Clinical trialPhase 2Bladder cancerOvarian cancerCervical cancer

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 · 2024267 treated patients in 7 cohorts

Meric-Bernstam F, Makker V, Oaknin A, et al. J Clin Oncol. 2024. 42:47-58

Study type: Clinical trial
Study name: DESTINY-PanTumor02
Phase: Phase 2
Design: Single-arm, open-label, multi-cohort (basket), international trial
Sample size: 267 treated patients in 7 cohorts
Source: J Clin Oncol · 2024
Trial registration: NCT04482309

In plain words

Some cancers, whatever organ they started in, have a large amount of the HER2 protein on the cell surface. Trastuzumab deruxtecan is a drug that, like a "guided missile", attaches to HER2 and delivers chemotherapy directly into the cancer cell. In this study of people with cancers of the womb, cervix, ovary, bladder and several other cancers who had been through earlier treatments, about a third of all patients and nearly two-thirds of those with very high HER2 (IHC ‎3+‎) saw their tumour shrink. The most important serious side effect is lung inflammation, so any new cough or shortness of breath should be reported to the doctor straight away.

Key results

37.1%

Objective response in all patients

n=99; 95% CI 31.3–43.2; median duration of response 11.3 months; median PFS 6.9 months; median OS 13.4 months

61.3%

Objective response in HER2 IHC 3+ (central confirmation)

n=75; 95% CI 49.4–72.4; median duration of response 22.1 months; median PFS 11.9 months; median OS 21.1 months

Endometrial 57.5%, cervical 50.0%, ovarian 45.0%, bladder 39.0%

Objective response by cohort (all patients)

Other tumours 30.0%, biliary tract 22.0%, pancreatic 4.0% (full text)

Endometrial 84.6%, cervical 75.0%, ovarian 63.6%, bladder 56.3%

Objective response in IHC 3+ by cohort

Number of IHC ‎3+‎ patients: endometrial 13, cervical 8, ovarian 11, bladder 16 (full text)

Drugs in this study:Trastuzumab (Herceptin)Trastuzumab deruxtecan (Enhertu)

Dose and schedule cards

Trastuzumab deruxtecan (DESTINY-PanTumor02)

Unresectable or metastatic HER2-positive (IHC 3+) tumours after prior systemic treatment with no satisfactory alternative options (FDA indication, accelerated approval); in the trial, IHC 3+ or 2+Cycle length: Every 3 weeksOn the page “Cervical cancer” · Metastatic or recurrent disease: second line and beyond

Unresectable or metastatic HER2-positive (IHC 3+) tumours after prior systemic treatment with no satisfactory alternative options (FDA indication, accelerated approval); in the trial, IHC 3+ or 2+

Drug	Dose	Route	Schedule
Trastuzumab deruxtecan	5.4 mg/kg (first infusion over 90 minutes, then 30 minutes if tolerated)	IV	Day 1

Cycle length: Every 3 weeks
Duration: Until progression or unacceptable toxicity

Do not substitute for trastuzumab or trastuzumab emtansine; premedication to prevent nausea and vomiting is required. Interstitial lung disease (ILD): Promptly evaluate new respiratory symptoms, and permanently discontinue the drug for grade 2 or higher ILD. Assess blood counts before each dose and LVEF before initiation and periodically. Across the whole study, drug-related ILD occurred in 10.5% of patients.

On the page “Cervical cancer” · Metastatic or recurrent disease: second line and beyond

Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.

Treatment arms and regimens

1Trastuzumab deruxtecan (single arm)

Trastuzumab deruxtecan (T-DXd) 5.4 mg per kg of body weight, IV infusion once every 3 weeks, until disease progression or unacceptable toxicity.

Source of the regimen details: Abstract and full text of the paper (JCO 2024, open access PMC10730032): T-DXd 5.4 mg/kg every 3 weeks

Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.

Study population

Adults with locally advanced or metastatic HER2-expressing solid tumours (immunohistochemistry IHC ‎3+‎ or ‎2+‎ by local or central testing) that had progressed after at least one systemic therapy or with no suitable alternative treatment option, with ECOG 0 to 1. Seven cohorts: endometrial, cervical, ovarian, bladder, biliary tract, pancreatic and other tumours (breast, colorectal, gastric and non-small-cell lung cancers were not enrolled). Median age 62 years (23 to 85) and a median of two prior lines of therapy.

Endpoints

Primary endpoint: investigator-assessed confirmed objective response rate (ORR).

Secondary endpoints: safety, duration of response (DOR), progression-free survival (PFS) and overall survival (OS).

Safety and side effects

Drug-related grade 3 or higher adverse events occurred in 40.8% of patients (most common: neutropenia 10.9% and anaemia 10.9%). Most common drug-related adverse events: nausea 55.1%, anaemia 27.7%, diarrhoea 25.8%, vomiting 24.7% and fatigue 24.7%. Drug-related interstitial lung disease (ILD)/pneumonitis (adjudicated by an independent committee) occurred in 10.5% of patients, three cases of which were fatal. Discontinuation due to adverse events in 8.6% and dose reduction in 20.2% of patients.

Clinical significance and place in guidelines

Based on the results of this study (together with DESTINY-Lung01 and DESTINY-CRC02), on 5 April 2024 the FDA granted accelerated approval to trastuzumab deruxtecan for adults with unresectable or metastatic HER2-positive (IHC ‎3+‎) solid tumours who have received prior systemic therapy and have no satisfactory alternative treatment options; the first tumour-agnostic approval for an antibody–drug conjugate. This approval is contingent on verification of clinical benefit in a confirmatory trial. Use in IHC ‎2+‎ or ‎1+‎ tumours (outside cancers with a separate approval) remains investigational and unapproved.

Limitations

Single-arm design with no comparator group; each cohort was small (about 40 patients) and the primary endpoint was investigator-assessed. Very few patients had HER2 IHC ‎1+‎, and only the cervical cohort began enrolling IHC ‎1+‎ patients. The pancreatic cohort was closed for futility because of lack of response. HER2 status was determined by local testing in some patients.

Original article (DOI)PubMed ClinicalTrials.gov

This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.