CME
Physicians: Maximum of 0.75 AMA PRA Category 1 Credit™
Released: May 09, 2024
Expiration: November 08, 2025
Clinical Data for Anti-HER2 Therapy in Gynecologic Cancers
There is renewed interest in the nuances of testing for HER2 status among gynecologic oncologists because of the emerging clinical data for novel therapies targeting HER2—namely, anti-HER2 ADCs.
Phase II of Carboplatin + Paclitaxel + Trastuzumab vs SoC for Stage III/IV or Recurrent HER2+ Uterine Serious Carcinoma
Before we discuss the exciting data for ADCs, I would like to go back to the beginning and briefly discuss the early data and outcomes for the monoclonal antibody trastuzumab against HER2. I started this discussion by referencing the early work by Slamon and colleagues7 exploring the use of trastuzumab, mainly in patients with breast cancer and high HER2 expression, as well as other preclinical data, including in ovarian cancer models.8
Those earlier observations with trastuzumab were translated into a viable therapy for patients with uterine cancers with the work by Dr Amanda Nickles Fader.2 In a randomized phase II study, trastuzumab was added to the standard of care (SoC) of carboplatin plus paclitaxel and followed by trastuzumab maintenance vs SoC alone for patients with stage III/IV or recurrent (1 previous treatment allowed) HER2-positive (eg, HER2 IHC 3+ or 2+ and ISH+) uterine serous carcinoma. With the caveat that it was a relatively small study, those who received carboplatin plus paclitaxel and trastuzumab followed by trastuzumab maintenance had a significant improvement in median PFS compared with those receiving chemotherapy alone in the overall population (12.9 vs 8.0 months; HR: 0.46; P = .005), those undergoing primary treatment (17.7 vs 9.3 months; HR: 0.44; P = .015), and those with recurrent disease (9.2 vs 7.0 months; HR: 0.12; P = .004).
What I found most interesting, however, was PFS for stage III or IV disease when carboplatin plus paclitaxel and trastuzumab followed by trastuzumab maintenance was their first treatment. Here we saw a magnitude of benefit that was quite striking—from approximately 9 months to almost 18 months with no evidence of progressive disease. For this reason, this combination became listed by the NCCN clinical guidelines and became what most of us consider an SoC for this population.9
Phase II GOG Trial of Trastuzumab in Recurrent/Refractory Ovarian Cancer With HER2 Overexpression
The challenge with trastuzumab or pertuzumab is that although you do have occasional patients who receive these monoclonal antibodies in the recurrent setting and achieve clinical benefit, most often this treatment does not work well. Summarized on the right is the largest study ever done with trastuzumab in patients with persistent/recurrent epithelial ovarian or primary peritoneal carcinoma, which was published more than 20 years ago.10 For that study, investigators had to screen almost 900 patients to identify the 95 who had HER2-positive (IHC 3+ or 2+ and ISH+) ovarian cancer. Patients received trastuzumab 4 mg/kg intravenously as a loading dose and then weekly trastuzumab 2 mg/kg. Treatment was continued until disease progression or unacceptable toxicity. As you can see here, the ORR was approximately 7%, with 1 patient achieving a complete response and 2 achieving a partial response. Thus, when this treatment works, it can work quite well, but it did not work well as single-agent therapy in most patients with ovarian cancer.
A Case Report for Trastuzumab/Pertuzumab in Advanced Cervical Cancer
As we saw earlier, among the gynecologic cancers discussed, the prevalence of HER2 alterations (mutations and amplifications) is highest for cervical cancer.
The slide provides a summary case report from a patient with recurrent cervical cancer with adenocarcinoma histology.11
This particular patient had been treated with the SoC at the time—which consisted of topotecan, paclitaxel, and bevacizumab—as part of the large, international phase III GOG 240 trial.12 Until recently—prior to the approval of chemotherapy plus immunotherapy based on the results of KEYNOTE-82613—this was very much an acceptable frontline therapy. The patient unexpectedly developed lung metastases after 7 cycles, which is about the median time patients receive that frontline therapy. The lung biopsy was tested and found to be HER2 positive. She stopped topotecan‑based therapy and was started on trastuzumab and pertuzumab; that continued for 2 years and was followed by trastuzumab emtansine at progression, which resulted in target region size reduction. To restate, it is not that these agents have no benefit, but that it is rare to achieve benefit from anti-HER2 monoclonal antibodies alone in the recurrent disease setting.
Looking at these historical data for context, and seeing ORRs in advanced/recurrent ovarian cancer as low as 7%, that is why the new data for ADCs have really been so exciting for us in this treatment landscape.
