CME
Physicians: Maximum of 0.25 AMA PRA Category 1 Credit™
Released: July 10, 2024
Expiration: July 09, 2025
Introduction
In this module, Matthew Gubens, MD, MS, FASCO, discusses data on combination strategies incorporating TROP-2–targeted antibody–drug conjugates (ADCs) in the treatment of advanced non-small-cell lung cancer (NSCLC), including updates from the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting.
The key points discussed in this module are illustrated with thumbnails from the accompanying downloadable PowerPoint slideset, which can be found here or downloaded by clicking any of the slide thumbnails in the module alongside the expert commentary.
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TROPION-Lung02: Dato-DXd + Pembrolizumab ± Platinum CT in Advanced NSCLC
There is a recent update of the TROPION‑Lung02 trial (NCT04526691), which evaluated Dato‑DXd plus pembrolizumab with or without platinum chemotherapy. As shown in the study schema, Cohorts 1 and 2 received Dato-DXd with pembrolizumab, and Cohorts 3-6 received Dato-DXd plus pembrolizumab with either carboplatin or cisplatin. Cohorts 3-6, as well as part of Cohort 2, included treatment‑naive patients.1
TROPION-Lung02: Best Overall Tumor Change From BL
Previously, at ASCO 2023, investigators reported on efficacy and safety observed during this trial. These waterfall plots depict the change in tumor diameter and show robust response to doublet or triplet therapy including Dato‑DXd in all patients (N = 124) and in the subgroup of 84 patients who were receiving this treatment as first‑line therapy for metastatic disease. In the first-line setting, ORR were 50% with doublet therapy and 57% with triplet therapy, although the data were not yet mature enough to report a median duration of response.1
TROPION-Lung02: Safety
The safety profile of doublet and triplet therapy with Dato-DXd in the TROPION‑Lung02 study was as expected from previous studies, with the inclusion of chemotherapy in triplet therapy not necessarily adding unexpected toxicity. However, Dato‑DXd was associated with oral mucositis and stomatitis in a significant number of patients, with grade 3 events occurring at a rate of between 6% and 8%. Interstitial lung disease was identified in approximately 17% to 22% of patients, with 3% of patients experiencing grade ≥3 events. Ocular surface toxicity was also reported in a number of patients.1
TROPION-Lung02 Subgroup Analysis: Dato-DXd + Pembrolizumab ± Platinum CT in Advanced NSCLC
At the 2024 ASCO Annual Meeting, Levy and colleagues2 presented a subgroup analysis of Dato‑DXd plus pembrolizumab with or without platinum chemotherapy in the first‑line setting for NSCLC without AGAs. As shown in the waterfall plot, the change in tumor size demonstrates a robust response rate to both doublet and triplet therapy. In addition, the PFS curve shows a median PFS of 11.1 months for doublet therapy and 6.8 months for triplet therapy.
TROPION-Lung02: Safety
Among this subgroup of patients, safety was consistent with the profile that investigators previously reported.2
TROPION-Lung04: Dato-DXd + Durvalumab ± Carboplatin in Advanced NSCLC Without AGAs
Dato-DXd is also being evaluated in the TROPION‑Lung04 study, a phase Ib trial comparing the combination of Dato‑DXd plus durvalumab with or without carboplatin in advanced NSCLC without AGAs. The bulk of these patients were treatment naive, and the primary endpoints in this initial study are safety and tolerability.3
TROPION-Lung04: Best Overall Tumor Change From Baseline in First-line Setting
Here, investigators report the overall response data in terms of change in tumor diameter from baseline. Although this study enrolled small numbers, the response rate is similar to the data we saw before: A 50% confirmed ORR with doublet therapy and a 76.9% confirmed ORR with triplet therapy. These data are encouraging and suggest that this combination merits further study.3
Select Ongoing Trials of Dato-DXd Combination Regimens in Advanced or Metastatic NSCLC
Altogether, the data from TROPION-Lung02 and TROPION-Lung04 are very promising, and we eagerly await the results of phase III registrational trials of first‑line Dato‑DXd.
