Erika P. Hamilton, MD

Erika P. Hamilton, MD, lead investigator and director of the Breast and Gynecologic Cancer Research Program at the Sarah Cannon Research Institute/Tennessee Oncology, discusses the findings from a phase 1 trial of DS-6000a in patients with advanced renal cell carcinoma (RCC) and ovarian cancer (NCT04707248).

data from the trial showed there to be acceptable tolerability

 and early signals of efficacy in heavily pretreated individuals with advanced RCC and ovarian cancer. These findings were presented at the 2022 American Society of Clinical Oncology Annual Meeting.

Nineteen patients had treatment-emergent adverse events (TEAEs), including fatigue (45.5%), nausea (45.5%), and vomiting (27.3%). There were grade 3 or greater TEAEs observed in 4 patients (18.2%) and the most frequent was neutropenia (13.6%). Grade 3 febrile neutropenia was observed in 1 patient and 1 dose-limiting toxicity of grade 4 thrombocytopenia (9.6 mg/kg) also occurred.

We saw that nausea, vomiting and fatigue are the most common side effects, but there were no cases of nausea, vomiting, or fatigue that were grade 3 or greater, meaning that although they were common side effects, they tended to be quite mild. Of our patients that were evaluable, there were 20, and we saw 6 partial responses, 4 that were confirmed, and 2 that were unconfirmed as of this safety data cutoff.

We also looked at a tumor marker that we check often in our patients with ovarian carcinoma called CA 125. A lot of times the CA 125 decrease of half or more can be really meaningful for us and for patients kind of regardless of how much shrinkage we get on scans. What we saw was that 8 of our 17 patients evaluable for CA 125 had a decrease of at least 50% while on study. A lot of these actually had stable disease as their best response. Although their tumors hadn't shrunk substantially yet, they had drops in their CA 125 of at least 50%.

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Erika P. Hamilton, MD, discusses the findings from a phase 1 trial of DS-6000a in patients with advanced renal cell carcinoma and ovarian cancer.

Trial of DS-6000a Elicits Early Efficacy/Safety Data in RCC and Ovarian Cancer

Erika P. Hamilton, MD, director of the Breast and Gynecologic Cancer Research Program at the Sarah Cannon Research Institute and medical oncologist at Tennessee Oncology, discusses the wide-ranging impacts of the introduction of fam-trastuzumab deruxtecan-nxki (Enhertu) for patients with HER2-positive breast cancer.

Hamilton says that the success of trastuzumab deruxtecan in the phase 3 DESTINY-Breast03 study (NCT03529110) has led to its approval for HER2-positive breast cancer. In addition, it was also approved in HER2-positive gastric or gastroesophageal carcinoma based on the DESTINY-Gastric01 trial (NCT03329690) and for HER2-low breast cancer based on the DESTINY-Breast04 trial.

These trials have demonstrated the potential of antibody-drug conjugates (ADCs) as a targeted method for delivering cytotoxic payloads into cancer cells while avoiding toxicity toward healthy cells, according to Hamilton.

Additionally, there are other ADCs in development in breast cancer with different targets including HER3 ADCs and a TROP2-directed ADC. New ADCs are also showing potential in other disease types. 

, a CDH6 ADC for renal cell carcinoma (RCC) and ovarian cancer, in a phase 1 clinical trial (NCT04707248).

I think that trastuzumab deruxtecan was a massive win and we're seeing that in HER2-positive breast cancer. We are seeing it in areas like gastrointestinal cancers, or the ASCO [American Society of Clinical Oncology] plenary, even patients that have HER2-low breast cancers. I think this provides more excitement for ADCs as a way to get powerful payload or chemotherapy into the cancer cells while trying to spare a lot of the normal body through the ADC platform.

We know that there are some similar ADCs in terms of platform and structure coming, some HER3 ADCs, a new TROP2 ADC, as well in some other cancers, such as a CDH6 ADC that is being looked at in RCC and ovarian cancer.

Erika P. Hamilton, MD, discusses the wide-ranging impacts of the introduction of fam-trastuzumab deruxtecan-nxki for patients with HER2-positive breast cancer.

Expanded Roles for Trastuzumab Deruxtecan in HER2+ Breast Cancer

Erika P. Hamilton, MD, director of the Breast and Gynecologic Cancer Research Program at the Sarah Cannon Research Institute and medical oncologist at Tennessee Oncology, discusses the next steps following the successful outcomes of the phase 3 DESTINY-Breast03 trial (NCT03529110) of fam-trastuzumab deruxtecan-nxki (Enhertu) in patients with HER2-positive breast cancer.

