Back Back
Think Tank on ADCs: GU, GI, and GYN
Think Tank on Emerging HER2-Targeted ADCs in Genitourinary, Gastrointestinal, and Gynecologic Malignancies

Released: March 22, 2024

Activity Information

Activity

Progress
1
Course Completed
Continue
Key Takeaways
  • Immunohistochemistry is a common method for assessing HER2 status across solid tumors for either recommending anti‒HER2 ADC therapy or assessing eligibility for a clinical trial.
  • Most clinical studies in genitourinary, gastrointestinal, and gynecologic cancers show encouraging efficacy and manageable safety for anti‒HER2 ADC therapy in patients with HER2-positive (IHC 3+ or 2+) disease.
  • The toxicity profile of ADCs often can be linked to the mechanism of action of the cytotoxic payload; management of ILD/pneumonitis with T-DXd is supported by a clear grading system and guidance to support patients.


In recent years, much interest has surrounded the development of antibody‒drug conjugates (ADCs) against the HER2 proto-oncogene in advanced solid tumors. The use of a monoclonal antibody to deliver a cytotoxic payload into tumor cells via an intracellular cleavable linker has generated a window of opportunity to improve upon patient outcomes where other traditional anti‒HER2 treatments have failed. In this commentary, 3 experts provide brief answers to remaining challenging topics and discuss where we currently stand on HER2 biomarker testing in genitourinary (GU), gastrointestinal (GI), and gynecologic solid tumors; the latest clinical data for anti‒HER2 ADCs; and insights on managing the safety profile of ADCs.

What is your approach for HER2 testing in GU, GI, and gynecologic cancers?

Elizabeth R. Plimack, MD, MS, FASCO:
One of the challenges we have for GU cancers is that there are currently no HER2-targeted therapies approved for clinical use, therefore testing for HER2 biomarker status is currently recommended specifically for the purpose of matching a patient to a clinical trial. For this reason, HER2 testing—either via immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), or next-generation sequencing (NGS)—may not be routinely done in clinical practice, particularly when a matching trial is not readily available. HER2 alterations may be “picked up” in the context of standard of care NGS panel testing, which is done for currently actionable biomarkers (eg, FGFR, PD-L1), although we could use the HER2 results to inform options for our patients at a later point. Beyond NGS, HER2 testing via IHC may be a consideration in patients with advanced or recurrent disease who are being considered for enrollment on clinical trials evaluating anti-HER2‒targeted ADCs in bladder cancers. Approximately 17% to 20% of GU tumors harbor mutations in HER2. A recent survey conducted by Clinical Care Options found that 6% to 8% of healthcare professionals are currently performing HER2 testing for GU cancers, presumably for the purpose of clinical trial enrollment.

Zev A. Wainberg, MD:
In GI cancers, we have considerable data supporting the use of HER2 testing, as this is an actionable biomarker for us, particularly for gastric and gastroesophageal junction (GEJ) tumors. The National Comprehensive Cancer Network guidelines have a uniform recommendation for HER2 testing in GI cancers, which includes HER2 testing for advanced metastatic GI cancers. HER2 testing is recommended in gastric and GEJ adenocarcinomas in all patients with metastatic disease (IHC and in situ hybridization [ISH] first; NGS may be considered). HER2 testing also is recommended in patients with colorectal cancer (IHC, ISH, or NGS) unless they are known to have a RAS or RAF mutation, and in biliary tract cancers (BTCs), HER2 testing is recommended in all patients (IHC, FISH, or NGS). HER2 testing in pancreatic cancer is recommended using NGS under circumstances where one would be considering anti‑HER2 therapy. The preferred testing modality in gastric and GEJ adenocarcinoma is IHC and/or FISH testing, with NGS also considered. In other GI cancers (eg, colon, pancreatic, BTCs), NGS often is used while assessing for other alterations beyond HER2.

Kathleen N. Moore, MD, MS:
For gynecologic cancers, we have been testing serous endometrial cancer for HER2 alterations for quite some time based on the work by Dr Nikles-Fader and colleagues. HER2 testing by IHC for that study is defined as positive if IHC results are 3+ or 2+/ISH positive. For those patients with HER2-positive serous endometrial cancer, we often recommend treatment with carboplatin, paclitaxel, and trastuzumab based on randomized phase II clinical trial data. New guideline recommendations also favor fam-trastuzumab deruxtecan (T-DXd), an ADC targeting HER2, in patients whose tumors are HER2 positive, here defined by gastric scoring IHC 3+ or 2+. Most clinical practitioners are beginning to check for HER2 status in ovarian and cervical cancer, as well. That was not previously done unless in the context of a clinical trial. In ovarian cancer, HER2-positive status is expected in approximately 10% of cases. We also have known for a while that in cervical adenocarcinomas, which comprise approximately 40% of cervical cancers, HER2-positive status varies from 5% to 30% depending on subtype. Fortunately, more patients with advanced and/or recurrent gynecologic cancers are receiving gene panel testing and HER2 expression analysis by IHC. It would be ideal to have an FDA approval supporting a specific biomarker cutoff and agnostic use of ADCs such as T-DXd. That would help us speak more definitively about how we would use HER2 as a biomarker going forward. I also say this because HER2 status does not currently inform how we proceed in the frontline setting other than for endometrial cancer. At this time, we could benefit from additional research into HER2 biology in gynecologic cancers.