Novel Anti-HER2 ADCs in Gynecologic Cancers
I wish to highlight a couple of these ADCs targeting HER2 in this discussion. I am going to discuss those that have released clinical trial data in gynecologic cancers with an appreciable number of patients represented.
HER2-Targeted ADC: Trastuzumab Deruxtecan (T-DXd)
The first ADC I would like to discuss is T-DXd, for which you can see the molecular structure and components on this slide. In T-DXd, the antibody portion is an IgG1 monoclonal antibody targeting HER2 that is linked to the cytotoxic payload by an intracellular cleavable linker.14 This means the linker is designed to hold on to the payload until the antibody is endocytosed into the cancer cell, and then the payload is released. The payload in T-DXd is highly potent and membrane permeable. The cytotoxic DXd moiety has a short half-life, an intracellular cytotoxic effect on tumor cells, and a bystander killing effect on adjacent tumor cells.
Phase II DESTINY-PanTumor02: T-DXd in HER2-Positive Gynecologic Cancer Cohorts
The phase II DESTINY-PanTumor02 basket trial is evaluating T-DXd in several advanced solid tumors, including in gynecologic cancers, not eligible for curative therapy. In this clinical trial, patients had received ≥2 previous therapies and had HER2 expression defined as IHC 3+ or 2+ performed locally (HercepTest) per ASCO/CAP gastric cancer guidelines (NCT04482309).15,16 Previous HER2-targeted therapy was allowed. The primary endpoint was confirmed ORR by the investigator per Response Evaluation Criteria in Solid Tumors version 1.1.
It is important to note that gastric scoring was used for determination of IHC 3+ or 2+ disease. With gastric scoring, they did not require FISH confirmation in those with HER2 IHC 2+ tumors, which is how it appears in the NCCN guidelines and how T-DXd recently received the FDA accelerated approval as a tumor-agnostic therapy for adult patients with unresectable or metastatic HER2-positive (IHC 3+) solid tumors who have received prior systemic treatment and have no satisfactory alternative treatment options.
As a reminder, the difference between HER2 expression using breast cancer scoring vs gastric scoring is that the membranous distribution of the HER2 antibody in breast cancer cells is circumferential, whereas in gastric tumor scoring it is not circumferential. In gastric cells, HER2 antibody staining is often incomplete, looks like a U shape, parallel lines phenotype, with lateral expression—but it is definitely not circumferential. The second difference between gastric and breast HER2 scoring is the intratumor heterogeneity of the HER2 staining. In gastric cancer and other solid tumors—such as cervical, endometrial, and ovarian cancers—there is significant intratumoral heterogeneity in HER2 staining, which means there are areas with different HER2 scores within the same tumor. As you can imagine, this can make giving a single score somewhat complex. The gastric tumor scoring system was developed to account for the intratumor heterogeneity applicable to other solid tumors, as well.
DESTINY-PanTumor02: T-DXd Responses in Gynecologic Cancers and by HER2 Status
The slide shows best overall response with T-DXd in gynecologic cancers. These are responses in tumors that are largely refractory to effective therapies in each of their respective disease types. Keeping that in mind, an ORR of 50% for a recurrent cervical cancer tumor is orders of magnitude better than anything we have ever seen in this space.12 Another medication that is approved by the FDA in this space is tisotumab vedotin,17 which is also an ADC, but it targets tissue factor. Tisotumab vedotin is approved for recurrent or metastatic cervical cancer with disease progression on or after chemotherapy. For context, ORR with tisotumab vedotin in patients with refractory cervical cancer in the innovaTV 204 trial was 24%.18 Here, with DESTINY-PanTumor02 and T-DXd, we achieved an ORR of 50%, including 5% of patients achieving a complete response.
For endometrial cancers, we see very similar results, with an ORR of approximately 60%. Of note, this is for second-line therapy and beyond, where your benchmark for chemotherapy alone is approximately 15% and for lenvatinib plus pembrolizumab is approximately 33%.19 Thus, this signal is almost double that of even our best second‑line agent—lenvatinib plus pembrolizumab, which is now in question if immunotherapy moves into the front line with chemotherapy.
In ovarian cancer, we see an ORR of 45% in all patients, and your benchmark for single-agent chemotherapy is approximately 15%.20
All these are in 40-patient cohorts, but these are incredibly strong signals to move forward into larger trials.
The DoR also was quite remarkable, ranging from approximately 10 months in endometrial cancer to up to 14.2 months in cervical cancer, which for the recurrent setting is quite impressive. We are excited about these results and for this study to move forward.
