Throughout the 2024 ASCO Annual Assembly, investigators shared preliminary and up to date findings from 2 part 3 research evaluating the HER2-directed antibody-drug conjugate (ADC) fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) in opposition to totally different comparators in sufferers with metastatic breast most cancers with differing HER2 standing with the potential to broaden the usage of the agent: DESTINY-Breast06 (NCT04494425) and DESTINY-Breast03 (NCT03529110).
In August 2022, the FDA accepted T-DXd for the therapy of grownup sufferers with unresectable or metastatic HER2-positive breast most cancers following prior therapy with an anti–HER2-based routine in both the metastatic setting or the neoadjuvant or adjuvant setting who’ve skilled illness recurrence throughout or inside 6 months of finishing therapy. The approval was supported by earlier findings from DESTINY-Breast03.1
“I anticipate that the usage of the [T-DXd] will broaden throughout classes of HER2 expression; it would broaden and might be utilized in earlier settings when it’s wanted and required,” Paolo Tarantino, MD, a researcher on the European Institute of Oncology in Milan, Italy, and a medical analysis fellow at Dana-Farber Most cancers Institute in Boston, Massachusetts, mentioned in an interview with OncologyLive. “I used to be impressed once I noticed the primary part 1 trial of T-DXd when it was nonetheless known as DS-8201, and I’m nonetheless impressed each time I see a brand new medical trial with this drug. It’s extraordinarily efficient, each for HER2-positive metastatic breast most cancers [and] HER2-low and even ultralow [disease].”
Up to date Findings From DESTINY- Breast03 Additional Solidify T-DXd in HER2+ Illness
The open-label, multicenter DESTINY-Breast03 trial enrolled sufferers with unresectable or metastatic HER2-positive breast most cancers who had beforehand obtained trastuzumab (Herceptin) and a taxane. Eligible sufferers wanted to have documented radiographic illness development and sufficient renal and hepatic operate. Those that had beforehand obtained a HER2-directed ADC within the metastatic setting, had uncontrolled or important heart problems, or had a historical past of or present interstitial lung illness have been excluded. Prior remedy with ado-trastuzumab emtansine (T-DM1; Kadcyla) was not permitted (Determine 1).2,3
After enrollment, sufferers have been randomly assigned 1:1 to obtain T-DXd 5.4 mg/kg each 3 weeks or 3.6 mg/kg T-DM1 each 3 weeks. Sufferers have been stratified by hormone receptor standing, prior therapy with pertuzumab (Perjeta), and historical past of visceral illness.
On the November 20, 2023, information cutoff, up to date survival findings from DESTINY- Breast03 offered throughout ASCO 2024 confirmed that sufferers who obtained T-DXd (n=261) achieved a median investigator-assessed PFS of 29.0 months (95% CI, 23.7-40.0) in contrast with 7.2 months (95% CI, 6.8-8.3) within the T-DM1 arm (n=263; HR, 0.30; 95% CI, 0.24- 0.38). The 36-month PFS charges have been 45.7% (95% CI, 38.9%-52.2%) and 12.4% (95% CI, 8.1%- 17.7%), respectively.3
DESTINY-Breast03 Part 3 Trial Design
The median investigator-assessed OS within the T-DXd arm was 52.6 months (95% CI, 48.7-not evaluable [NE]) in contrast with 42.7 months (95% CI, 35.4-NE) within the T-DM1 arm (HR, 0.73; 95% CI, 0.56-0.94). The 36-month OS charges have been 67.6% (95% CI, 61.3%-73.0%) and 55.7% (95% CI, 49.2%-61.7%), respectively. The respective 42-month OS charges have been 62.5% (95% CI, 56.2%- 68.3%) and 50.1% (95% CI, 43.6%-56.2%).
“What we knew already was that T-DXd improved each PFS and OS in contrast with T-DM1, however on the prior shows of this examine, we by no means had an precise quantity of enchancment in OS as a result of it was not reached within the therapy arms,” Tarantino defined. “Now, at this ASCO, we had the ultimate presentation of the OS that was printed concurrently in Nature Medication. It confirmed that the usage of T-DXd within the second line in contrast with T-DM1 extended OS by 10 months. That is extremely related and extremely clinically impactful to see nearly a 1-year enchancment in OS, probably the most significant finish level.”
The median follow-up was 43.0 months (vary, 0.0-62.9) within the T-DXd arm vs 35.4 months (vary, 0.0-60.9) within the T-DM1 arm. The median therapy length was 18.2 months (vary, 0.7-56.6) vs 6.9 months (vary, 0.7-55.2), respectively.
