HER2-Directed ADCs Spread Like Wildfire Across the Spectrum of Solid Malignancies

Antibody-drug conjugates (ADCs) targeting HER2 are rapidly being established as standard-of-care therapies across breast, gynecologic, gastrointestinal (GI), lung, and genitourinary (GU) cancers, but the paradigm is far from homogeneous with current and potential future indications spanning distinct categorizations including HER2-positive, -mutated, and -amplified disease.

“HER2 can mean many different things [in the realm of cancer care]; when it’s amplified it’s a driver and contributing to the cancer’s biology,” Vijayakrishna Gadi, MD, PhD, said. “Another way these proteins can contribute to the cancer’s biology is if there’s an activating mutation in the tyrosine kinase domain. Through next-generation sequencing, fluorescence in situ hybridization, and protein immunohistochemistry [IHC], we can identify these [aspects] in many different cancers. More recently, [HER2 has become] a target of convenience. Sometimes you can have a skosh of this protein present on a cancer and still have it be actionable because some of these monoclonal antibodies attached to chemotherapy warheads can still [kill] using that target.”

“[The consensus] is rapidly evolving in terms of what HER2 overexpression means. There are some data that [indicate potentially] 50% of all solid tumors have some [level of] HER2 [expression]. If you’re using it as your anchor to get your warhead in, there may be many possibilities in terms of expanding [our use of these agents to] other cancers that may not be conventionally HER2-high,” Aparna Parikh, MD, added.

During a recent OncLive Peer Exchange®, a panel of expert clinicians who specialize in various tumor types took stock of the current standing of HER2-directed ADCs in solid tumors, including breast, gynecologic, GI, lung, and GU cancers. They summarized findings that led to the FDA approvals of several ADCs across disease settings in recent years, discussed updated data from clinical trials examining HER2-directed ADCs in solid tumors presented during the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting, and tried to discern the agents’ current and future standing in the treatment paradigm of these disease settings.

HER2-Directed ADCs in Breast Cancer Set the Precedent for Solid Tumors

There are 2 FDA-approved HER2-targeted ADCs for the treatment of patients with breast cancer: ado-trastuzumab emtansine (T-DM1; Kadcyla) and fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu). In 2013, the FDA first approved T-DM1 for the treatment of patients with HER2-positive metastatic breast cancer who have received prior treatment with trastuzumab (Herceptin) and taxane-based chemotherapy.¹ Subsequently T-DXd was approved by the FDA for patients with unresectable or metastatic HER2-positive breast cancer who have received a prior anti–HER2-based regimen in the metastatic setting or in the neoadjuvant setting and have developed disease recurrence during or within 6 months of completing therapy. The approvals were supported by findings from the phase 3 EMILIA (NCT00829166) and DESTINY-Breast03 (NCT03529110) trials, respectively.²

T-DXd later earned another indication for patients with HER2-low IHC1+ or IHC2+/in situ hybridization–negative disease who had received chemotherapy in the metastatic setting or experienced disease recurrence during or within 6 months of completing adjuvant chemotherapy based on positive data from the phase 3 DESTINY-Breast04 trial (NCT03734029). The agent is also indicated for the adjuvant treatment of patients with HER2-positive early breast cancer with residual invasive disease following neoadjuvant taxane and trastuzumab-based treatment. The 2019 regulatory decision was supported by findings from the phase 3 KATHERINE trial (NCT01772472).^2,3

“ADCs in solid tumors began with T-DM1 in the EMILIA trial,” Gadi said. “The standard of care at the time in the second line was lapatinib [Tykerb] plus capecitabine [Xeloda]. T-DM1 was both more effective and more tolerable [than that combination], with a progression-free survival [PFS] difference of several months. It had an overall survival [OS] benefit as well. This led to the approval [of T-DM1] and a renaissance of [asking], ‘What else can we do with ADCs?’”

During the 2024 ASCO Annual Meeting, investigators presented updated exploratory findings from the phase 3 DESTINY-Breast03 study, which compared T-DXd to T-DM1 in patients with HER2- positive metastatic breast cancer who had received at least 1 prior anti-HER2 regimen. The primary end point was blinded independent centrally reviewed PFS; secondary end points included OS, objective response rate (ORR), duration of response (DOR), and safety.⁴

At the November 20, 2023, data cutoff, patients in the T-DXd (n = 261) and T-DM1 (n = 263) arms experienced a median investigator-assessed PFS of 29.0 months (95% CI, 23.7-40.0) vs 7.2 months (95% CI, 6.8-8.3), respectively (HR, 0.30; 95% CI, 0.24- 0.38). The confirmed investigator-assessed ORRs were 78.9% (95% CI, 73.5%-83.7%) vs 36.9% (95% CI, 31.0%-43.0%), respectively. The median OS was 52.6 months (95% CI, 48.7-not evaluable [NE]) vs 42.7 months (95% CI, 35.4-NE), respectively.

