T-DM1 and T-DXd were also recently studied in patients with HER2-amplified salivary gland tumors with encouraging results.^55-57 The NCI-MATCH trial (NCT02465060), a national precision medicine study, evaluated the efficacy of T-DM1 in HER2-amplified histologies other than breast and gastroesophageal tumors, including 3 patients with SGC.⁵⁵ Notably, NGS was used to test for HER2 status, defined as positive if the copy number was greater than 7. With improvements in cost and availability, NGS testing is increasingly recommended and utilized in solid tumors. In this trial, a PR was observed in 2 of 3 patients with advanced SGC. The DOR lasted 9 months and 23.7 months in the 2 patients with mucoepidermoid carcinoma and parotid gland carcinoma, respectively.⁵⁵

Lastly, results of a subgroup analysis of 2 dose-expansion, phase 1 studies evaluating T-DXd at 5.4 mg/kg (n = 9) and 6.4 mg/kg (n = 8) in patients with HER2-expressing SDC demonstrated an ORR of 58.8% (95% CI, 32.9%-81.6%), median DOR of 17.6 months (95% CI, 4.0-NE), and median PFS of 20.5 months (95% CI, 11.1-NE).⁵⁷ Differences in ILD and other AEs of interest were not reported. Given the limited number of treatment options in metastatic SGC, trastuzumab alone or in combination with pertuzumab or docetaxel, T-DM1, and T-DXd are recommended systemic therapies for HER2+ tumors in the NCCN guidelines.¹⁰ Although there are currently no anti-HER2 targeted agents approved in SGC, there is still potential for significant response in this extremely rare and highly heterogeneous disease.

Uterine Cancer

The incidence of HER2 positivity in uterine tumors is estimated to be 14% to 20%, with higher rates in the epithelial component compared with the sarcoma component of uterine carcinosarcoma tumors.^26,27 Efficacy of carboplatin-paclitaxel with and without trastuzumab was assessed in a phase 2, randomized trial with patients with advanced or recurrent uterine serous carcinoma who overexpressed HER2.⁵⁸ Primary outcome was median PFS, which favored the carboplatin-paclitaxel with trastuzumab cohort (12.6 months vs 8 months; HR, 0.44, P = .005). A greater improvement was observed in those with later-stage disease (17.9 months vs 9.3 months; HR, 0.40; P = .013) as well as those with recurrent disease (9.2 months vs 6.0 months; HR, 0.14; P = .003).⁵⁸ As such, triplet therapy with carboplatin, paclitaxel, and trastuzumab is recommended as a preferred therapy option for patients with stage III/IV and recurrent HER2+ uterine serous carcinoma or carcinosarcoma who have not received prior trastuzumab therapy.²⁴

Furthermore, the DESTINY-PanTumor02 trial (NCT04482309) evaluated T-DXd in a small cohort of patients with uterine cancer.⁵⁹ In an interim analysis, ORR was 57.5% in the endometrial cohort (95% CI, 40.9%-73.0%) with higher response rates reported in the IHC 3+ patients (84.6%; 95% CI, 54.6%-98.1%). Median PFS and OS were 11.1 months (95% CI, 7.1-NR) and 26.0 months (95% CI, 12.8-NR), respectively.⁵⁹ Thus, T-DXd is recommended as a subsequent-line therapy option for HER2+ tumors.²⁴

More recently, the TAPUR trial investigated the combination of trastuzumab and pertuzumab in a small cohort of heavily pretreated patients with patients with HER2/3-amplified, -overexpressed, or -mutated endometrial cancer (n = 28).⁶⁰ Results demonstrated disease control in 37% (95% CI, 21%-50%) of patients primarily resulting in stable disease or partial response. While neither trastuzumab, pertuzumab, nor T-DXd is FDA approved for use in uterine cancers, the clinical utilization of anti-HER2 targeted therapy in uterine cancer is actively evolving.

Future Directions and Pipeline Agents

This review summarizes the current utilization of anti- HER2 targeted therapy across several non-breast cancer settings, primarily based on data impacting guideline recommendations for advanced disease, as summarized in Table 4.^{20,30-35,37-42,47-49,54,55,57-60} The anticipated role of anti-HER2 targeted agents will continue to evolve, especially with the introduction of novel ADCs and emerging bispecific and trispecific agents to the market, in addition to the inclusion of HER2-low cohorts in clinical trials.

CPS, combined positive score; EGJ, esophagogastric junction; FISH, fluorescence in situ hybridization; ICI, immune checkpoint inhibitor; IHC, immunohistochemistry; mOS, median overall survival; mPFS, median progression-free survival; NCCN, National Comprehensive Cancer Network; ORR, objective response rate; SOC, standard of care; T-DXd, trastuzumab deruxtecan.

BTC, biliary tract cancer; CRC, colorectal cancer; FISH, fluorescence in situ hybridization; IHC, immunohistochemistry; NCCN, National Comprehensive Cancer Network; ORR, objective response rate; SMKI, small-molecule kinase inhibitor; WT, wild type.

CRC, colorectal cancer; FISH, fluorescence in situ hybridization; IHC, immunohistochemistry; ILD, interstitial lung disease; NCCN, National Comprehensive Cancer Network; NSCLC, non–small cell lung cancer; ORR, objective response rate; T-DXd, trastuzumab deruxtecan; WT, wild type.

FISH, fluorescence in situ hybridization; IHC, immunohistochemistry; mPFS, median progression-free survival; NCCN, National Comprehensive Cancer Network; ORR, objective response rate; PR, partial response; SGC, salivary gland cancer; T-DM1, ado-trastuzumab emtansine; T-DXd, trastuzumab deruxtecan.

