At the recent European Society for Medical Oncology Congress 2023, a number of trials evaluated antibody-drug conjugates in non–small cell lung cancer.
Antibody-drug conjugates (ADCS) have emerged as a pillar of therapy across several advanced cancer types, including non–small cell lung cancer (NSCLC). However, beyond confirmatory phase 3 trials, questions about optimal agent sequencing, novel combinations, and management of their toxicities remain.
“There is a lot of excitement surrounding the potential of ADCs and it’s attributable to how they are made because these agents are not antibodies entirely, and they are not chemotherapy, and yet, they are both,” Karen L. Reckamp, MD, MS, said during an interview with Targeted Therapies in Oncology. “Further, some ADCs have specifi c biomarkers that they target, such as MET or carcinoembryonic antigen-related cell adhesion molecule 5 [CEACAM5], and there are some ADCs that are agnostic to biomarkers,” Reckamp, a professor of medicine and director, division of medical oncology at Cedars-Sinai Medical Center in Los Angeles, California.
Overall, ADCs consist of an antibody that targets a tumor epitope that is connected by a linker to a cytotoxic payload that has antitumor activity.1
ADCs across all stages of development are being explored. At the recent European Society for Medical Oncology (ESMO) Congress 2023, a number of trials were presented evaluating the agents in NSCLC.
Findings from the TROPION-Lung01 trial (NCT04656652) that evaluated the ADC datopotamab deruxtecan (Dato-DXd) vs docetaxel in previously treated patients with NSCLC showed improved median progression-free survival (PFS) rates associated with the agent, according to data presented at ESMO Congress 2023.2
In the intention-to-treat population, patients treated with Dato-DXd (n = 299) achieved a median PFS of 4.4 months (95% CI, 4.2-5.6) vs 3.7 months (95% CI, 2.9-4.2) in the docetaxel arm (n = 305). Aaron Lisberg, MD, coauthor on the study and a thoracic medical oncologist at the University of California Los Angeles, reported that this was a statistically significant improvement in PFS (HR, 0.75; 95% CI, 0.62-0.91; P = .004). The objective response rate (ORR) was 26.4% (95% CI, 21.5%-31.8%) in the treatment arm compared with 12.8% in the control arm (95% CI, 9.3%-17.1%). Investigators reported a median duration of response (DOR) of 7.1 months in the treatment arm (95% CI, 5.6-10.9) vs 5.6 months in the control arm (95% CI, 5.4-8.1).2
A key subgroup analysis further revealed a PFS benefit in almost all subgroups, with the exception of patients with squamous histology. Those subgroups who most benefitted had actionable genomic alterations (38%), non-squamous histology (63%), and brain metastases at baseline (64%).2
For patients with nonsquamous histology, median PFS was 5.6 months for patients in the Dato-DXd arm (95% CI, 4.4-7.0) compared with 3.7 months in the docetaxel arm (HR, 0.63; 95% CI, 0.51-0.78).
Patients with this histology had an ORR of 31.2% vs 12.8% with a DOR of 7.7 months vs 5.6 months, respectively.2 Patients with squamous histology did not do as well. They had a median PFS of 2.8 months (95% CI, 1.9-4.0) in the Dato-DXd arm (n = 70) vs 3.9 months (95% CI, 2.8-4.5) in the docetaxel arm (n = 73; HR, 1.38; 95% CI, 0.94-2.02). The ORR was 9.2% vs 12.7%, respectively, and the DOR was 5.9 months in the Dato-DXd arm vs 8.1 months in the docetaxel arm.2
Adjudicated drug-related interstitial lung disease of grade 3 or higher occurred in 3.4% of patients treated with Dato-DXd vs 1.4% of patients who received docetaxel. Fewer drug- related grade 3 or higher treatment-emergent adverse events (TEAEs) and AEs leading to dose reduction or discontinuation were reported with Dato-DXd vs the control arm. In the treatment arm, any grade TEAEs were 86.5% and grade 3 or greater TEAEs were 24.6%. In the control arm, any grade TEAEs was 86.9%, compared with 41.4% for grade 3 or greater TEAEs. Investigators reported no new safety signals for Dato-DXd during the trial, with the most common treatment-related adverse events (TRAEs) being stomatitis (47% in the Dato-DXd arm vs 16% in the control arm), nausea (34% vs 17%), alopecia (32% vs 35%), and neutropenia (4% vs 26%), respectively.2
“Dato-DXd is the first antibody drug conjugate to demonstrate a statistically significant improvement in PFS over docetaxel in patients with previously treated locally advanced or metastatic NSCLC,” Lisberg concluded. “The data make it very clear that the PFS benefit we have observed was primarily driven by patients with non-squamous histology both with and without actionable genomic alterations, and patients with squamous cell lung cancer did not derive the same benefit. Grade 3 or higher interstitial lung disease was observed, which highlights the need for careful monitoring and adherence to ILD management guidelines.”