Investigators are also examining the potential role of T-DXd alone and in combination with pertuzumab (Perjeta) in patients with previously untreated HER2-positive advanced/metastatic breast cancer in the phase 1/2 DESTINY-Breast07 study (NCT04538742). The primary end points of the trial are safety and tolerability; key secondary end points include investigator-assessed ORR and PFS.⁵

Findings from the dose-expansion interim analysis of DESTINY-Breast07 presented during the 2024 ASCO Annual Meeting demonstrated that patients who received T-DXd monotherapy (n = 75) and as a combination component (n = 50) experienced similar safety profiles, with only 1 case of grade 3 interstitial lung disease in the combination arm. Patients in both arms experienced any-grade adverse effects (AEs; 100% vs 100%), grade 3 or higher AEs (52.0% vs 62.0%), and serious AEs (17.3% vs 26.0%). Preliminary efficacy data were promising in both arms, with confirmed ORRs of 76.0% (80% CI, 68.5%-82.4%) and 84.0% (80% CI, 75.3%-90.5%), respectively. The 12-month PFS rates were 80.8% (80% CI, 73.7%-86.1%) vs 89.4% (80% CI, 81.9%-93.9%), respectively.

“[Also during the 2024 ASCO Annual Meeting], investigators presented findings from [the phase 3] DESTINY-Breast06 trial [NCT04494425],” Gadi added. “This trial involved patients with HER2-low disease, with an IHC of 2+ or 1+ and [compared T-DXd] with chemotherapy, showing a 5-month improvement in PFS and a hint of OS improvement. So we went from [using ADCs only in] HER2-positive [disease to now also] HER2-low [disease], and now we’re getting this rollout [in the first-line setting].”

Phase 2 Data Alleviate Doubts for HER2-Directed ADCs in Gynecologic Cancers

Beyond breast cancer, T-DXd is also being examined in multiple gynecologic malignancies, primarily in the phase 2 DESTINY-PanTumor02 trial (NCT04482309). Although there are presently no HER2-targeted ADCs approved for the treatment of patients with gynecologic cancers, recent findings from DESTINY-PanTumor02 have made a strong case for the use of T-DXd in these patients.⁶

“[The excitement around T-DXd] stems from DESTINY-PanTumor02, [findings from which] were transformational,” Susana M. Campos, MD, MPH, said. “This was a simple phase 2 study across multiple disciplines—not only gynecologic malignancies—[that included patients with] endometrial, cervical, and ovarian cancer. Patients had to be HER2 IHC2+ or 3+ and ORR was the primary end point of the study. Secondary end points [included] DOR and PFS. Looking specifically at the endometrial, ovarian, and cervical cancer [cohorts comprising] 40 patients each, the response rates were monumental.”

At the June 8, 2023, data cutoff, updated findings from DESTINY-PanTumor02 demonstrated that among all-comers with endometrial, cervical, and ovarian cancer, the ORRs were 57.5% (95% CI, 40.9%- 73.0%), 50.0% (95% CI, 33.8%-66.2%), and 45.0% (95% CI, 29.3%-61.5%), respectively. The median PFS was 11.1 months (95% CI, 7.1-not reached [NR), 7.0 months (95% CI, 4.2-11.1), and 5.9 months (95% CI, 4.0-8.3), respectively.

Notably, patients with confirmed HER2 expression of IHC3+ with endometrial (n = 13), cervical (n = 8), and ovarian cancer (n = 11) achieved ORRs of 84.6% (95% CI, 95% CI, 54.6%- 98.1%), 75.0% (95% CI, 34.9%-96.8%), and 63.6% (95% CI, 30.8%-89.1%), respectively. The median PFS for these patients was NR (95% CI, 7.3-NR), NR (95% CI, 3.9-NR), and 12.5 months (95% CI, 3.1-NR), respectively.

“The median PFS was very respectable; it changed the way we looked at this drug in the management of gynecologic malignancies. It was incredibly inviting and that was just 1 study, which changed the way we do things in gynecologic [cancer],” Campos added.

