Expert Point of View: Shanu Modi, MD

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Shanu Modi, MD, of the Breast Medicine Service at Memorial Sloan Kettering Cancer Center, New York, called the DESTINY-Breast03 results,1 which showed a highly significant benefit for fam-trastuzumab deruxtecan-nxki (T-DXd) over trastuzumab emtansine (T-DM1), “unprecedented.” She suggested they could change the treatment paradigm of HER2-positive metastatic breast cancer.

“In the first line, I will still treat with THP [docetaxel, trastuzumab, pertuzumab], but in the second line, T-DXd is now my preferred HER2 antibody-drug conjugate,” she said. She plans to relegate T-DM1—which has been the choice of second-line therapy for a decade—to the third line.

“If the waterfall plot from DESTINY-Breast012 was dramatic, I think the progression-free survival curves from DESTINY-Breast03 are startling, as is the hazard ratio (HR) of 0.28 and the P value of 10-22. I don’t believe I’ve seen a hazard ratio like this in HER2-positive breast cancer,” Dr. Modi continued. By investigator assessment, patients remained in remission three times longer with T-DXd than with T-DM1.

Shanu Modi, MD

Shanu Modi, MD

EMILIA,3 which led to the approval of T-DM1 in the second line, and CLEOPATRA,4 which led to the approval of pertuzumab in the first line, produced “the kind of incremental gains” that one typically sees when “one good drug is compared to another,” Dr. Modi said. “This makes the DESTINY-Breast03 results even more exceptional.”

In all predefined subgroups, benefit was “clear and convincing,” with tight confidence intervals for patients with stable brain metastases (HR = 0.3796 [95% confidence interval = 0.2267–0.6357]), who remained progression-free three times longer with T-DXd. “This is a very clinically important difference to highlight between these two agents,” she added.

Also of note, the response rate was more than doubled, and more patients achieved complete responses with T-DXd (16%) than with pertuzumab in CLEOPATRA (5.5%).4 One could speculate, Dr. Modi commented, that this could herald a large proportion of patients achieving long-term disease remission.

‘Reassuring’ Safety

DESTINY-Breast03 is also reassuring in terms of safety, according to Dr. Modi, who reminded listeners that about 16% of DESTINY-Breast012 patients developed lung toxicity. This ranged from asymptomatic grade 1 radiographic changes to symptomatic pneumonitis as well as a few rare but fatal cases of interstitial lung disease. These safety concerns led to some uncertainty as to how and when to best use T-DXd.

“If the efficacy of T-DXd is impressive, I’d say the safety from DESTINY-Breast03 is reassuring,” stated Dr. Modi. Interstitial lung disease was observed in 10.5% of patients, but 9.7% were grade 1 or 2, and none were grade 4 or 5. The less heavily pretreated population may be one reason for this improvement, but another may be that clinicians are simply better now at recognizing and managing this side effect.

“We can put many of these safety concerns aside, based on the results of the highly anticipated randomized DESTINY-Breast03 trial,” she commented. However, “vigilance and early intervention are absolutely mandatory for delivering T-DXd safely.”

Pharmacologic Differences May Explain Efficacy

“We have entered a really exciting era of next-generation antibody-drug conjugates,” Dr. Modi concluded. “T-DXd has improved and advantageous pharmaceutical properties that differentiate it from T-DM1.”

Unlike T-DM1, T-DXd has a cleavable linker that when cleaved releases the cytotoxic agent in such a way that it retains membrane permeability and thus produces a bystander effect. “It can kill neighboring cells, including those that are HER2-negative. This is a key feature in treating HER2-positive breast cancer, where we know there is heterogeneity of HER2 expression within tumors themselves,” she explained.

Future Considerations and Trials 

In closing, Dr. Modi advocated “using the best agents early, to give more patients a chance to experience their benefits.” This means prescribing T-DXd in the second line and moving T-DM1 to the third line. However, for patients with active brain metastases, she will still consider tucatinib in both the second and third lines.

Dr. Modi continued: “What we have yet to learn is whether T-DM1 will work after T-DXd, or even more broadly, what will work after T-DXd? The current data vacuum should not be a reason for withholding a better drug…. Future studies may show that sequence of delivery does affect survival with this potent antibody-drug conjugate.”

DISCLOSURE: Dr. Modi has reported financial relationships (research, consultancy, and advisory) with Novartis, AstraZeneca/MedImmune, Seattle Genetics, Daiichi Sankyo, Carrick, Eli Lilly, ­MacroGenics, and GSK.


1. Cortés J, Kim S, Chung W, et al: Trastuzumab deruxtecan (T-DXd) vs trastuzumab emtansine (T-DM1) in patients with HER2+ metastatic breast cancer: Results of the randomized phase III DESTINY-Breast03 study. ESMO Congress 2021. Abstract LBA1. Presented September 18, 2021.

2. Krop IE, Saura C, Yamashita T, et al: [Fam-] trastuzumab deruxtecan (T-DXd; DS-8201a) in subjects with HER2-positive metastatic breast cancer previously treated with T-DM1: A phase 2, multicenter, open-label study (DESTINY-Breast01). 2019 San Antonio Breast Cancer Symposium. Abstract GS1-03. Presented December 11, 2019.

3. Verma S, Miles D, Gianni L, et al: Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med. 367:1783-1791, 2012.

4. Swain SM, Miles D, Kim SB, et al: Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA): End-of-study results from a double-blind, randomised, placebo-controlled, phase 3 study. Lancet Oncol 21:519-530, 2020.


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