Updated findings for BL-B01D1, a bispecific antibody-drug conjugate evaluated in patients with NSCLC were also presented during ESMO Congress 2023. The first-in-human phase 1 trial (NCT05194982) demonstrated encouraging efficacy in heavily pretreated metastatic/locally advanced NSCLC, especially in patients whose tumor harbors EGFR mutation. The observed toxicity was determined to be acceptable.
As of the data cutoff, 114 patients with NSCLC who progressed after standard treatment were enrolled to receive at least 1 dose of BL-B01D1. The agent was given at 2.5 mg/kg, 3.0 mg/kg, 3.5 mg/kg doses every 3 weeks on day 1 and day 8 and doses of 5.0 mg/kg and 6.0 mg/kg on day 1 every 3 weeks.3
Common TRAEs that occurred in more than 10% of patients or all grade/grade 3 or higher were anemia (59%/25%), leukopenia (59%/28%), neutropenia (51%/32%), thrombocytopenia (48%/23%), and nausea (36%/less than 1%). Investigators reported that no cases of interstitial lung disease were observed.3 In patients with EGFR mutation (n = 38), ORR was 63.2% (95% CI, 46.0%-78.2%) with 24 patients reporting a partial response (PR), and a disease control rate (DCR) of 89.5% (95% CI, 75.2%-97.1%).
In patients with EGFR wild-type, the ORR was 44.0% (95% CI, 30.0%-58.7%), with 22 patients reporting a PR, and a DCR of 94.0% (95% CI, 83.5-98.8).3
In the EGFR-mutant subgroup, all were treated with EGFR TKI previously and 89% had received prior third-generation EGFR TKI and 74% received prior platinum-based chemotherapy. In the wild-type subgroup, all received platinum-based chemotherapy, 90% were treated with prior anti–PD-1/L1 agents and platinum-based chemotherapy.3
Findings from a phase 1 dose escalation and expansion study (NCT04721015) evaluated ABBV-637 in combination with osimertinib (Tagrisso) in the second and third-line setting in patients with relapsed/refractory (R/R) NSCLC with EGFR mutation.4 ABBV637 is an ADC that includes an EGFR-targeting antibody and a BCL-XL inhibitor.
Investigators reported clinical activity and a manageable safety profile in 42 pretreated patients who were administered 12 mg/kg or 20 mg/kg of ABBV-637 every 4 weeks and osimertinib at 80 mg given daily in 28-day cycles. Primary end points were rates of TEAEs, ORR, and DCR.4
ORR in the second line was 10% (N = 42) compared with 14% in the third line. DCR was 65% in the second line compared with 73% in the third line.4 In the second-line cohort (n = 20), 10% of patients had a confirmed partial response, and in the third-line cohort (n = 22), 14% had a confirmed partial response. Half the patients had stable disease across both lines of therapy and 35% of second-line patients and 27% of third-line patients had disease progression.4
Patients were a median age of 65 years (range, 44-79) and 64% had received 2 or more prior lines of treatment. The median duration of treatment was 113 days (range, 28-288). Investigators reported that the most common TEAEs were increases in aspartate levels (38%) and alanine aminotransferase (33%), nausea (33%), and fatigue (21%).4
Fam-trastuzumab deruxtecan-nxki (Enhertu) was approved by the European Commission for patients with advanced NSCLC whose tumors harbor an activating HER2 mutation.5 The approval was based on data from the phase 2 DESTINY-Lung02 trial (NCT04644237), which showed that patients with previously treated, HER2- mutated, advanced or metastatic NSCLC treated with 5.4 mg/kg of the ADC (n = 102) experienced a confirmed overall response rate (ORR) of 49.0% (95% CI, 39.0%-59.1%) per blinded independent central review (BICR) assessment.6
Among responders, 1.0% achieved a complete response (CR) and 48.0% experienced a partial response (PR); 44.1% of patients had stable disease (SD), and 3.9% had progressive disease (PD). The disease control rate (DCR) was 93.1% (95% CI, 86.4%-97.2%). The median duration of response (DOR) was 16.8 months (95% CI, 6.4-not evaluable), and the median time to initial response (TTIR) was 1.8 months (range, 1.2-7.0).