Additionally, T-DXd is being evaluated in patients with HER2-expressing advanced or recurrent uterine carcinosarcoma, a rare high-grade endometrial malignancy with limited treatment options, in the phase 2 STATICE trial (UMIN00002956, NCCH1615). The Japanese study enrolled patients with uterine carcinosarcoma with a HER2 IHC of at least 1+ who had previously received chemotherapy. The primary end point was ORR per central review in patients who had a HER2 IHC of at least 2+ (HER2-high; n = 22); secondary end points included ORR in patients with a HER2 IHC1+ (HER2-low; n = 10), PFS, OS, and safety.⁷

Per central review, the ORR in the HER2- high and HER2-low groups was 54.5% (95% CI, 32.2%-75.6%) and 70.0% (95% CI, 34.8%-93.3%), respectively. The median PFS was 6.2 months (95% CI, 4.0-8.8) and 6.7 months (95% CI, 2.6-13.8), respectively, and the median OS was 13.3 months (95% CI, 8.8-NR) and NR (95% CI, 9.8-NR), respectively.

“We’re measuring HER2 in all [patients with] uterine carcinosarcoma,” Campos said. “It’s such a rare tumor, we don’t usually have much to offer these individuals once they relapse, and now we have a target.”

Pursuing the Frontline Potential of T-DXd–Based Therapy in GI Cancers

In GI cancer, T-DXd was granted FDA approval in January 2021 for the treatment of adult patients with locally advanced or metastatic HER2-positive gastric or gastroesophageal (GEJ) adenocarcinoma who had received a previous trastuzumab-based regimen. The approval was supported by findings from the phase 2 DESTINY- Gastric01 study (NCT03329690). The primary end point of the trial was ORR; key secondary end points included OS, DOR, PFS, and safety.⁸

Final survival data from DESTINY-Gastric01 presented during the 2022 ASCO Gastrointestinal Cancers Symposium showed that patients who received T-DXd (n = 119) achieved an ORR of 51.3% (95% CI, 41.9%-60.5%) compared with
14.3% (95% CI, 6.4%-26.2%) among patients who received physician’s choice of irinotecan or paclitaxel (n = 56; P < .0001). The median OS was 12.5 months (95% CI, 10.3-15.2) vs 8.9 months (95% CI, 6.4-10.4), respectively (HR, 0.60; 95% CI, 0.42-0.86), and the median PFS was 5.6 months (95% CI, 4.3-6.9) vs 3.5 months (95% CI, 2.0-4.3), respectively (HR, 0.47; 95% CI, 0.31-0.71).⁹

Another study, the phase 1b/2 DESTINY- Gastric03 trial (NCT04379596), is aiming to determine the potential role of T-DXd, both as monotherapy and as a combination component, in patients with treatment-naive, HER2-positive or HER2-low gastric cancer. The ongoing, multi-center trial is enrolling patients with locally advanced or metastatic, unresectable gastric, GEJ, or esophageal adenocarcinoma. In the dose-expansion phase, patients will receive T-DXd in combination with investigator’s choice of fluorouracil (5-FU) or capecitabine plus pembrolizumab (Keytruda) in part 2 and T-DXd plus investigator’s choice of 5-FU or capecitabine plus volrustomig in part 3. The primary end point in parts 2 and 3 is investigator-assessed confirmed ORR; secondary end points include DOR, PFS, OS, and safety.¹⁰

“In gastric [cancer] we’re starting to see [activity with T-DXd] in the intermediate [HER2] expressors, [although] it’s not as striking as the breast data,” Parikh said. “Unfortunately, pancreatic cancer is the notable disease [with a] lack of efficacy, but across other GI indications [there is] good efficacy.”

Carving Out Another Path for HER2 Targeting in Lung Cancer

In HER2-mutant metastatic non–small cell lung cancer (NSCLC), T-DXd is approved by the FDA. The agent received accelerated approval in August 2022 for the treatment of patients with unresectable or metastatic NSCLC with activating HER2 mutations, as detected by an FDA-approved test, who have received prior systemic therapy. The approval was supported by findings from the phase 2 DESTINY-Lung02 trial (NCT04644237) and marked the first agent to be approved for HER2-mutated NSCLC.¹¹

“Our story [in lung cancer] has been a little bit different as our genomic abnormality is a little bit different; it has not been based on amplification,” Edward B. Garon, MD, MS, said. “We have tended to focus much more on the mutations, and that is a place where there is currently an approval for T-DXd. That has been an area of enthusiastic development, [although] it is a fairly small population; HER2 mutations are seen in [approximately] 1% to 2% of all patients.”