Based on the primary analysis of the study, trastuzumab deruxtecan showed a 72% reduction in the risk of progression or death versus trastuzumab emtansine (TDM-1) in these patients and adverse events were manageable. These patients must have received a prior trastuzumab (Herceptin)-based regimen, but Hamilton says there are now trials investigating earlier use of trastuzumab deruxtecan in the frontline, adjuvant, and neoadjuvant settings, with the latter 2 showing whether this will be a curative option for patients.

Another area that needs to be investigated is the sequencing of current agents once trastuzumab deruxtecan is used in the second line. Other agents used in HER2-positive disease including capecitabine (Xeloda), tucatinib (Tukysa), and trastuzumab (Herceptin) will need to be investigated in terms of their efficacy following the newer agent and what the optimal sequence is. The role of TDM-1 as a subsequent treatment after trastuzumab deruxtecan will also need to be determined.

 We are going to continue to bring trastuzumab deruxtecan up into earlier settings, meaning there are ongoing trials in the first-line with trastuzumab deruxtecan as well as both neoadjuvant and adjuvant studies, so studies where patients are in the curative setting. We're excited to see, with how fantastic the results have looked in DESTINY-Breast03, what we might see in earlier lines.

One big remaining question is how do we sequence the drugs we have? If we're conceivably using trastuzumab deruxtecan in the second-line, we have drugs like capecitabine [Xeloda], tucatinib [Tukysa], and trastuzumab that we can use [in the] third-line. We have TDM-1 that we are not…using in the first or second line now. So how do we sequence these and what are the activities of our existing HER2 drugs going to be after patients have already seen trastuzumab deruxtecan? Because we don't have a lot of data on that.

Erika P. Hamilton, MD, discusses the next steps following the successful outcomes of the phase 3 DESTINY-Breast03 trial of fam-trastuzumab deruxtecan-nxki in patients with HER2-positive breast cancer.

Next Steps Following DESTINY-Breast03 for HER2+ Breast Cancer

Erika P. Hamilton, MD, lead investigator and director of the Breast and Gynecologic Cancer Research Program at the Sarah Cannon Research Institute/Tennessee Oncology, discusses the key safety and efficacy findings from the phase 3 DESTINY-Breast03 study (NCT03529110).

 54.9% of patients discontinued from receiving treatment trastuzumab deruxtecan-nxki (Enhertu) vs 85.1% who discontinued T-DM1. Between arms, the rates of treatment-emergent adverse events (TEAEs) were similar and any-grade TEAEs were experienced by 99.6% of the trastuzumab deruxtecan arm vs 95.4% in the T-DM1 arm.

TEAEs which were grade 3 or greater were experienced by 53.3% and 49.8% for each arm, and serious TEAEs of any grade were seen in 21.0% of patients in the trastuzumab deruxtecan arm and 19.2% of patients in the T-DM1 arm, respectively. Additionally, grade 3 or greater serious TEAEs were observed in 15.2% and 14.6% of patients for each treatment, respectively.

The main efficacy finding with DESTINY-Breast03 was reported previously and showed a 72% reduction in the risk of progression, so really outstanding results compared with T-DM1 which previously was our standard in the second-line setting. Again, what we saw was although things like nausea, vomiting, and hair loss were more common with trastuzumab deruxtecan, overall serious events, or grade 3 or greater events, were very similar between the arms.

When we use these exposure adjusted incidence rates to compare how many AEs were happening compared with how long patients could remain on the therapy and continue to get benefit, we saw that, almost across the board, those were lower with trastuzumab deruxtecan than T-DM1.

Erika P. Hamilton, MD, discusses the key safety and efficacy findings from the phase 3 DESTINY-Breast03 study.


Updated Safety and Efficacy Findings of the Phase 3 DESTINY-Breast03 Study

Erika P. Hamilton, MD, director of the Breast and Gynecologic Cancer Research Program at the Sarah Cannon Research Institute, discusses the purpose of a safety follow-up analysis for the DESTINY-Breast03 trial (NCT03529110) of fam-trastuzumab deruxtecan-nxki (Enhertu) in patients with HER2-positive breast cancer.

The phase 3 trial randomly assigned patients 1:1 to receive either trastuzumab deruxtecan or trastuzumab emtansine (TDM-1; Kadcyla) intravenously (IV) every 3 weeks. Based on the primary analysis, trastuzumab deruxtecan showed a 72% reduction in the risk of progression or death in these patients. The safety follow-up presented at the 2022 American Society of Clinical Oncology Annual Meeting showed no new safety signals.