In August 2022,7 the FDA granted accelerated approval to trastuzumab deruxtecan for adult patients with unresectable or metastatic NSCLC whose tumors have activating HER2 mutations, as detected by an FDA-approved test, and who have received previous systemic therapy. That decision was also based on findings from DESTINY-Lung02.
A phase I dose-escalation study (NCT02187848)8 evaluated tusamitamab ravtansine, an ADC that targets CEACAM5. The trial evaluated 2 schedules: intravenous tusamitamab ravtansine at 120 to 170 mg/m2 [loading dose (LD)], then 100 mg/m2 every 2 weeks (n = 28), or 120 to 190 mg/m2 fixed dose every 3 weeks (n = 15).
Both dosages demonstrated a favorable safety profile. However, in the cohort treated every 2 weeks, investigators noted 21 of 28 patients had dose-limiting toxicities (DLTs), notably keratopathy. No DLTs were observed in patients receiving tusamitamab ravtansine at lower doses (120, 135, and 150 mg/m2).
Telisotuzumab vedotin (teliso-v) targets c-Met and has a tolerable safety profile with antitumor activity as a monotherapy, according to findings from a phase 1 study (NCT02099058).9 The trial evaluated teliso-v (2.7 mg/kg once every 21 days) and erlotinib (Tarceva; 150 mg once daily) in patients with c-Met–positive NSCLC.
At data cutoff, 42 patients had enrolled with 36 deemed eligible for evaluation. Investigators reported median PFS for all efficacy-evaluable patients was 5.9 months (95% CI, 2.8-not reached) with an ORR of patients who were EGFR-M-positive (n = 28) was 32.1%. Among these patients, those who were c-Met high (n = 15) had an ORR of 52.6%. Median PFS was 6.8 months for non-T790M-positive and for those whose T790 M status was unknown, vs 3.7 months for T790M-positive.9 The most common any-grade AEs were peripheral sensory neuropathy (43%), dermatitis acneiform (38%), diarrhea (33%), and hypoalbuminemia (33%). Grade 3 or greater AEs occurred in 27 patients (64%); most common were pulmonary embolism (PE) (14%), hypokalemia (10%), and diarrhea, malignant neoplasm progression, peripheral sensory neuropathy, and hypophosphatemia (7% each).
Findings from a phase 2 trial (NCT04619004)10 evaluating paritumab deruxtecan (HER3-DXd) in patients with advanced EGFR-mutated NSCLC previously treated with an EGFR tyrosine kinase inhibitor and platinum-based chemotherapy showed notable efficacy and durable responses.
The ADC was administered to 225 patients every 3 weeks in 5.6 mg/kg doses or an uptitration regimen of 3.2 mg/kg, 4.8 mg/kg, and 6.4 mg/kg. The primary end point was confirmed ORR.10
Results revealed an ORR of 29.8% (95% CI, 23.9%-36.2%), with a median DOR of 6.4 months, a median PFS of 5.5 months, and median OS of 11.9 months.10
Treatment-emergent adverse events (TEAEs) of grade 3 or greater severity occurred in 64.9% and 28.9% of patients, respectively. The most common grade 3 or greater TEAEs were hematologic toxicities, and were reported in more than 15% of patients were thrombocytopenia (20.9%) and neutropenia (19.1%).
A phase 3 trial (NCT05338970) in patients with EGFR-mutated NSCLC after progression on an EGFR TKI is ongoing.
Although development of ADCs is promising, in community practice, the issue of toxicity is paramount, said Reckamp. Broadly, clinicians have learned to manage other toxicities associated with therapies, such as immunotherapy, but ADCs bring a unique set of challenges.
“I think that’s where we see things like interstitial lung disease and cardiac toxicity,” Reckamp said. “So, for example, the TROP-2 inhibitors can cause stomatitis that tends to be different from the stomatitis that we [traditionally] associate with chemotherapy.”
Reckamp emphasized the importance of training the staff and patients to recognize these AEs and address them appropriately before they become more challenging issues.
To date, multiple ADCs are undergoing investigation, either alone or in combination. However, identifying an optimal patient strategy and treatment sequence order needs further delineation.