Jacob M. Sands, MD
The novel trophoblast cell-surface antigen 2 (TROP2)-directed antibody-drug conjugate datopotamab deruxtecan (Dato-DXd) vs docetaxel conferred a numerical improvement in overall survival in previously treated patients with advanced non–small cell lung cancer (NSCLC), according to the phase III, open-label, global TROPION-Lung01 trial. At the International Association for the Study of Lung Cancer (IASLC) 2024 World Conference on Lung Cancer (WCLC), Jacob M. Sands, MD, of the Dana-Farber Cancer Institute, Boston, and colleagues presented the final analysis of the second dual primary endpoint of overall survival and updated safety findings,1 which were concurrently published in the Journal of Clinical Oncology.2
Dr. Sands commented: “The results, when looking specifically at the nonsquamous cohort with a statistically significant improvement in the median progression-free survival, a substantial improvement in the overall response rate, an improvement in the median duration of response, and a favorable toxicity profile, now along with a numerical improvement in median overall survival on a par with progression-free survival benefit, support the use of Dato-DXd as a potential new therapeutic option.”
Of note, in a separate presentation, the TROPION-2 investigators reported that they have developed a new way of measuring the biomarker TROP2 that may effectively predict outcomes to Dato-DXd.3
About TROPION-Lung01
In the pivotal TROPION-Lung01 trial, patients were randomly assigned in a 1:1 ratio to receive 6 mg/kg of Dato-DXd (n = 299) or 75 mg/m2 of docetaxel (n = 305) every 3 weeks. Baseline characteristics seemed to be balanced between the arms, and follow-up data were provided for a median of 23.1 months for both.
The dual primary endpoints of the study were progression-free survival by blinded independent central review and overall survival. In prespecified subgroup analyses, progression-free and overall survival were evaluated by histology. Safety, including treatment-related adverse events, was assessed as a secondary endpoint. The trial was deemed positive if either dual primary endpoint was statistically significant.
In a prior analysis, the trial met its dual primary endpoint of improved progression-free survival with Dato-DXd vs docetaxel (median, 4.4 vs 3.7 months; hazard ratio [HR] = 0.75, 95% confidence interval [CI] = 0.62–0.91; P = .004).4 However, Dr. Sands stated, “the real benefit was noted in the nonsquamous cohort,” with a median of 5.5 months with Dato-DXd and 3.6 months with docetaxel (HR = 0.63, 95% CI = 0.51–0.79); the overall response rates were 31.2% and 12.8%, respectively.
Numerical Overall Survival Benefit
The present analysis showed a median overall survival of 12.9 months (95% CI = 11.0–13.9 months) with Dato-DXd vs 11.8 months (95% CI = 10.1–12.8 months) with docetaxel (HR = 0.94, 95% CI = 0.78–1.14; P = .530). The investigators reported a clinically meaningful trend toward prolonged overall survival with Dato-DXd in the prespecified subgroup of patients with nonsquamous histology (14.6 vs 12.3 months; HR = 0.84, 95% CI = 0.68–1.05).
“[Based on sensitivity analyses in the nonsquamous population, subsequent anticancer therapies] were not what was causing the overall survival difference,” Dr. Sands added at a WCLC press conference. “On all accounts, it really seems to be from the therapy given during the study.”
Updated Safety Findings
At the press conference, Dr. Sands also commented on the safety profile of Dato-DXd: “With the additional 11 months of follow-up, there was no change in the safety profile and no late toxicities observed. The median treatment duration for Dato-DXd compared with docetaxel was longer [4.2 vs 2.8 months]; despite that, there were fewer dose reductions [20% vs 30%] and treatment discontinuations [8% vs 12%] for treatment-related adverse events.”
The most frequently reported treatment-related adverse events with Dato-DXd were stomatitis (47% vs 16% with docetaxel) and nausea (34% vs 17% with docetaxel); they were alopecia (35% vs 32% with Dato-DXd) and neutropenia (26% vs 5% with Dato-DXd) with docetaxel. Treatment-related adverse events of grade 3 or higher were documented in 26% of patients treated with Dato-DXd vs 42% of those who received docetaxel. The most common were stomatitis (7%) and pneumonitis/interstitial lung disease (4%) with Dato-DXd, and neutropenia (23%) and leukopenia (13%) with docetaxel.