During the 2024 ASCO Annual Meeting, investigators presented findings from the final analysis of DESTINY-Lung02. Patients were randomly assigned to receive T-DXd at a dose of 5.4 mg/kg (n = 102) or 6.4 mg/kg (n = 50) once every 3 weeks. The primary end point was confirmed ORR; key secondary end points included DOR, PFS, OS, and safety.¹²

At the August 25, 2023, data cutoff, patients in the 5.4-mg/kg arm and the 6.4-mg/kg arm experienced a confirmed ORR of 50.0% (95% CI, 39.9%-60.1%) vs 56.0% (95% CI, 41.3%-70.0%), respectively. The median DOR was 12.6 months (95% CI, 6.4-NE) vs 12.2 months (95% CI, 7.0-NE), respectively, the median PFS was 10.0 months (95% CI, 7.7-15.2) vs 12.9 months (95% CI, 7.2-16.7), respectively, and the median OS was 19.0 months (95% CI, 14.7-NE) vs 17.3 months (95% CI, 13.8-NE), respectively.

“There is also an ongoing study of T-DXd vs chemoimmunotherapy,” Garon added. “The reality is, in the group of patients it is testing—those with HER2 mutations—it’s hard to know the degree of efficacy that would be seen with immune checkpoint inhibitors; it’s certainly anticipated to be lower. Our driver mutation–positive cases generally have had a much lower response rate to immune checkpoint inhibitors. But because it is a small subgroup, we don’t have great numbers in terms of efficacy. The control arm in that study is carboplatin, pemetrexed [Alimta], and pembrolizumab. This is a study that the field is certainly interested in seeing the results from.”

T-DM1 was also investigated in patients with HER2-overexpressing NSCLC in a phase 2 study (NCT02289833). The study enrolled previously treated patients who received platinum-based chemotherapy and targeted therapy for those with an EGFR mutation or ALK gene rearrangement. The primary end point was confirmed ORR; secondary end points included PFS, DOR, OS, and safety.¹³

The latest findings from the study showed that, at the May 29, 2017, data cutoff, patients with HER2 IHC3+ disease (n = 20) experienced an ORR of 20% (95% CI, 5.7%-43.7%), a median PFS of 2.7 months (95% CI, 1.4-8.3), and a median OS of 15.3 months (95% CI, 4.1-NE). No patients with HER2 IHC2+ disease (n = 29) experienced a response.

T-DXd Shows Potential in High HER2-Expressing, Heavily Pretreated Urothelial Cancer

Beyond gynecologic malignancies, DESTINY-PanTumor02 also included findings from a cohort of patients with bladder cancer. During the 2024 ASCO Annual Meeting investigators presented findings from a cohort of 41 patients with urothelial cancer who received T-DXd; most of these patients (65.9%) had received at least 2 previous treatment regimens.¹⁴

At a median follow-up of 12.65 months (range, 0.4-26.8), the ORR was 39.0% (95% CI, 24.2%- 55.5%), the median DOR was 8.7 months (95% CI, 4.3-11.8), and the median PFS was 7.0 months (95% CI, 4.2-9.7). Among patients with an HER2 IHC score of 3+ (n = 16), these figures were 56.3% (95% CI, 29.9%-80.2%), 8.7 months (95% CI, 2.8-10.6), and 7.4 months (95% CI, 3.0-11.9), respectively. In the HER2 IHC2+ subgroup (n = 20), they were 35.0% (95% CI, 15.4%-59.2%), 10.3 months (95% CI, 4.3-17.8), and 7.8 months (95% CI, 2.6-11.6), respectively.

On April 5, 2024, the FDA granted accelerated approval to T-DXd for the treatment of adult patients with previously treated unresectable or metastatic HER2-positive solid tumors with an IHC score of 3+ who have no satisfactory treatment options.¹⁵

“In patients with [HER2 IHC] 3-plus–expressing tumors [T-DXd] has become a go-to strategy for us since the approval came in,” Matthew Galsky, MD, said. “A frontline ADC plus immune checkpoint blockade is our standard treatment strategy now with enfortumab vedotin-ejfv [Padcev] plus pembrolizumab. The ADC/IO [immune-oncology] combinations have been well entrenched in our disease at this point. There’s a conversation occurring about how much the payload matters in immune checkpoint blockade–based combinations. There’s some hand waving around these small, independent data sets; we’ll need to see larger data sets to know that for sure.”

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