Antibody–drug conjugates promising in advanced NSCLC
medwireNews: Three early-phase studies presented at the IASLC 2020 World Conference on Lung Cancer point to the potential of antibody–drug conjugates (ADCs) for the treatment of different populations of patients with advanced non-small-cell lung cancer (NSCLC).
Datopotamab deruxtecan for relapsed, refractory NSCLC
Alexander Spira (Virginia Cancer Specialists, Fairfax, USA) reported on the phase 1 TROPION-PanTumor01 trial of the TROP-2-directed ADC datopotamab deruxtecan (Dato-DXd), focusing on the NSCLC dose expansion cohort comprising 175 patients with stage III or IV disease who had relapsed or were refractory to standard treatment options. The majority had received prior immunotherapy (84%) and platinum-based chemotherapy (94%).
Participants were given Dato-DXd intravenously at a dose of 4 mg/kg (n=50), 6 mg/kg (n=45), or 8 mg/kg (n=80) every 3 weeks and were followed up for a median of 7.4 months.
The incidence of treatment-related treatment-emergent adverse events (TEAEs) of at least grade 3 was lower in the 4 and 6 mg/kg groups than the 8 mg/kg group, at 10% and 16%, respectively, versus 34%; this was also the case for treatment-related serious TEAEs, at rates of 8%, 9%, and 20%, respectively.
Accordingly, the rate of discontinuation due to toxicity was also lower in the 4 and 6 mg/kg than 8 mg/kg arm, at 4% and 7%, respectively, versus 15%, and the median relative dose intensity was higher, at 99.7% and 98.6% versus 93.9%.
Treatment-related interstitial lung disease (ILD) occurred in one patient each in the 4 and 6 mg/kg groups and 12 patients in the 8 mg/kg group, of whom three had a grade 5 event.
The overall response rate (ORR) by blinded review was 23%, 21%, and 25% in the 4, 6, and 8 mg/kg groups, respectively, while the corresponding disease control rates (DCRs) were 73%, 67%, and 80%, and the median progression-free survival (PFS) times were 4.3, 8.2, and 5.4 months.
The presenting author highlighted, however, that the PFS data were preliminary and noted that the shorter median PFS in the 8 mg/kg arm was likely “due to the toxicity requiring dose reductions and some patients coming off study.”
And Spira concluded: “Based on promising efficacy and safety, the 6 mg/kg dose of datopotamab has been selected for the phase 3 TROPION-Lung01 study in advanced or metastatic [NSCLC] previously treated with immunotherapy and platinum-based chemotherapy.”
Patritumab deruxtecan in EGFR-mutated NSCLC
Helena Yu (Memorial Sloan Kettering Cancer Center, New York, USA) presented data from the dose-expansion part of the phase 1 study of the HER3-directed ADC patritumab deruxtecan (HER3-DXd) in people with EGFR-mutated advanced NSCLC who had progressed on EGFR–tyrosine kinase inhibitor (TKI) therapy and platinum-based chemotherapy.
She explained that these patients have “few treatment options,” but as HER3 is expressed in more than 80% of EGFR mutation-positive tumors, it “represents a promising therapeutic target.”
In all, 57 patients received intravenous HER3-DXd at a dose of 5.6 mg/kg every 3 weeks in the dose-escalation and dose-expansion parts, and nearly half (49%) remained on-treatment at data cutoff, which was at a median follow-up of 5 months.
Among the 56 participants evaluable for efficacy, the ORR was 25%, with complete responses in 2% and partial responses in 23%, and the DCR was 70%.
Of note, HER3-DXd showed “clinically meaningful antitumor activity in patients with diverse TKI resistance mechanisms,” including on-target resistance (such as EGFR C797S mutation) and off-target resistance (such as MET amplification and HER2 mutation), reported Yu.
TEAEs of grade 3 or worse occurred in 67% of patients, with thrombocytopenia (28%) and neutropenia (19%) the most common events, while treatment-related serious TEAEs were experienced by 19%.
But the incidence of discontinuation due to TEAEs was low, at 9%, and there were no fatal treatment-related TEAEs. Three patients were deemed to have treatment-related ILD.
“These data support further clinical investigation of this HER3 directed ADC in a patient population with no available targeted therapy treatments,” concluded Yu, adding that a phase 2 trial of HER3-DXd monotherapy is currently enrolling participants.
Trastuzumab deruxtecan for HER2-overexpressing NSCLC
Kazuhiko Nakagawa (Kindai University Hospital, Osaka, Japan) shared data on trastuzumab deruxtecan (T-DXd) – an anti-HER2 ADC – in patients recruited to the HER2-overexpressing cohort of the phase 2 DESTINY-Lung01 study.
The 49 participants had received a median of three prior lines of treatment for HER2-overexpressing (immunohistochemistry score of 2+ or 3+), nonsquamous, metastatic NSCLC; 91.8% had received platinum-based chemotherapy and 73.5% had received PD-1 or PD-L1 inhibitors.
As reported by Nakagawa, approximately a quarter (24.5%) of patients achieved an objective response following treatment with T-DXd 6.4 mg/kg every 3 weeks. One patient had a complete response and the remaining 11 had a partial response. An additional 22 participants had stable disease, giving a DCR of 69.4%.
After a median follow-up of 6.1 months, the median PFS and overall survival durations were 5.4 and 11.3 months, respectively.
A total of 55.1% of participants had grade 3–5 TEAEs attributable to the study drug, while treatment-related serious TEAEs occurred in 16.3% of patients and 12.2% discontinued due to treatment-related TEAEs. One death due to toxicity was considered related to the study drug.
The presenter noted that “ILD remains a known serious risk that requires proactive monitoring and care.” There were eight cases of treatment-related ILD in the cohort, three of which were of grade 5.
In conclusion, he said that “[t]hese encouraging early efficacy results support the continued exploration of T-DXd in patients with HER2-overexpressing NSCLC.”
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