“All of [these data] together highlight [Dato-DXd] as a potential new therapeutic option for patients with nonsquamous NSCLC,” Dr. Sands concluded at the press conference. “This drug is currently in front of the U.S. Food and Drug Administration for review.”
New Way to Measure TROP2
A novel, digitally defined biomarker that determines the TROP2 normalized membrane ratio (NMR) by quantitative continuous scoring (QCS) was shown to be predictive for improved overall response rate and longer progression-free survival in TROPION-Lung01 patients treated with Dato-DXd.3 The exploratory analysis was presented at the meeting by Marina Chiara Garassino, MD, of the University of Chicago.
Marina Chiara Garassino, MD
In patients with tumors testing TROP2 QCS-NMR–positive, the objective response rate for Dato-DXd was 32.7% compared with 10.3% for docetaxel, and median progression-free survival was 6.9 months vs 4.1 months (HR = 0.57; 95% CI = 0.41–0.79). In the TROP2 QCS-NMR–negative group, response rates were 16.9% and 15.1%, respectively, and median progression-free survival was 2.9 months and 4.0 months, respectively (HR = 1.16; 95% CI = 0.79–1.70).
“This is the first TROP2 biomarker. Of note, this is the first computational pathology biomarker I recall in oncology. This will open a new era of biomarker development in lung cancer,” Dr. Garassino said. This biomarker applies only to Dato-DXd and not to other TROP2 antibody-drug conjugates, she noted.
KEY POINTS
- As previously reported, the trial met its first dual primary endpoint of improved progression-free survival with Dato-DXd vs docetaxel in previously treated patients with advanced NSCLC, with the benefit primarily driven by those with nonsquamous histology.
- Dato-DXd appeared to confer a numerical improvement in the second dual primary endpoint of overall survival, especially in patients with nonsquamous histology.
- The investigators reported no change in the safety profile of Dato-DXd.
- Taken together, these results seem to support Dato-DXd as a new option in those with nonsquamous histology who are eligible for subsequent therapy.
“It’s a very easy process. You stain the tissue with the TROP2 antibody, scan the image, and receive automated differentiation of tumor from nontumor. Then in each tumor cell, you are able to calculate the TROP2 intensity in the membrane and in the cytoplasm,” resulting in a ratio that indicates a positive or negative result, she explained during a press briefing. To work, Dr. Garassino explained, Dato-DXd must bind to the membrane and be internalized in the cytoplasm to produce a cytotoxic effect. The NMR calculation used membrane density divided by membrane density plus cytoplasm density. Patients with at least 75% of tumor cells with a measurement of TROP NMR of up to 0.56 were considered “positive.”
There were 107 patients with positive TROP2 QCS-NMR status in the Dato-DXd arm and 107 in the docetaxel arm, and 65 and 73, respectively, with a negative test.
Since Dato-DXd appears more effective in nonsquamous tumors, it was no surprise that more patients with nonsquamous histology had positive normalized membrane ratio tests, and the outcomes for these patients was much better with Dato-DXd than with docetaxel. In patients with nonsquamous tumors lacking normalized membrane ratio positivity, Dato-DXd did not improve progression-free survival over docetaxel, she noted.
Dr. Garassino emphasized that this new biomarker test applies only to Dato-DXd and not to other TROP2-directed agents. It is being incorporated into several Dato-DXd studies.
EXPERT POINT OF VIEW
Saiama N. Waqar, MBBS, MSCI
Saiama N. Waqar, MBBS, MSCI, of Washington University School of Medicine, St. Louis, served as a discussant to the session at the 2024 World Conference in Lung Cancer (WCLC) entitled “The New Generation of Cytotoxics.” She started by highlighting that, since the first U.S. Food and Drug Administration approval of docetaxel over 20 years ago, it has remained the standard of care in the second-line setting. However, this recent era in cytotoxic therapies has been marked by the emergence of several potential new “challengers,” such as datopotamab deruxtecan (Dato-DXd), plinabulin plus docetaxel, sacituzumab govitecan-hziy, and tusamitamab ravtansine.