In particular, the 3 arms of TROPION‑Lung07 (NCT05555732) will look at the combination of Dato‑DXd, immunotherapy, and chemotherapy vs Dato‑DXd with immunotherapy vs chemoimmunotherapy for patients with tumor PD‑L1 expression <50%. TROPION‑Lung08 (NCT05215340) is currently enrolling patients with PD‑L1 high–expressing tumors (≥50%). Participants in this study will be randomized to Dato‑DXd with pembrolizumab or pembrolizumab alone. Both TROPION-Lung07 and TROPION-Lung08 have dual primary endpoints of PFS and overall survival (OS).
Also of interest is AVANZAR (NCT05687266), which will compare the combination of Dato-DXd, durvalumab, and carboplatin to pembrolizumab and platinum-based chemotherapy. Of note, the primary endpoint encompasses PFS and OS specifically in patients whose tumors express TROP‑2.
Finally, the phase II ORCHARD trial (NCT03944772) will investigate combinations of various treatments, including Dato-DXd with osimertinib, based on patients’ tumor molecular profile.
EVOKE-02: Sacituzumab Govitecan + Pembro ± Carbo for Previously Untreated mNSCLC Without AGAs
Next, we discuss recent data on the TROP‑2–targeting ADC sacituzumab govitecan. EVOKE‑02 is a phase II study examining sacituzumab govitecan plus pembrolizumab with or without chemotherapy for patients with stage IV NSCLC without AGAs who have not had received previous systemic therapy. This study encompasses multiple cohorts, with cohorts A and B receiving sacituzumab govitecan plus pembrolizumab without chemotherapy, and cohorts C and D receiving the same treatment in addition to platinum chemotherapy. The primary endpoints of this study are ORR and dose-limiting toxicity, and secondary endpoints include disease control rate, duration of response, PFS, OS, and safety.
Investigators previously reported data from cohort A, comprising patients whose tumors have PD‑L1 expression ≥50%, and cohort B, comprising patients with <50% PD-L1 expression.4
EVOKE-02: Efficacy Summary With Sacituzumab Govitecan + Pembrolizumab
To summarize the data previously presented at the World Conference on Lung Cancer in 2023, investigators reported very encouraging first‑line results, albeit in small numbers, with an ORR of 69% in the PD-L1 high–expressing cohort and 44% in the lower-expressing cohort. At the time, the data on median duration of response were immature, but a high 6‑month duration of response rate was observed at this data cutoff.4
EVOKE-02: Antitumor Activity
This waterfall plot depicts antitumor activity of sacituzumab govitecan plus pembrolizumab among both cohorts in the first-line setting, with the dark blue bars indicating patients with high PD‑L1 expression and the light blue reflecting patients with low PD‑L1 expression. The data demonstrate responses across both cohorts.4
EVOKE-02: Treatment-Emergent AEs
Among cohorts A and B, toxicity was as expected for a treatment regimen containing sacituzumab govitecan. Of note, the rate of grade ≥3 pneumonitis was fairly low at 3%.4
EVOKE-02 Cohort A: Outcomes in 1L mNSCLC Without AGAs and PD-L1 ≥50%
At ASCO 2024, investigators presented an update on cohort A, which enrolled patients whose tumors express PD‑L1 at a level of ≥50%. The waterfall plot on the left shows a complete response in 1 patient (3.3%) and a partial response in 19 patients (63.3%), for a total response rate of approximately 67%. On the right, the PFS curve demonstrates a median PFS of 13.1 months.5
Select Ongoing Trials of Sacituzumab Govitecan Combination Regimens in Advanced or Metastatic NSCLC
Altogether, these results are encouraging, even in this small data set. I am looking forward to the results of the phase III EVOKE‑03 trial (NCT05609968), which will examine first‑line sacituzumab govitecan with pembrolizumab vs pembrolizumab alone for patients with advanced/metastatic NSCLC and high PD‑L1 expression, with dual primary endpoints of PFS and OS.