Can you comment on the latest clinical data for anti-HER2 ADCs in GU, GI, and gynecologic tumors?

Elizabeth R. Plimack, MD, MS, FASCO:
There are currently no HER2 directed therapies approved in GU cancers, despite prior trials testing agents such as lapatinib, afatinib, trastuzumab duocarmazine, and trastuzumab plus pertuzumab. The historical overall response rate (ORR) in these trials has ranged from 0% to 25.0% in patients with recurrent/metastatic urothelial cancer (UC). However, there is much interest in exploring the newer class of anti‒HER2 agents, the ADCs, in GU cancers. The phase II DESTINY-PanTumor02 trial is evaluating T-DXd, an ADC with a topoisomerase I inhibitor payload, in a bladder cancer cohort (n = 41), and in those patients the ORR ranges from 35% to 56% for HER2 IHC 2+ and 3+, respectively. There is also a phase Ib study evaluating T-DXd plus nivolumab in a cohort of patients with advanced/metastatic UC who had not previously received T-DXd or immunotherapy. In that study, the confirmed ORR was approximately 37%—so not as robust as we have come to expect with other immunotherapy combinations, such as enfortumab vedotin, an ADC targeting nectin‑4, plus pembrolizumab as first-line therapy for advanced disease. Another promising anti‒HER2 ADC being evaluated for locally advanced/metastatic UC is disitamab vedotin, which has a monomethyl auristatin E cytotoxic payload. In a phase II trial, disitamab vedotin was given to patients with locally advanced/metastatic UC and progression on ≥1 previous systemic treatment (N = 107). In those patients, the ORR (complete response plus partial response) was 50%. In patients with HER2‑negative disease (n = 19), however, the ORR was 26%. This is a somewhat counterintuitive result—but certainly very provocative—and more research is needed to better understand how HER2 negative tumors can respond to disitamab vedotin. Another phase II trial is exploring the combination of disitamab vedotin plus toripalimab, a PD-L1 inhibitor, in refractory metastatic UC, and there we see an ORR of approximately 80%, which could reflect the small sample size of that study (n = 14).

Zev A. Wainberg, MD:
The first pivotal study evaluating anti‒HER2 therapy in GI cancers was the randomized phase III ToGA study of chemotherapy with or without trastuzumab in patients with HER2-positive gastric or GEJ cancer (N = 594). This study showed a significant overall survival (OS) advantage of 13.8 months vs 11.1 months (HR: 0.74; P = .0046), which led to chemotherapy plus trastuzumab becoming the standard of care. Now, a large study has just been reported that added pembrolizumab to that standard of care, supported by the presence of PD‑L1 staining and preclinical data suggesting a high response rate in earlier studies. The randomized phase III KEYNOTE-811 trial is evaluating chemotherapy plus trastuzumab with or without pembrolizumab in patients with HER2-positive advanced gastric or GEJ adenocarcinoma who had not received prior therapy in the advanced setting (N = 694). The coprimary endpoints were OS and progression-free survival (PFS) per blinded independent central review. In the interim analysis 3, in all patients, the ORR was 73% vs 60%, median PFS was 10.0 months vs 8.1 months (HR: 0.73), and median OS was 20.0 months vs 16.8 months (HR: 0.84). In the population with a PD-L1 combined positive score ≥1, median PFS was similarly improved at 10.9 months vs 7.3 months (HR: 0.71), as was median OS at 20.0 months vs 15.7 months (HR: 0.81).

As in other solid tumors, there is growing interest in evaluating the role of anti‒HER2 ADC therapies in GI cancers. The phase II DESTINY-Gastric01 trial, for instance, is evaluating T-DXd vs irinotecan or paclitaxel in patients with gastric or GEJ tumors with failure on 2 previous treatments. In that group of patients, the ORR was 51% vs 14% in favor of T-DXd. But what about patients with failure on previous first-line treatment with trastuzumab? The single-arm phase II DESTINY-Gastric02 trial is exploring T-DXd in patients with gastric or GEJ tumors with failure on previous trastuzumab therapy. In that group of patients, the ORR was 33%, with a median PFS of 5.6 months and a median OS of 12.1 months.

