Patritumab Deruxtecan Elicits Clinical Activity in Some Patients With Lung and Breast Cancer

Updated data from phase 1 and phase 1/2 trials (NCT03260491; NCT02980341) evaluating patritumab deruxtecan have shown encouraging activity in select patients with metastatic non–small cell lung cancer (NSCLC) and breast cancer.¹

These findings come from the first presentation of data from a cohort of patients with EGFR-mutated metastatic NSCLC, and a subgroup analysis by HER2 expression of patients with HER3-expressing metastatic breast cancer. Both studies were featured during 2 Presidential Sessions at the Japanese Society of Medical Oncology Annual Meeting.

In the phase 1 study which evaluated patritumab deruxtecan in heavily pretreated patients with EGFR-mutated locally advanced or metastatic NSCLC, a pooled analysis of 102 patients showed an objective response rate (ORR) of 40.2% (95% CI, 30.6-50.4), including 1 complete response (CR), 40 partial responses (PRs) and 39 cases of stable disease (SD). The disease control rate (DCR) for these patients was 78.4% (95% CI, 69.2-86.0) and the median duration of response (DOR) was 7.6 months (95% CI, 6.9-14.7). Additionally, the median progression-free survival (PFS) was 6.4 months (95% CI, 5.3-8.3) and median overall survival (OS) was 15.8 months (95% CI, 10.8-21.5).

In the phase 1/2 trial, patients with HR-positive breast cancer who were HER2-low (n = 58) had a confirmed ORR of 36.2% (95% CI, 24.0-49.9) and patients with HER2 zero (n = 39) had an ORR of 28.2% (95% CI: 15.0-44.9) in disease were observed. Among these patients, the median DOR was 7.2 months (95% CI, 5.5-NE) and 7.0 months (95% CI, 3.0-NE), the median PFS was 5.8 months (95% CI, 4.1-8.5) and 8.2 months (95% CI, 5.8-9.1) and the median OS was 13.7 months (95% CI, 8.5-20.1) and 14.6 months (95% CI, 11.0-21.0) between subgroups, respectively.

“Most patients with lung or breast cancer involved in these two early-stage trials were heavily pretreated, underscoring the need for new and innovative treatment options to help improve outcomes,” said Mark Rutstein, MD, global head, oncology clinical development, Daiichi Sankyo, in a press release. “These results further add to the growing body of evidence that targeting HER3 with patritumab deruxtecan may be a promising therapeutic option for a wide array of patients across several subtypes of metastatic lung and breast cancer.”

Patritumab deruxtecan is a specifically engineered potential first-in-class HER3-directed antibody drug conjugate (ADC) that wasgranted a breakthrough therapy designation by the FDA in December 2021 for the treatment of patients with metastatic or locally advanced EGFR-mutated NSCLC with disease progression on or after treatment with a third generation TKI and platinum-based therapies.

In the global, multicenter, open-label, two-part phase 1 trial of patritumab deruxtecan in previously treated patients with metastatic or unresectable NSCLC, dose-escalation and dose-expansion portions are being used.² The dose-escalation portion will evaluate patients with -mutated disease either with progression on osimertinib or T790M-negative after progression on erlotinib (Tarceva), gefitinib (Iressa), or afatinib (Gilotrif). The dose-expansion portion will look at patritumab deruxtecan at the recommended dose for the expansion part of 5.6 mg/kg every 3 weeks in 3 cohorts.

Cohort 1 consists of patients with locally advanced or metastatic EGFR-mutated NSCLC who experienced disease progression after taking one or more EGFR TKIs and at least 1 platinum-based chemotherapy regimen. Cohort 2 will assess patients with squamous or non-squamous NSCLC who do not harbor EGFR-activating mutations after platinum-based chemotherapy and an anti-PD-1 or anti-PD-L1 antibody regimen. Lastly, cohort 3 is evaluating patients with NSCLC who have EGFR-activating mutations including any histology other than combined small cell lung cancer (SCLC) and NSCLC. This third cohort will randomize patients in a 1:1 fashion to receive the 5.6 mg/kg regimen (cohort 3a) or an escalating up-titration regimen of patritumab deruxtecan (cohort 3b). A fourth cohort will then include patients with NSCLC and will include any histology other than SCLC or combined SCLC and NSCLC.

The primary end point of the dose-escalation cohort is to evaluate the safety and tolerability of the agent, and to determine the recommended dose for the expansion portion of the trial. For expansion cohorts 1, 2 and 3, primary end points will assess the efficacy of patritumab deruxtecan as measured by confirmed ORR, and secondary end points are investigator-assessed ORR, DCR, DOR, PFS, OS, safety and pharmacokinetics. Cohort 4 will evaluate the primary end point of relative bioavailability of clinical study vs commercial patritumab deruxtecan in cohort 3a.

A total of 264 patients were enrolled across multiple sites in Asia, Europe and North America who were heavily pretreated receiving a median of 4 prior lines of systemic therapy in the locally advanced/metastatic setting (range, 1-14). The median treatment duration was 5.5 months (range, 0.7-27.5).¹

In updated data from a pooled analysis of a phase 1 trial of patritumab deruxtecan administered at the recommended dose of 5.6 mg/kg, heavily pretreated patients with EGFR-mutated locally advanced or metastatic NSCLC in cohort 3a had promising clinical efficacy after a median follow-up of 23 months (range, 11.8-36.0).

The efficacy outcomes from this cohort were consistent with a subgroup of 78 patients previously treated with third-generation EGFR TKI and platinum-based chemotherapy. Moreover, treatment with patritumab deruxtecan elicited respondes in a number of patients across a broad range of HER3 expression and across multiple mechanisms of EGFR TKI resistance.

