DESTINY-CRC02 Trial Continues to Support the Use of T-DXd in HER2+ Metastatic CRC

Kanwal Pratap Singh Raghav MBBS, MD

Treatment with fam-trastuzumab deruxtecan-nxki (Enhertu; T-DXd) at a low intravenous dose showed encouraging antitumor activity and a positive benefit-risk profile for patients with HER2-positive metastatic colorectal cancer (mCRC).1 This indicates that T-DXd may be an optimal therapeutic strategy for patients with RAS/BRAF wild-type disease, who often develop resistance to standard anti-EGFR drugs, according to Kanwal Pratap Singh Raghav MBBS, MD.

T-DXd was previously evaluated in HER2-positive mCRC in the phase 2 DESTINY-CRC01 trial (NCT03384940). Results demonstrated strong and durable antitumor activity at a dose level of 6.4 mg/kg. In cohort A, which enrolled patients with HER2 immunohistochemistry (IHC) 3+ or IHC 2+/in situ hybridization positivity, the agent produced an objective response rate (ORR) of 45.3% (95% CI, 31.6%-59.6%) and a median duration of response (DOR) of 7 months (95% CI, 31.6-59.6). Although interstitial lung disease (ILD) remains an important drug-related toxicity associated with T-DXd, events were predominantly low grade.²

Primary findings from the phase 2 DESTINY-CRC02 trial(NCT04744831) presented at the2023 ASCO Annual Meeting showed that patients who received the lower 5.4-mg/kg dose of T-DXd (n = 82) experienced numerically higher responses than those with the higher 6.4-mg/kg dose (n = 40). Confirmed ORR was 37.8% (95% CI, 27.3%-49.2%) at the lower dose vs 27.5% (95% CI, 14.6%-43.9%) at the higher dose. Median DOR was 5.5 months at both dose levels, and the disease control rate was 86.6% (95% CI, 77.3%-93.1%) with the low dose and 85.0% (95% CI, 70.2%-94.3%) with the higher dose. Notably, the study was not powered to determine statistical significance between the 2 dose cohorts.

Preliminary efficacy was observed regardless of RAS mutational status and was also seen in patients previously exposed to HER2-targeted agents. The safety profile of T-DXd was consistent with prior data, although the lower dose level was deemed more tolerable.¹

“Our conclusions were that the risk-benefit profile favors the 5.4 mg/kg dose,” said Raghav, who is an associate professor in the Department of Gastrointestinal Medical Oncology, in the Division of Cancer Medicine and medical director of the Division of Ambulatory Treatment Centers, at The University of Texas MD Anderson Cancer Center in Houston.

In an interview with OncLive®, Raghav discussed data from DESTINY-CRC01 that supported the DESTINY-CRC02 trial, key efficacy and safety data from the trial, and the importance of identifying patients with HER2-positive CRC who may benefit from antibody-drug conjugates (ADCs) like T-DXd in clinical practice.

OncLive: What was the rationale for conducting the DESTINY-CRC02 trial, and how did previously reported data from DESTINY-CRC01 support the continued study of T-DXd in HER2-positive mCRC?

Raghav: The DESTINY-CRC02 study [was designed for patients with] HER2-positive metastatic CRC. This is a rare but unique [molecular] subset found in 2% to 3% of all [patients with] CRC. [HER2] is highly enriched in the RAS/BRAF wild-type population and appears to be a negative predictive biomarker for the efficacy of anti-EGFR [therapy]. Recent evidence has shown that HER2-targeted therapies work well in this subset. DESTINY-CRC01 was one of the first studies exploring the value of this ADC. This [study] was done in the RAS/BRAF wild-type population. At that time, results showed us [that T-DXd elicited] a response rate of around 45% in that population, especially the high HER2-expressing population. Another class of drugs called dual anti-HER2 inhibitors also work in this subset.

Could you discuss the main objectives of the DESTINY-CRC02 trial?