Further outcomes demonstrated that the confirmed investigator-assessed ORR was greater than doubled with T-DXd vs T-DM1, at 78.9% (95% CI, 73.5%-83.7%) vs 36.9% (95% CI, 31.0%- 43.0%), respectively. The whole response (CR) charges have been 12.6% and 4.2%, respectively. The respective median DOR charges have been 30.5 months (95% CI, 23.0-NE) and 17.0 months (95% CI, 14.1-23.7); the 36-month DOR charges have been 48.9% (95% CI, 41.3%-56.1%) and 28.7% (95% CI, 18.9%-39.2%), respectively.
By way of security, sufferers within the T-DXd and T-DM1 arms skilled any-grade drug-related treatment-emergent adversarial results (TEAEs) at charges of 98.1% and 87.4%, respectively. Sufferers in each arms skilled drug-related TEAEs of at the least grade 3 severity (48.6% vs 42.5%), critical drug-related TEAEs (13.6% vs 7.7%), drug-related TEAEs related to dose interruption (44.0% vs 18.4%), drug-related TEAEs related to dose discount (28.0% vs 15.3%), and drug-related TEAEs related to therapy discontinuation (22.6% vs 7.3%). No sufferers in both arm skilled drug-related TEAEs resulting in dying.
“These information strengthened what we already knew and strengthened the place of T-DXd in sufferers whose illness progressed after chemotherapy and trastuzumab in earlier traces for HER2-positive metastatic breast most cancers,” Tarantino mentioned. “We await [results from] the first-line trial, [the phase 3] DESTINY-Breast09 examine [NCT04784715], which is ongoing, [results of which] we might hear about inside the subsequent 12 months.”
Information From DESTINY-Breast06 to Set up T-DXd in Earlier-Line HER2-Low Illness
The open-label, multicenter DESTINY-Breast06 examine enrolled sufferers with hormone receptor–optimistic, HER2-low metastatic breast most cancers, with HER2-low standing being outlined as an immunohistochemistry (IHC) of 1+ or 2+/in situ hybridization detrimental and HER2- ultralow standing being an IHC of 0. Sufferers wanted to have obtained at the least 2 prior traces of endocrine remedy with or with out focused remedy for metastatic breast most cancers or 1 prior line for metastatic breast most cancers with development at or earlier than 6 months of initiating frontline endocrine remedy plus a CDK4/6 inhibitor or illness recurrence at or earlier than 24 months of initiating adjuvant endocrine remedy. Different inclusion standards included being at the least 18 years outdated and never having obtained prior chemotherapy for superior or metastatic breast most cancers (Determine 2).4,5
After enrollment, sufferers have been randomly assigned 1:1 to obtain 5.4 mg/kg T-DXd each 3 weeks or doctor’s alternative of capecitabine (Xeloda), nab-paclitaxel (Abraxane), or paclitaxel. Sufferers have been stratified by prior CDK4/6 inhibitor use, HER2 expression, and prior therapy with a taxane within the nonmetastatic setting.
The first finish level was PFS within the inhabitants with hormone receptor–optimistic, HER2-low illness. Secondary finish factors included OS, ORR, DOR, and PFS within the intention-to-treat (ITT) inhabitants, which comprised the HER2-low and HER2-ultralow populations, in addition to security. Determine 2.
DESTINY-Breast06 Part 3 Trial Design
“DESTINY-Breast06 was a trial that [intended to] prolong the footprint of T-DXd. This can be a drug that’s now been FDA accepted for a couple of years; it was initially [approved for] sufferers who’ve HER2- optimistic illness that’s comparatively late line, so these are sufferers whose cancers are literally pushed by the HER2 oncogene,” V. Ok. Gadi, MD, PhD, a professor within the Division of Medication, Division of Hematology/Oncology, on the College of Illinois School of Medication and the deputy director of the College of Illinois Most cancers Heart in Chicago, mentioned in an interview with OncologyLive. “Nevertheless, [with T-DXd] being an ADC, the query was, May we get the lively molecule—the chemotherapy portion of it—into cells which have decrease ranges of HER2 and see efficacy there?”
On the March 18, 2024, information cutoff, major findings from DESTINY-Breast06 offered throughout ASCO 2024 demonstrated that sufferers with HER2-low illness who obtained T-DXd (n=359) achieved a median PFS by blinded impartial central assessment of 13.2 months in contrast with 8.1 months within the doctor’s alternative arm (n=354; HR, 0.62; 95% CI, 0.51-0.74; P<.0001). Equally, the median PFS within the ITT inhabitants was 13.2 months vs 8.1 months within the T-DXd (n = 436) and the doctor’s alternative (n=430) arms (HR, 0.63; 95% CI, 0.53-0.75; P < .0001).