The antibody-drug conjugate Dato-DXd targets TROP2, which Dr. Waqar emphasized is expressed in approximately 100% of adenocarcinomas and 92% of squamous cell carcinomas. The payload is an antitopoisomerase agent, she noted.
Dr. Waqar briefly summarized the prior results of the “potentially practice-changing” TROPION-Lung01 trial, which showed a progression-free survival benefit with Dato-DXd vs docetaxel in previously treated patients with advanced non–small cell lung cancer (NSCLC); it was found to be primarily driven by those with nonsquamous histology. Building upon these findings, the final analysis revealed a nonsignificant trend toward improved overall survival with Dato-DXd in the intention-to-treat population, patients with nonsquamous histology, and those with actionable genomic alterations.
“The overall survival for the docetaxel arm exceeded expectations when compared with historic controls [11.8 vs 5.7–9.6 months],” Dr. Waqar added.
Regarding safety, she highlighted that mucositis (7%) and pneumonitis/interstitial lung disease (4%) was among the most frequently reported adverse events of grade 3 or higher with Dato-DXd. “My conclusion is, if this regimen is approved, it would be a possible treatment option for patients with previously treated nonsquamous NSCLC; however, given that small but real risk of interstitial lung disease, patients with interstitial lung disease or pneumonitis should be excluded,” Dr. Waqar commented. “Further biomarker refinement is ongoing, and there are studies looking at mechanisms of resistance.”
In addition, Dr. Waqar noted that recent research efforts have focused on broadening the therapeutic potential of Dato-DXd. In particular, the ongoing phase III AVANZAR trial (ClinicalTrials.gov identifier NCT05687266) is designed to evaluate the agent in combination with platinum-based chemotherapy and immunotherapy in the first-line setting.
Upon review of all the abstracts presented during this session, Dr. Waqar concluded: “We need more cytotoxic agents with fewer toxicities, and we need to define and refine our patient populations that will derive benefit from them.”
DISCLOSURE: Dr. Sands has served as a consultant to AbbVie, Amgen, AstraZeneca, Boehringer Ingelheim, Curadev, Daiichi Sankyo, Gilead Sciences, Eli Lilly, Medtronic, Pfizer, PharmaMar, and Sanofi and has received research funding from Amgen and Harpoon. Dr. Garassino reported financial relationships with AstraZeneca, Abion, MSD International GmbH, Bayer, BMS, Boehringer Ingelheim Italia S.p.A, Celgene, Eli Lilly, Incyte, Nuvation Bio, Novartis, Pfizer, Roche, Takeda, Seattle Genetics, Mirati Therapeutics, Daiichi Sankyo, Regeneron, Merck, Blueprint, Janssen, Sanofi, AbbVie, BeiGeneius Academy, Oncohost, Medscape, Gilead Sciences, Io Biotech, and Revolution Medicines. Dr. Waqar has served on advisory boards for AstraZeneca, Gilead Sciences, Pfizer, Boehringer Ingelheim, Janssen, and Daiichi Sankyo.
REFERENCES
1. Sands J, Lisberg A, Okamoto I, et al: Datopotamab deruxtecan vs docetaxel in patients with non–small cell lung cancer: Final overall survival from TROPION-Lung01. 2024 World Conference on Lung Cancer. Abstract OA08.03. Presented September 9, 2024.
2. Ahn MJ, Tanaka K, Paz-Ares L, et al: Datopotamab deruxtecan versus docetaxel for previously treated advanced or metastatic non–small cell lung cancer: The randomized, open-label phase III TROPION-Lung01 study. J Clin Oncol. September 9, 2024 (early release online).
3. Garassino MC, Sands J, Paz-Ares L, et al. Normalized membrane ratio of TROP2 by quantitative continuous scoring is predictive of clinical outcomes in TROPION-Lung01. 2024 World Conference on Lung Cancer. Abstract PL02.11. Presented September 8, 2024.
4. Ahn M, Lisberg AE, Paz-Ares L, et al: Datopotamab deruxtecan vs docetaxel in previously treated advanced/metastatic non–small cell lung cancer: Results of the randomized phase III study TROPION-Lung01. ESMO Congress 2023. Abstract LBA12. Presented October 23, 2023.