The DESTINY-CRC02 study was built [to address] 2 major questions. Number one, would a dose of [T-DXd at] 5.4 mg/kg, as opposed to the 6.4 mg/kg dose used in DESTINY-CRC01, be as effective and have a better risk benefit profile? The second [goal] was to include [patient] subsets, such as the RAS-mutant population, that can also have HER2 amplification but do not benefit from traditional HER2-targeted therapy.

Please expand on the trial design for DESTINY-CRC02.

The first stage of this trial was a randomized, non-comparative analysis between a 5.4 mg/kg dose and 6.4 mg/kg dose, [administered] every 3 weeks. Stage 2 was an expansion of the 5.4 [mg/kg dose] in additional patients. In total, about 83 patients were enrolled on the 5.4 mg/kg dose, and about 42 patients were enrolled in the 6.4 mg/kg dose [level].

What key efficacy and safety findings from this study were presented at this year’s meeting?

We presented the primary analysis and certain key secondary end points. The primary end point of the study was confirmed ORR by blinded independent confirmation. ORR [with] the 5.4 mg/kg dose was about 37.8% and was 27.5% in the 6.4 mg/kg dose [cohort]. The first message to be taken away [from these data] is that this therapy was active at both of those doses.

We also presented the [adverse effect (AE)] profile [of the agent], which appeared to favor the 5.4 mg/kg dose overall.

In the safety [analysis], the main [finding] was that bone marrow toxicity was lower for the 5.4 mg/kg dose. [This] included ILD, which is a primary concern with this agent. In fact, we did not have any grade 3 or greater ILD or pneumonitis.

Based on these findings, what next steps are planned for this research?

The next steps are to find more combinations that can help us expand the therapeutic effect of these drugs. Also, [we should] try to bring these therapies [into] earlier lines of treatment for CRC.

What is your main message for colleagues from this presentation?

The main message is that [we need] to identify this rare subset of CRC. I would encourage HER2 testing on all patients with metastatic CRC because there are now [several] good therapeutics [available], including dual anti-HER2 inhibition and ADCs. With proper application of these therapies, patients can have very good outcomes.

What other presentations from the 2023 ASCO Annual Meeting did you find exciting?

From a HER2 perspective, we have some additional analysis for other trials like [the phase 2] MOUNTAINEER [(NCT03043313) study]. There are lots of correlative [analyses] planned for this study that are also correlative for other prospective trials in the HER2[-positive] space. With appropriate correlatives, I hope that we can sub-select the population that can benefit most from these drugs.

Disclosures: Dr Raghav reported receiving institutional research grant/funding from Daiichi Sankyo, Bayer, UCB Biosciences, HiberCell, Merck, Janssen, Eisai, AbbVie, Guardant, Innovent, and Xencor; receiving honoraria from Bayer, Daiichi Sankyo, and Seagen; and serving on an advisory board for Daiichi Sankyo, Eisai/Merck, SAGA Diagnostics, Bayer, Seagen, Pfizer, and AstraZeneca.

References

1. Raghav KPS, Siena S, Takashima A, et al. Trastuzumab deruxtecan (T-DXd) in patients (pts) with HER2-overexpressing/amplified (HER2+) metastatic colorectal cancer (mCRC): primary results from the multicenter, randomized, phase 2 DESTINY-CRC02 study. J Clin Oncol. 2023;41(suppl 16):3501. doi:10.1200/JCO.2023.41.16_suppl.3501
2. Yoshino T, Di Bartolomeo M, Raghav KPS, et al. Trastuzumab deruxtecan (T-DXd; DS-8201) in patients (pts) with HER2-expressing metastatic colorectal cancer (mCRC): final results from a phase 2, multicenter, open-label study (DESTINY-CRC01). J Clin Oncol. 2022;40(suppl 4):119. doi:10.1200/JCO.2022.40.4_suppl.119