In colorectal cancer, the phase II DESTINY-CRC01 trial evaluated T-DXd in patients with unresectable/metastatic HER2-positive, RAS/BRAF wild-type tumors with failure on ≥3 previous therapies. In those patients, the ORR was 45%. The phase II DESTINY-CRC02 trial evaluated T-DXd in patients with recurrent/metastatic HER2-positive, RAS/BRAF wild-type tumors with failure on ≥2 previous therapies. In those patients, the ORR was approximately 38%. In previously treated metastatic BTCs, anti‒HER2 therapies (pertuzumab plus trastuzumab, FOLFOX plus trastuzumab, or zanidatamab) have yielded an ORR of 30% to 45%. In a similar group of patients with BTCs, T-DXd has yielded an ORR of 30%. Overall, responses to anti‒HER2 therapies hover at approximately 30% to 40% in BTCs.

Kathleen N. Moore, MD, MS:
Some promising data are emerging for ADCs against HER2 in gynecologic cancers. For instance, the phase II DESTINY-PanTumor02 trial also is evaluating T-DXd in patients with gynecologic cancers. We have seen that in previously treated patients with endometrial, cervical, and ovarian cancers, the ORR is 57%, 50%, and 45%, respectively. If we look at the response in those with a HER2 IHC of 3+ specifically, however, ORR was approximately 84%, 75%, and 64% for endometrial, cervical, and ovarian cancers, respectively. These results fare very well compared with historical data for trastuzumab in gynecologic cancers, with responses as low as 7.3% in patients with ovarian cancer. A global, open-label phase I/IIa trial is evaluating another anti-HER2 ADC, called DB-1303/BNT 323. Preliminary results from cohort 2b, consisting of HER2 overexpression plus HER2-low endometrial cancer, showed an unconfirmed ORR of approximately 59% in 17 patients. Overall, these results are in a relatively small number of patients and leave us with a few unanswered questions. Is the cutoff of HER2 IHC 3+/2+ appropriate for all patients? Should HER2 testing be done on archival tissue, or should it be done in current or fresh tissue? We need to explore such questions further.

What has been your experience with the safety profile of anti-HER2 ADC therapies in solid tumors?

Elizabeth R. Plimack, MD, MS, FASCO:
The toxicity profile for the ADCs we covered is mainly driven by the payload used: for T-DXd, the topoisomerase I inhibitor, and with disitamab vedotin, a monomethyl auristatin E—more taxane like. The key toxicities to watch for, specifically for T-DXd, are interstitial lung disease (ILD)/pneumonitis and ejection fraction decrease, observed in 7.5% (grade ≥3: 0.4%) and 2.6% (grade ≥3: 0.4%) of patients enrolled on DESTINY-PanTumor02. In addition to this, we should routinely assess blood counts and organ function test with these therapies. In patients with suspected ILD, however, we must hold the drug, assess symptoms, and use a CT scan for confirmation and/or involve a pulmonologist. The key is to rule out an alternate cause such as pneumonia (eg, with blood cultures, bronchoscopy). Regarding management of confirmed ILD/pneumonitis, of any grade, drug should be held and corticosteroids considered (prednisolone 0.5 mg/kg/day). The drug can be restarted if symptoms resolved within ≤28 days from onset. For those in whom ILD persist past 28 days from onset, treatment should be done only with caution after full resolution and at a reduced dose. However, if grade 1 ILD has not resolved within 49 days from last infusion, as well as for any grade 2-4 ILD, we must discontinue the drug and promptly initiate systemic corticosteroid treatment (eg, prednisolone ≥1 mg/kg/day or equivalent for ≥14 days, followed by taper for ≥4 weeks).

Zev A. Wainberg, MD:
The risk factors for developing ILD/pneumonitis with T-DXd have been described in the literature in numerous cancers. This seems to suggest a trend. Underlying conditions affecting risks remain unclear, but certainly patients who have baseline lung comorbidities may be at higher risk. Regarding management, I agree with what already has been said.

Your Thoughts?
Would you like to learn more regarding HER2 testing in solid tumors and the evolving role of anti‒HER2 ADC therapy in the management of GU, GI, and gynecologic cancers? Check out the brief self-guided lectures we have put together that go into more detail on the nuances of HER2 testing in solid tumors. We would highly recommend that our readers visit the program page to access these lectures and other free educational resources.

Continue

Poll

1.

Which of the following topics for anti‒HER2 ADCs would you like to learn more about?

Submit