Agnostic Approval of Trastuzumab Deruxtecan Ushers in New Option for Advanced HER2+ Solid Tumors


Ronan J. Kelly, MD, MBA

Ronan J. Kelly, MD, MBA

The previous integration of HER2 testing and fam-trastuzumab deruxtecan-nxki (Enhertu) into clinical practice will ease the transition of using the antibody-drug conjugate (ADC) as a treatment for patients with various types of advanced HER2-positive solid tumors, according to Ronan J. Kelly, MD, MBA.

On April 5, 2024, the FDA granted accelerated approval to trastuzumab deruxtecan for the treatment of adult patients with unresectable or metastatic HER2-positive (immunohistochemistry [IHC] 3+) solid tumors who have received prior systemic therapy and have no satisfactory alternative treatment options.1

The regulatory decision was supported by data from 192 adult patients with previously treated, unresectable or metastatic HER2-positive solid tumors treated with the ADC in the phase 2 DESTINY-PanTumor02 (NCT04482309), DESTINY-Lung01 (NCT03505710), and DESTINY-CRC02 (NCT04744831) trials.2-4

Patients treated in DESTINY-PanTumor02 achieved an overall response rate (ORR) of 51.4% (95% CI, 41.7%-61.0%) and a median duration of response (DOR) of 19.4 months (range, 1.3 to 27.9+). In DESTINY-Lung01, the ORR was 52.9% (95% CI, 27.8%-77.0%), and the median DOR was 6.9 months (range, 4.0 to 11.7+). In DESTINY-CRC02, the ORR and median DOR were 46.9% (95% CI, 34.3%-59.8%) and 5.5 months (range, 1.3+ to 9.7+), respectively.1

“This is one of the most exciting tumor-agnostic approvals we've seen to date, and it's going to be game changing for many patients who maybe haven't had such great treatment options in the past,” Kelly explained in an interview with OncLive®.

In the interview, Kelly detailed the significance of the pan-tumor approval of trastuzumab deruxtecan; expanded on the clinical trial data that supported the approval; and explained the potential next steps for investigating this agent and other ADCs in the treatment of patients with solid tumors.

Kelly is chief of oncology at Baylor Scott & White Health – North Texas, director of the Baylor Scott & White Charles A. Sammons Cancer Center at Baylor University Medical Center, and the W.W. Caruth Jr. Endowed Chair of Immunology at Baylor University Medical Center in Dallas.

OncLive: What is the significance of the FDA approval of trastuzumab deruxtecan for patients with unresectable or metastatic HER2-positive solid tumors?

Kelly: It's another tumor-agnostic approval, but this time it is for a target that's well known throughout both academia and the community alike. That's why it's exciting, and it joins the other tumor-agnostic approvals, which validate precision medicine. Up to this point, we've had only 6 [regimens receive] FDA tumor-agnostic approval. Some of them revolve around the immuno-oncology [IO] space, [such as] pembrolizumab [Keytruda] for patients with unresectable or metastatic microsatellite instability–high or mismatch repair–deficient [dMMR] solid tumors [or] dostarlimab-gxly [Jemperli] for patients with recurrent or advanced dMMR solid tumors.

Then you have another group [of pan-tumor approvals] with more targeted agents. For [patients with solid tumors harboring] NTRK fusions, we've had [approvals for] larotrectinib [Vitrakvi] and entrectinib [Rozlytrek]. Then in [patients with solid tumors harboring] BRAF V600E mutations, we have dabrafenib [Tafinlar] plus trametinib [Mekinist]. Finally, in [patients with solid tumors harboring] RET gene fusions, we have selpercatinib [Retevmo].

However, all of these [approvals] are for relatively small populations of patients, whereas [the population of patients with HER2-positive solid tumors] is a little bit higher in terms of amplification. It's also such a well-known target. We've been targeting [HER2] in breast and gastric cancers for many years. The [pan-tumor] indication that came through used the gastric ASCO/College of American Pathologists guidelines for scoring HER2 positivity in gastric cancer. Again, pathologists throughout the [United States] are very familiar with [HER2 testing].

What was the design of the DESTINY-PanTumor02 trial, and what were the patient populations evaluated?

DESTINY-PanTumor02 was a global, multicenter, multi-cohort, open-label phase 2 study that evaluated trastuzumab deruxtecan at 5.4 mg/kg once every 3 weeks in [patients with] locally advanced or metastatic disease after at least 1 line of systemic treatment. There were 7 cohorts [that included patients with different tumor types, including] endometrial, cervical, ovarian, bladder, biliary tract, pancreatic, and [other] tumor types. The HER2 assessment was done using the gastric paradigms.

However, the actual FDA approval went beyond [data from] DESTINY-PanTumor02. It also included the DESTINY-Lung01 and DESTINY-CRC02 trials. Now we've gotten approval [for trastuzumab deruxtecan] for [select] patients with any solid tumor that's HER2-positive [IHC 3+], which is exciting. It's a game changer for many patients.

There were some exclusions [from these trials, including], patients who had known interstitial lung disease [ILD] or needed treatment for ILD; patients with active brain metastases; or patients that didn't have a good ECOG performance status of [2 or higher].

