Pooled Analysis Supports Benefit/Risk Profile of Trastuzumab Deruxtecan in Various Advanced Cancers

The majority of independently adjudicated interstitial lung disease cases associated with the antibody-drug conjugate were low grade and occurred within the first 12 months of treatment.

According to data from a pooled analysis examining fam-trastuzumab deruxtecan-nxki (Enhertu) in several malignancies, the majority of independently adjudicated interstitial lung disease (ILD) cases associated with the antibody-drug conjugate (ADC) were low grade and occurred within the first 12 months of treatment, with lower risk of developing the effect observed in patients who were on the drug for longer than 1 year.1

Results presented during the virtual AACR Annual Meeting 2021 showed that of the 879 patients included in the pooled analysis, 15.8% (n = 139) experienced any-grade treatment-related ILD. In total, 15.5% (n = 38) of the 245 patients with HER2-positive breast cancer developed any-grade ILD with trastuzumab deruxtecan vs 11.5% (n = 17) of the 148 patients with lung cancer, 9.3% (n = 10) of the 107 patients with colorectal cancer (CRC), and 5.1% (n = 4) of the 78 patients with gastric cancer.

The majority of all patients included in the analysis experienced effects that were either grade 1 (4.6%; n = 40) or grade 2 (7.7%; n = 68) in severity (78%; n = 108/139), while 1.0% (n = 9), 0.1% (n = 1), and 2.4% (n = 21) experienced grade 3, 4, or 5 ILD, respectively.

“The [incidence of ILD] was lower in [those with] gastric cancer; however, this study began late, [therefore,] this could be due to the shorter duration of treatment for these patients. Of the patients with ILD, most had grade 1 or 2 [events],” Charles A Powell, MD, MBA, a professor of medicine, pulmonary, critical care, and sleep medicine and director of the Mount Sinai-National Jewish Health Respiratory Institute, said during a poster presentation on the findings.

Additionally, the all-grade risk of ILD was observed to decrease after 12 months of treatment with trastuzumab deruxtecan because the cumulative probability of adjudicated drug-related ILD started to plateau at this time point, according to Powell.

Of the total patients who developed ILD with the ADC, 88% experienced their first event within 12 months of treatment. The median time to adjudicated ILD onset was 5.5 months (range, <0.1-46.8 months), while the median duration of treatment was 6.90 months (range, 0.7-50.1 months). Twenty-eight percent of patients remained on treatment for more than 12 months.

Trastuzumab deruxtecan was approved by the FDA in December 2019 for the treatment of patients with unresectable or metastatic HER2-positive breast cancer who had received 2 or more prior anti-HER2 therapies in the metastatic setting.2 The ADC was also approved for patients with this disease in the United Kingdom and Europe. Moreover, in March 2020, trastuzumab deruxtecan was approved in Japan for patients with HER2-positive unresectable or recurrent breast cancer who had previously received chemotherapy and were refractory or intolerant to standard therapies.

As ILD has been identified as an important risk for patients who received treatment with trastuzumab deruxtecan,4 investigators set out to further characterize ILD and evaluate possible associated factors through a pooled analysis of 8 single-arm phase 1 and 2 studies examining the single-agent use of the ADC.

As of June 8, 2020, investigators pooled data from 879 patients who had received 1 or more doses of trastuzumab deruxtecan at either 5.4 mg/kg, 6.4 mg/kg, 7.4 mg/kg, or 8.0 mg/kg. The data were collected from all 8 single-arm monotherapy studies included in the developmental program for the ADC; 4 of these trials were phase 1 and 4 were phase 2.

The phase 1 trials included DS8201-A-J101 (NCT02564900; n = 280) and DS8201-A-A104 (NCT03383692; n = 40), which examined the ADC in multiple tumor types, as well as DS8201-A-J102 (NCT03366428; n = 51) and DS8201-A-A103 (NCT03368196; n = 12), which examined the agent in breast cancer. The phase 2 trials included DESTINY-Breast01 (NCT03248492), DESTINY-CRC01 (NCT03384940), DESTINY-Lung01 (NCT03505710), and DESTINY-Gastric02 (NCT04014075), which examined trastuzumab deruxtecan in patients with breast cancer (n = 253), CRC (n = 86), non–small cell lung cancer (n = 125), and gastric cancer (n = 32), respectively.

“It began with J101 in 2015, which preceded the establishment of the ILD adjudication committee in 2017, the guidelines for management of ILD, and the education campaign in 2019,” Powell said. “Of note, the DESTINY-Gastric02 study did not begin until 2019.”

All potential ILD cases were reviewed through an independent adjudication committee that retrospectively analyzed imaging and clinical data to confirm whether an event was ILD and whether it was associated with trastuzumab deruxtecan.