Sacituzumab Tirumotecan (MK-2870; SKB264): TROP-2–Targeted ADC
At ASCO 2024, there was also discussion of using sacituzumab tirumotecan with immunotherapy as first-line therapy. Sacituzumab tirumotecan is a TROP‑2–targeted ADC with a novel topoisomerase 1 inhibitor payload, a belotecan derivative. This compound has a high drug:antibody ratio of 7.4:1.0 and was designed to balance both stability in circulation with intracellular release of the payload.6,7
OptiTROP-Lung01 Cohort 1: Sacituzumab Tirumotecan + KL-A167 as 1L Tx for Advanced NSCLC
To that end, investigators at ASCO presented results of the phase II OptiTROP-Lung01 trial (NCT05351788), evaluating sacituzumab tirumotecan with KL‑A167, a PD‑L1 inhibitor, as first-line treatment for advanced NSCLC. This was a nonrandomized trial, with cohorts receiving sacituzumab tirumotecan at 5 mg/kg, accompanied by either 1200 mg of KL-A167 every 3 weeks or 900 mg of KL-A167 every 2 weeks. The primary endpoint of this study is investigator‑assessed ORR.7
OptiTROP-Lung01: Outcomes
The outcomes in this phase II trial were favorable with an ORR of 48.6% in patients treated every 3 weeks (cohort 1A) and 77.6% in those treated every 2 weeks (cohort 1B). The duration of response data were not yet mature, but, in cohort 1A, the median PFS was 15.4 months.7
OptiTROP-Lung01 Cohort 1B: Efficacy by Subgroup
To some extent, there was a gradient to the responses when stratified according to PD‑L1 expression, with a lower ORR of 63.2% in patients whose tumors expressed PD‑L1 <1% vs 87.0% for both patients with PD-L1 expression 1% to 49% and patients with PD-L1 expression ≥50%. Also of note, there was a fairly similar response rate in patients with nonsquamous and squamous histology (72.7% and 84.0%, respectively). Although interesting, investigators will need to continue to follow this analysis in subsequent studies to determine if these subgroup differences are significant.7
OptiTROP-Lung01: Safety
In terms of safety, the toxicity profile of this TROP-2–targeted ADC and immunotherapy combination was fairly comparable with other similar combinations. Generally, the grade ≥3 hematologic toxicities were more frequently observed with the every-2-week vs the every-3-week dosing. No grade ≥3 pneumonitis or interstitial lung disease was reported, and only 1 patient in cohort 1B had a grade 2 interstitial lung disease. Altogether, this regimen appears to have a toxicity profile consistent with other TROP‑2–targeting ADCs.7
Sacituzumab Tirumotecan + Pembrolizumab ± Carboplatin in Advanced Solid Tumors
Finally, MK-2870-004 (NCT06049212) is an ongoing open-label phase I trial evaluating sacituzumab tirumotecan as monotherapy and in combination with immunotherapy, with or without chemotherapy, for patients with untreated, advanced NSCLC. However, this is a phase I trial—the OptiTROP-Lung01 study previously discussed is a phase II trial—so I do not anticipate accrual of a phase III trial of sacituzumab tirumotecan in the near future. This will be an ADC that I will continue to follow, but the data will most likely come later than that with Dato‑DXd and sacituzumab govitecan.
Summary
In summary, future advances in the field of TROP‑2–targeted ADCs in NSCLC may come from the development of these drugs in combination with immunotherapy with or without chemotherapy, Hopefully, results in the first-line setting will be more favorable than in subsequent lines of therapy.
Here, I have discussed data that show combination regimens including both sacituzumab govitecan and Dato-DXd with a PD‑1/PD-L1 inhibitor are feasible, demonstrate reasonable safety, and exhibit encouraging antitumor activity, certainly enough to motivate the ongoing phase III trials for both of these TROP‑2–targeted ADCs.
Finally, there are other drugs being developed in this space. In particular, sacituzumab tirumotecan is certainly another promising ADC that I will keep track of over time.
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