Hamilton says trastuzumab deruxtecan appeared to have higher rates of nausea, vomiting, and hair loss, which peaked in the early cycles of treatment. Rates of fatigue were similar in both arms. In general, rates of any-grade adverse events (AEs), grade 3 or higher AEs, and serious AEs were similar across both arms, and were lower with trastuzumab deruxtecan when adjusted for exposure.

She notes that patients in the experimental arm were not required to receive antiemetic supportive care, which may have contributed to higher rates of nausea and vomiting. Now that trastuzumab deruxtecan is associated with these AEs, a multidrug anti-nausea regimen is now recommended when prescribing trastuzumab deruxtecan.

 The methods of the original study were treating patients randomized in a 1:1 fashion to either receive trastuzumab deruxtecan IV every 3 weeks or T-DM1 IV every 3 weeks. With this updated safety, we were looking at specific parameters that we were interested about: nausea, vomiting, alopecia or hair loss, hematologic or blood count parameters. What we saw was nausea and vomiting, as well as alopecia/hair loss, was more common with trastuzumab deruxtecan. It seemed to peak early in initial cycles and then stay about the same throughout the study, not get worse, etc. And for fatigue, it was very similar between trastuzumab deruxtecan and T-DM1.

An important caveat was during DESTINY-Breast03 enrollment, there were no mandatory antiemetics or nausea medicines as part of the protocol. It wasn't until during the study that trastuzumab deruxtecan was recognized as a moderately emetogenic drug. Now a multidrug nausea regimen is recommended from the very beginning and is actually included in the trastuzumab deruxtecan label. We hope that now we are doing an even better job of controlling nausea for the patients that are receiving trastuzumab deruxtecan.

Erika P. Hamilton, MD, discusses the purpose of a safety follow-up analysis for the DESTINY-Breast03 trial of fam-trastuzumab deruxtecan-nxki in patients with HER2-positive breast cancer.

Follow-Up Analyzes Safety of DESTINY-Breast03 for HER2+ Breast Cancer

Erika P. Hamilton, MD, lead investigator and director of the Breast and Gynecologic Cancer Research Program at the Sarah Cannon Research Institute/Tennessee Oncology, discusses the background of a phase 1 trial of DS-6000a in patients with advanced renal cell carcinoma (RCC) and ovarian cancer (NCT04707248).

This 2-part, multicenter, first-in-human, phase 1 study will evaluate DS-6000a given as a single agent once every 21 days in patients with platinum resistant ovarian cancer or RCC.

In the dose escalation phase of the trial, participants with ovarian cancer and RCC will be enrolled to assess the safety and tolerability of DS-6000a and to determine the maximum tolerated dose for the expansion portion. In the dose expansion portion of the trial, investigators will assess the clinical activity of DS-6000a.

[DS-6000a] is an antibody-drug conjugate that is targeting something called cadherin 6 or CDH6. It is the same platform as drugs that you might be more familiar with like fam-trastuzumab deruxtecan-nxki [Enhertu] or datopotamab deruxtecan [Dato-DXd]. Essentially, the drug to antibody ratio is 8 and it's given intravenously every 3 weeks like some of its cousins.

The patients that were enrolled onto this trial had either renal cell carcinoma or platinum resistant ovarian carcinoma. About a third of the patients on the trial had renal cell and about two thirds that had ovarian cancer. Now for the patients that had renal cell, the median number of priors was 2, whereas the patients that had ovarian cancer had a median number of priors of 4. A lot of patients remain on this drug. Upwards of almost 60% of the patients that we reported data on are still on drugs, still doing well, without their cancer growing.

Erika P. Hamilton, MD, discusses the background of a phase 1 trial of DS-6000a in patients with advanced renal cell carcinoma and ovarian cancer.

Erika P. Hamilton, MD | Authors

Articles

Trial of DS-6000a Elicits Early Efficacy/Safety Data in RCC and Ovarian Cancer

Expanded Roles for Trastuzumab Deruxtecan in HER2+ Breast Cancer

Next Steps Following DESTINY-Breast03 for HER2+ Breast Cancer

Updated Safety and Efficacy Findings of the Phase 3 DESTINY-Breast03 Study

Follow-Up Analyzes Safety of DESTINY-Breast03 for HER2+ Breast Cancer

Phase 1 Trial Evaluates DS-6000a in RCC and Ovarian Cancer