The confirmed ORRs of 36.4% (95% CI: 23.8-50.4) and 44.7% (95% CI: 30.2-59.9) were also seen in patients with and without a history of central nervous system (CNS) metastases, respectively.

Looking at safety, findings from this phase 1 trial were consistent with that previously observed in patients with EGFR-mutated NSCLC. Treatment-emergent adverse events (TEAEs) that were grade ≥ 3 were observed in 58 patients (56.9%). These TEAEs included platelet count decrease (26%), neutrophil count decrease (21%), fatigue (10%), anemia (9%), white blood cell count decrease (8%), nausea (7%), hypokalemia (7%), lymphocyte count decrease (7%), dyspnea (6%) and febrile neutropenia (6%). Moreover, 8 patients (7.8%) had confirmed treatment-related interstitial lung disease (ILD). However, most ILD events were low-grade, including 2 which were grade 1, 3 that were grade 2, 1 that was grade 3, and 2 that were grade 5 events.

At the data cut-off date of January 28, 2022, 8 patients remained on study treatment with patritumab deruxtecan.

“Patritumab deruxtecan demonstrated a median overall survival of more than 15 months, which is particularly impressive in heavily pretreated patients with locally advanced or metastatic EGFR-mutated non–small cell lung cancer,” said Hidetoshi Hayashi, MD, PhD, associate professor, department of medical oncology at Kindai University, Osaka, Japan, in the press release. “Further clinical evaluation of patritumab deruxtecan in EGFR-mutated NSCLC is underway.”

Then in the subgroup analysis of the open-label, global, 3-part phase 1/2 trial evaluating patients with HER2 expression in HER3-expressing metastatic breast cancer, a dose-escalation portion was utilized to determine the safety and tolerability of increasing doses of patritumab deruxtecan.³ Investigators also aimed to determine the maximum tolerated dose of the agent. In the dose-finding part of the trial, investigators looked at the safety and efficacy of patritumab deruxtecan at selected dosing levels to determine the recommended dose for the expansion portion.

Patients enrolled in the dose-escalation and dose-finding parts of the trial were required to have received 6 or fewer prior chemotherapy regimens, at least 2 of which were administered for treatment of advanced/unresectable metastatic disease. Patients must also have had 1 or more prior chemotherapeutic regimen which included a taxane, administered in the neoadjuvant, adjuvant or advanced setting, except in the dose-expansion part of the triple-negative breast cancer (TNBC) cohort of patients.

Across subgroups, patients enrolled were heavily pretreated and received a median of 7 prior lines of systemic therapy in the HR-positive, HER2-low, and HER2-zero subgroups. A median of 4 prior lines of systemic therapy were given to patients in the HR-negative, HER2-low subgroup, and 3 prior lines of systemic therapy were given in the HR-negative, HER2 zero subgroup.¹

The median duration of treatment was 5.5 months (range, 0.7-28.4) in the HR-positive, HER2-low subgroup, compared with 7.6 months (range, 1.4-22.8) in the HR-positive, HER2 zero subgroup, 4.9 months (range, 0.7-19.8) in the HR-negative, HER2-low subgroup, and 5.7 months (range, 0.7-22.5) in the HR-negative, HER2 zero subgroup.

Additional findings from this study showed that patients with TNBC had a confirmed ORR of 20.7% (95% CI, 8.0-39.7) when patients had HER2 low expression (n = 29). The ORR was 26.3% (95% CI, 9.1-51.2) in patients with HER2 zero expression (n = 19). Between these groups, the median DOR was 4.1 months (95% CI, 2.7-6.0) and 8.4 months (95% CI, 4.2-NE), the median PFS was 4.4 months (95% CI, 2.6-5.6) and 8.4 months (95% CI, 3.9-13.9), and OS was 12.7 months (95% CI, 9.2-21.8) and 16.6 months (95% CI, 9.3-23.8), respectively.

For safety, data showed that grade ≥ 3 TEAEs occurred in 99 patients (69.7%) in Japan and 21 patients (52.5%) in the United States. A total of 12 patients (8.5%) from Japan vs no patients from the United States had confirmed treatment-related ILD as determined by an independent adjudication committee. Additionally, the majority of ILD events were deemed to be low-grade, including 3 grade 1 events (2.1%), and 5 events were grade 2 (3.5%), 3 grade 3 (2.1%) and 1 grade 5 (0.7%).

At the data cut-off of August 16, 2021, 4 patients (10.6%) remained on treatment with patritumab deruxtecan.

“These data extend previous observations and demonstrate patritumab deruxtecan has shown clinical activity in patients with metastatic breast cancer and HER2-low or HER2 zero expression,” said Hiroji Iwata, MD, PhD, vice director and chief of breast oncology, Aichi Cancer Center Hospital, Nagoya, Japan, in the press release. “These data support the further evaluation of patritumab deruxtecan as a potential treatment option for breast cancer and learning more about appropriate sequencing approaches with other therapies.”

REFERENCES:

1. Patritumab deruxtecan continues to show encouraging clinical activity in distinct patient populations with metastatic lung and breast cancer in updated results of two early trials. News release. Daiichi Sankyo. March 20, 2023. Accessed March 20, 2023. https://bwnews.pr/42BwmFY

2. U3-1402 in metastatic or unresectable non-small cell lung cancer. ClinicalTrials.gov Updated February 16, 2023. Accessed March 20, 2023. https://clinicaltrials.gov/ct2/show/NCT03260491?term=U3-1402

3. Phase I/II study of U3-1402 in subjects with human epidermal growth factor receptor 3 (HER3) positive metastatic breast cancer. ClinicalTrials.gov. Updated December 12, 2022. Accessed March 20, 2023. https://clinicaltrials.gov/ct2/show/NCT02980341