“Whenever you have a look at the PFS curves, they separate early, they keep separated, and that translated right into a median distinction of 5.1 months. At totally different time factors [on the PFS curves], T-DXd is comfortably above standard-of-care chemotherapy,” Gadi famous.
Furthermore, the 12-month OS charges amongst sufferers with HER2-low illness who obtained T-DXd and doctor’s alternative of therapy have been 87.6% and 81.7%, respectively (HR, 0.83; 95% CI, 0.66-1.05; P =.118). Within the ITT inhabitants, the 12-month OS charges have been 87.0% and 81.1%, respectively (HR, 0.81; 95% CI, 0.65-1.00).
Notably, the median PFS enchancment noticed with T-DXd (n=76) vs doctor’s alternative of remedy (n=76) within the inhabitants with HER2-ultralow illness was according to the general findings, at 13.2 months vs 8.3 months, respectively (HR, 0.78; 95% CI, 0.50-1.21). The 12-month OS charges amongst these sufferers have been 84.0% and 78.7%, respectively (HR, 0.75; 95% CI, 0.43-1.29).
Within the security inhabitants within the T-DXd (n=434) and doctor’s alternative (n=417) arms, sufferers skilled any-grade TEAEs at respective charges of 98.8% and 95.2%. Sufferers in each arms skilled treatment-related TEAEs (96.1percentvs 89.4%), critical TEAEs (20.3% vs 16.1%), TEAEs related to therapy discontinuation (14.3% vs 9.4%), TEAEs related to dose interruptions (48.4% vs 38.4%), TEAEs related to dose reductions (24.7% vs 38.6%), and TEAEs resulting in dying (2.5% vs 1.4%).
“There’s an opportunity that [T-DXd] will get regulatory approval to maneuver up into this line [of therapy],” Gadi mentioned.
“Then the opposite query [comes down to safety because] T-DXd is, in some methods, extra poisonous than what we use in any other case [in this setting].
Capecitabine is an exceptionally well-tolerated drug for many sufferers; T-DXd is much less so. Nevertheless, the efficacy margin is large enough that it’s tempting to take a look at this [as a treatment option]. Will probably be an individualized affected person resolution.”
“This was a optimistic trial, and we’re all enthusiastic about it. Now, how will we put this into play? How are we going to individualize [treatment] selections? There are numerous considerate issues that we should transfer by as the subsequent part of issues,” Gadi added in conclusion.
References
- FDA grants common approval to fam-trastuzumab deruxtecan-nxki for breast most cancers. FDA. Could 4, 2022. Up to date Could 11, 2022. Accessed June 19, 2024. bit.ly/3ybhZLL
- DS-8201a versus T-DM1 for human epidermal development issue receptor 2 (HER2)-positive, unresectable and/or metastatic breast most cancers beforehand handled with trastuzumab and taxane [DESTINY-Breast03]. ClinicalTrials.gov. Up to date June 12, 2024. Accessed June 19, 2024. https://basic.clinicaltrials.gov/ct2/ present/NCT03529110
- Hamilton EP, Hurvitz SA, Im SA, et al. Trastuzumab deruxtecan versus trastuzumab emtansine in sufferers with HER2-positive metastatic breast most cancers: up to date survival outcomes of DESTINY- Breast03. J Clin Oncol. 2024;42(suppl 16):1025. doi:10.1200/ JCO.2024.42.16_suppl.1025
- Examine of trastuzumab deruxtecan (T-DXd) vs investigator’s alternative chemotherapy in HER2-low, hormone receptor optimistic, metastatic breast most cancers (DB-06). ClinicalTrials.gov. Up to date April 12, 2024. Accessed June 19, 2024. https://basic. clinicaltrials.gov/ct2/present/NCT04494425
- Curigliano G, Hu X, Dent RA, et al. Trastuzumab deruxtecan (T-DXd) vs doctor’s alternative of chemotherapy (TPC) in sufferers (pts) with hormone receptor-positive (HR+), human epidermal development issue receptor 2 (HER2)-low or HER2-ultralow metastatic breast most cancers (mBC) with prior endocrine remedy (ET): major outcomes from DESTINY-Breast06 (DB-06). J Clin Oncol. 2024;42(suppl 17):LBA1000. doi:10.1200/JCO.2024.42.17_ suppl.LBA1000