What were some of the key efficacy findings from DESTINY-PanTumor02, DESTINY-Lung01, and DESTINY-CRC02?

The major efficacy outcomes in all three of those trials were ORR and DOR. If you look at the topline data in terms of all comers in DESTINY-PanTumor02, the ORR was 51.4% and the median DOR was 19.4 months. In the DESTINY-Lung01, the ORR in all comers was 52.9% with a median DOR of 6.9 months. Finally, in DESTINY-CRC02, the ORR was 46.9% with a median DOR of 5.5 months. [These were] exciting data.

If we go back into DESTINY-PanTumor02, the median follow-up was 12.75 months. However, if you [look at] those patients that had [HER2 positivity of] IHC 3+ [n = 75], which is what the FDA approval [covers], the ORR across all cohorts was 61.3%, the median DOR was 22.1 months, the median progression-free survival was 11.9 months, and the median overall survival was 21.1 months.2

I was especially pleased to see the data in gynecologic malignancies. Those patients have not been seeing tremendous advances for years, but we saw a high magnitude of responses in those women who were IHC 3+ with endometrial [ORR, 84.6%], cervical [75.0%], and ovarian [63.6%] cancers, which is unheard of in those tumors.2 [These data are] exciting across multiple solid tumors, but they are especially exciting for gynecologic malignancies, where we really haven't seen the incremental improvements that we've seen lung cancer or breast cancer over the last number of years.

Although doctors will need to check for HER2 IHC 3+ expression, the nice thing is, most oncologists either in academia or the community know how to do this. [HER2] is not a target that we're going to have to educate pathologists on. Our pathology group [at Baylor Scott & White Charles A. Sammons Cancer Center] has already started checking [HER2 status] in every solid tumor type. They were getting ready for this approval, and now they're able to hit the ground running. We will be able to get [HER2 status] as part of our panels moving forward.

What should colleagues be cognizant of regarding the safety profile of trastuzumab deruxtecan?

The safety [data in these studies] were consistent with the established safety profile of the [trastuzumab deruxtecan]. Up to this point, we already had FDA approvals [for trastuzumab deruxtecan] in breast cancer, gastric cancer, and HER2-mutated lung cancer. We had seen the safety profile [in clinical practice], and it was consistent.

The one [adverse effect (AE)] that we always need to point out is ILD/pneumonitis. However, the good news is that we've got multidisciplinary guidelines now established for the management of this toxicity. They’ve been published, and doctors just need to follow the guidelines in terms of how to manage these particular AEs, if they occur.

The other AEs that occurred in at least 20% of [patients treated in these trials] were ones that we've seen before, [including] hematologic toxicities, nausea, fatigue, and increased aspartate aminotransferase/alanine aminotransferase. Again, there were no new safety signals in these particular studies that we hadn't seen in other tumor types, so that's reassuring.

What are the next steps for investigating trastuzumab deruxtecan as a treatment option for patients with solid tumors? Could these efforts include combination regimens?

We are fully in the era of ADCs. We've gone from the era of targeted agents to the IO era, and now we're in the era of ADCs. Question number one is: Can we give this [trastuzumab deruxtecan] to patients with lower HER2 expression? We saw data in [HER2-low] breast cancer. Can we see efficacy in other [HER2-low] tumors? That will be something that would need to be evaluated further. Then there are combination strategies, both with targeted agents and IO agents, in particular the PD-1 inhibitors. Those studies are also ongoing.

If you look into the future, I am excited about where ADCs can go. We’ve moved beyond proof of concept, and we are seeing tremendous benefit in patients. However, we've only been targeting 1 antigen with 1 antibody. Now they're developing [ADCs] with dual antibodies to see if we can overcome resistance. What about adding additional payloads? Most of the time has been 1 payload. Or can the payload be changed to be an immunologic payload that may stimulate the immune response? Above and beyond targeting HER2, we now have other ADCs in a whole realm of different targets, such as HER3 or TROP2. We've seen tremendous benefits with NECTIN-4 in other tumor types. I'm excited about where the field is going to move.

However, for trastuzumab deruxtecan, [future research will center around patients with] lower HER2 expression and combination strategies with targeted agents and IO drugs. [Over] the next couple years, we'll see the actual molecules being altered, such as dual antibodies, different payloads, different targets, and the addition of immune stimulants to see if we can alter the immune microenvironment.


  1. FDA grants accelerated approval to fam-trastuzumab deruxtecan-nxki for unresectable or metastatic HER2-positive solid tumors. FDA. April 5, 2024. Accessed May 6, 2024.
  2. Meric-Bernstam F, Makker V, Oaknin A, et al. Efficacy and Safety of Trastuzumab Deruxtecan in Patients With HER2-Expressing Solid Tumors: Primary Results From the DESTINY-PanTumor02 Phase II Trial. J Clin Oncol. 2024;42(1):47-58. doi:10.1200/JCO.23.02005
  3. Smit EF, Felip E, Uprety D, et al. Trastuzumab deruxtecan in patients with metastatic non-small-cell lung cancer (DESTINY-Lung01): primary results of the HER2-overexpressing cohorts from a single-arm, phase 2 trial. Lancet Oncol. 2024;25(4):439-454. doi:10.1016/S1470-2045(24)00064-0
  4. Raghav K, 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
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