Collectively, patients included in the analysis had a median age of 58.0 years (range, 23-96), with 30.8% aged 65 years or older. The majority of patients were female (76.7%) and 41.4% were Japanese. Additionally, 54.2% of patients had an ECOG performance status of 0, while 45.6% and 0.2% had a status of 1 or 2, respectively. Fifty-eight percent of patients had breast cancer, 8.9% had gastric cancer, 16.8% had lung cancer, 12.2% had CRC, and 3.9% had another malignancy.

The patient population was heavily pretreated, having received a median of 5.0 prior regimens (range, 1-27). The majority of patients (61.1%) received the ADC at a dose of 6.4 mg/kg, while 35.8% received a 5.4-mg/kg dose and 3.1% received a dose that was greater than 6.4 mg/kg. Additionally, 46.3% of patients received treatment for a median duration of 0 to 6 months, 25.4% received the ADC for longer than 6 to 12 months, 21.8% for longer than 12 to 24 months, and 6.5% for longer than 24 months. The median number of treatment cycles was 9.0 (range, 1-67).

“All cases of potential drug-related ILD were referred to the ILD adjudication committee who determined if ILD was present, if it was related to the study drug, and the date of onset,” Powell said. “In 48.0% of cases, the onset date identified by the investigators was later than [what had been identified by] the adjudication committee; this is important because a mainstay of management of drug-related ILD is withdrawal of study drug.”

Investigators also examined systemic steroid use by grade of adjudicated drug-related ILD. Of the 80 grade 2-4 events observed with trastuzumab deruxtecan, 60.0% (n = 48) were treated with systemic steroids. Among the 21 events of grade 5 ILD reported, 76.1% (n = 16) were managed with systemic steroids. The median time from adjudicated ILD onset to start of steroid use was 21.0 days (range, 1-87).

Notably, nearly all adjudicated ILD incidence (95%; n = 141/148) occurred before December 15, 2019, which was when updated toxicity management guidelines were implemented in clinical trials, according to Powell.

“To highlight the management guideline updates, first, the mainstay management is to interrupt study drug if there is suspected ILD [and] to do clinical evaluation to identify whether there are other causes for the identified clinical abnormalities or imaging abnormalities,” Powell explained. “The guidelines have been updated to be more specific regarding the use of steroids and its duration.”

After implementing these guidelines, the incidence of grade 3 or higher ILD was significantly lower, according to Powell. Although the incidence rate of grade 3 or higher ILD was reported to be 4.5% in 2019, following the update, it dropped to 1.9% in 2020. Similarly, incidence of grade 5 ILD dropped from 2.8% in 2019 to 1.3% in 2020 and any-grade ILD decreased from 15.6% in 2019 to 6.9% in 2020. However, Powell noted that these improvements could be, in part, due to shorter treatment duration with the agent.

To evaluate potential factors associated with the time to occurrence of any-grade ILD, a stepwise, multivariate Cox regression model was used. Investigators identified the following 6 factors of interest:

  1. Patients treated in Japan vs non-Japanese countries
  2. Dose of 7.4 mg/kg or greater vs 5.4 mg/kg
  3. Baseline oxygen saturation of less than 95% vs greater than or equal to 95%
  4. Moderate or severe renal impairment at baseline vs no impairment
  5. Presence of lung comorbidities, such as asthma, chronic obstructive pulmonary disease, prior ILD or pneumonitis, pulmonary fibrosis, pulmonary emphysema, or radiation pneumonitis vs none
  6. Time since initial diagnosis of 3.9 years or greater vs less than 3.9 years

“However, given the limitations of the present analysis, which includes the heterogeneity of the patient population, the identified factors of interest [need] to be confirmed and will be further evaluated with future data in larger, more homogeneous patient populations and in randomized trials,” Powell concluded.


1. Powell CA, Modi S, Iwata H, et al. Pooled analysis of drug-related interstitial lung disease (ILD) in 8 single-arm trastuzumab deruxtecan (T-DXd) studies. Presented at: AACR Annual Meeting 2021; April 10-15, 2021; Virtual. Abstract CT167.

2. FDA approves new treatment option for patients with HER2-positive breast cancer who have progressed on available therapies. News release. FDA. Published December 20, 2019. Accessed April 12, 2021. https://bit.ly/2tzcabv

3. ENHERTU approved in Japan for treatment of patients with HER2 positive unresectable or metastatic breast cancer. News release. Daiichi-Sankyo. Published March 25, 2020. Accessed April 12, 2021. https://bit.ly/3mGvVp3

4. Modi S, Park H, Murthy R, et al. Antitumor activity and safety of trastuzumab deruxtecan in patients with HER2-low-expressing advanced breast cancer: results from a phase Ib study. J Clin Oncol. 2020;38(17):1887-1896. doi:10.1200/JCO.19.02318

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