We also saw pathology rescoring, but despite some discordance between local and centralized testing, those tumors that were reconfirmed to be HER2 IHC 3+ and 2+ had substantially higher ORR shown here—as high as 75% in cervical cancer, which is higher than we have seen with chemotherapy plus immunotherapy.21
For HER2 IHC 3+ endometrial cancer, the ORR was 85%. For HER2 IHC 3+ ovarian cancer, the ORR was 64%.
DESTINY-PanTumor02: Safety Summary
The figure shows the safety summary of DESTINY-PanTumor02, specifically in the gynecologic cancer cohorts (n = 120), which is really no different from what we have seen with T-DXd in the thousands of patients who already have been treated on clinical trials in breast cancer to date. We do not see any new safety signals.
Most patients (88.3%) experienced drug-related treatment-emergent adverse events (TEAEs), with 45% having a grade ≥3 event.
In total, 13 patients (10.8%) experienced ILD/pneumonitis adjudicated as related to T-DXd, with 1 patient death on study related to ILD/pneumonitis (0.8%) and another death due to pneumonia (organizing pneumonia).
In general, we saw frequent but low-grade gastrointestinal toxicities of nausea (64%), diarrhea (32.5%), and vomiting (27.5%). We also saw some expected hematologic toxicities, for example, anemia (30.8%), neutropenia (28.3%), and thrombocytopenia (15.0%). Grade ≥3 hematologic toxicities were neutropenia (19.2%), anemia (13.3%), and thrombocytopenia (6.7%), which are expected with this class of medication.
In addition to the less common but worrisome area of ILD/pneumonitis, which is still sitting just below 10%, we need to watch out for left ventricular dysfunction, which is very uncommon with ADCs compared with the monoclonal antibodies trastuzumab and pertuzumab. In DESTINY-PanTumor02, approximately 3% of patients experienced any‑grade ejection fraction decrease, and most were of low grade.16 Nonetheless, we do have to monitor for this.
Global, Open-label Phase I/IIa Trial of HER2-Targeting ADC (DB-1303) in Recurrent/Metastatic Endometrial Cancer
The other ADC against HER2 that I would like to discuss also has released clinical data. DB‑1303 (or BNT323) has a similar structure to T-DXd but it is a distinct ADC with a topoisomerase I proprietary payload and a maleimide tetrapeptide-based cleavable linker.22 DB-1303 has a drug-to-antibody ratio of 8, bystander antitumor effect, and chemotherapy payload‒mediated cytotoxic activity via internal release within targeted cancer cells. DB-1303 has moved into a global registration‒enabling clinical trial with availability for the recurrent postimmunotherapy population for uterine cancer (NCT05150691).
A global, open‑label phase I/II trial is evaluating DB-1303 in patients with pathology-documented HER2-positive or ‑expressing (eg, a preexisting diagnosis of HER2 status or fresh biopsy by IHC 3+, 2+, 1+, or ISH+ or HER2 amplification or mutation by NGS) solid tumors, predominantly endometrial cancer and breast cancer.6 Study investigators are looking at central reconfirmation HER2 status, as well, but all the data here are based on local testing. The primary objectives of the study were determining the maximum tolerated dose, efficacy, pharmacokinetics, and immunogenicity. For the purpose of this discussion, we are going to focus on cohort 2b including patients with HER2 overexpression plus HER2-low endometrial cancer with both uterine serous carcinoma and uterine carcinosarcoma.
Phase I/IIa of DB-1303: Responses
The image shows the response data for the endometrial cohort. The ORR was approximately 60% (24% confirmed, 35% pending confirmation). We also saw responses across the HER2 IHC spectrum (eg, 1+ through 3+). The safety profile was very similar to what I covered earlier for T-DXd and in a relatively similar number of patients: 32 patients in this study compared with 40 patients in DESTINY-PanTumor02.
In total, 93% of patients experienced any-grade TEAEs. Grade ≥3 TEAEs were observed in 29% of patients. There were no reports of ILD/pneumonitis or grade ≥3 left ventricular ejection fraction decrease, but we saw dose reductions in 3% of patients and dose interruptions in fewer than 10%. However, at later time points, and not dissimilar to T-DXd, some patients had to discontinue treatment because of development of pneumonitis. In summary, the 2 agents have a very similar efficacy and safety profile based on the data available to date.
When Should You Incorporate Anti-HER2 in Patients With Gynecologic Cancers?
When thinking about incorporating anti‑HER2 agents in patients with gynecologic cancers:
If we break it down by disease site, as shown on the slide, in uterine serous cancer we want to test for HER2 status up front because it does inform anti-HER2 therapy in the front line and at the time of disease recurrence. In ovarian cancer and cervical cancer, I would recommend knowing HER2 status at the time of disease recurrence, and if you do not already know HER2 status at that time, this should be obtained.
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