FISH, fluorescence in situ hybridization; IHC, immunohistochemistry; NCCN, National Comprehensive Cancer Network; ORR, objective response rate; T-DXd, trastuzumab deruxtecan.

A new ADC, disitamab vedotin (RC48-ADC; RemeGen Co) was recently studied in a phase 2, single-arm study (NCT04879329) of patients with HER2+, locally advanced, or metastatic urothelial carcinoma (UC).⁶¹ In a median follow-up of 20.3 months, the observed ORR was 51.2% (95% CI, 35.5%-66.7%), raising interest in further investigation of disitamab vedotin in UC. More recently, in a combined analysis of two phase 2, single-arm studies, RC48-C005 (NCT03507166) and RC48-C009 (NCT03809013), in patients with HER2+ locally advanced or metastatic UC, disitamab vedotin demonstrated similarly promising results with median ORR of 50.5% (95% CI, 40.6%-60.3%).⁶² The median PFS and OS were 5.9 months (95% CI, 4.3-7.2) and 14.2 months (95% CI, 9.7-18.8), respectively. In UC, limited targeted treatment options are available in the metastatic setting including ICIs, erdafitinib (Balversa; Janssen Biotech) for susceptible FGFR3 or FGFR2 genetic alterations, and enfortumab vedotin (Padcev; Astellas Pharma US and Seagen) for cisplatin-ineligible patients.⁶³ Anti-HER2 targeted therapies offer an alternative for HER2+ patients with reduced toxicities compared with SOC chemotherapy.

Several bispecific and trispecific agents have emerged in phase 1/2 trials, including cinrebafusp alfa (PRS-343), a bispecific fusion protein combining a HER2-targeted monoclonal antibody and 4-1BB–targeting proteins (Anticalin; Pieris Pharmaceuticals), currently under investigation in HER2+ gastric cancer.⁶⁴ Zanidatamab (Jazz Pharmaceuticals) is another novel bispecific antibody directed against 2 non-overlapping domains of HER2.^65,66 Zanidatamab is under investigation in the phase 1/2 setting across a range of HER2+ solid tumors.⁶⁵ Another area of study is zanidatamab in combination with evorpacept (ALX Oncology) in advanced HER2-expressing solid tumors.⁶⁶ Lastly, a trispecific agent under evaluation in relapsed/refractory HER2-expressing solid tumors is SAR443216 (Sanofi).⁶⁷ With trispecific binding at HER2, CD3, and CD28, SAR443216 induces antitumor T-cell responses in a variety of HER2+ tumors, including patients with low levels of HER2 expression.⁶⁷ As such, the future market of available anti-HER2 targeted agents is rapidly developing with the addition of novel mechanistic approaches to the treatment armamentarium for advanced solid tumors.

Several studies discussed in this review included small cohorts of HER2-low patients, defined as having an IHC score of 1+ or 2+ with negative ISH test results.⁶⁸ Characterization of low levels of HER2 expression identified as HER2-low began as early as 2017, around the same time the 2018 American Society of Clinical Oncology/College of American Pathologists guideline update was published.⁶⁹ It is estimated that as many as 60% of breast cancer patients express low levels of HER2, which would not meet current criteria for HER2 positivity.⁶⁹ Recharacterization of this large subpopulation and utilization of novel ADCs, such as trastuzumab deruxtecan in the landmark DESTINY-Breast04 trial (NCT03734029), has greatly improved access to anti-HER2 therapy in breast cancer.⁷⁰ While the terminology HER2-low is not officially recognized in current guidelines, assessment of HER2-low cohorts in non-breast solid tumors and the development of novel anti-HER2 targeted agents have the potential to drastically improve the availability of targeted therapies across the board in non-breast solid tumors. However, differences in testing algorithms and methodologies must also be considered for HER2-low cohorts. This raises the question of whether novel anti-HER2 therapies will provide additional benefit in patients with HER2-low tumors and how this will translate to other tissue types with varying HER2 expression. Ongoing and future trials may elucidate the place in therapy for anti-HER2 targeted agents in this setting and unravel uncertainties with the identification and characterization of HER2-low cohorts.

The pace at which HER2 therapies are being investigated far outweighs the capacity of this review. High heterogeneity in the expression of HER2, differences in prognostic significance, and a wide range of patient response rates within various histologic subtypes contribute to the need for further evaluation in non-breast cancers. Additionally, the uptrend of large basket trials allowing for the treatment of cancer through common biomarker targets, such as altered HER2 expression, has accelerated research and utilization of these agents. Furthermore, the addition of HER2-low cohorts and improved testing algorithms and methods is likely to increase access to anti-HER2 targeted agents for patients who have historically been considered HER2 negative. These recent changes in the HER2 landscape will undoubtedly result in greater utilization of targeted treatment in advanced solid cancers and may improve the prognostic implications of HER2 amplification or mutations.

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About the Authors

Megan Alhadeff, PharmD, MBA, is a PGY2 oncology pharmacy resident at the University of Washington Medicine and Fred Hutchinson Cancer Center in Seattle, Washington.

Tiffany Tam, PharmD, BCOP, is a clinical oncology pharmacist at the University of Washington Medicine and Fred Hutchinson Cancer Center in Seattle, Washington.

Hanh Bui, PharmD, is a clinical pharmacist, general oncology, at the University of Washington Medicine and Fred Hutchinson Cancer Center in Seattle, Washington.

Disclosures

The authors have nothing to disclose regarding financial or personal relationships with commercial entities that may have a direct or indirect interest in the subject matter of this manuscript.