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Antibody-Drug Conjugate Improves PFS in Pretreated Breast, Lung Cancers

— Still some unanswered questions about benefit over other drug regimens, expert says

Ƶ MedicalToday

MADRID -- Treatment with an investigational TROP2-directed antibody-drug conjugate (ADC) significantly improved progression-free survival (PFS) in patients with previously treated metastatic breast cancer and non-small cell lung cancer (NSCLC), according to two phase III trials presented here.

In TROPION-Breast01 among patients with hormone receptor (HR)-positive/HER2-negative breast cancer, median PFS by blinded independent central review was 6.9 months with datopotamab deruxtecan (Dato-DXd) compared with 4.9 months in those treated with chemotherapy (HR 0.63, 95% CI 0.52-0.76, P<0.0001), reported Aditya Bardia, MD, of Mass General Cancer Center and Harvard Medical School in Boston.

In TROPION-Lung01, the PFS benefit among the entire population of patients with previously treated NSCLC was more modest with the ADC, with a median of 4.4 months versus 3.7 months in patients treated with docetaxel (HR 0.75, 95% CI 0.62-0.91, P=0.004), noted Aaron Lisberg, MD, of the University of California Los Angeles.

Both studies were presented at the European Society for Medical Oncology (ESMO) annual congress.

The PFS benefit in the lung trial was driven by patients with non-squamous NSCLC, who had a median PFS of 5.6 months with Dato-DXd compared with 3.7 months with docetaxel (HR 0.63, 95% CI 0.51-0.78). On the other hand, patients with squamous histology had inferior PFS with Dato-DXd (median 2.8 months vs 3.9 months; HR 1.38, 95% CI 0.94-2.02).

"Clearly Dato-DXd has benefit over standard-of-care docetaxel in second-line non-squamous NSCLC, and over later-line HR-positive metastatic breast cancer after one chemotherapy," said ESMO-designated discussant Sarat Chandarlapaty, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York City.

However, its utility over -- or before or after -- other newer regimens and agents in the same space "is uncertain, and I think translational research is urgently needed if we were ultimately to deliver on the promise of these agents in the clinic," he added.

TROPION-Breast01

Patients were eligible for if they had experienced progression on or were unsuitable for endocrine therapy and had received one to two previous lines of systemic chemotherapy. The study included 732 patients (median age 54-56 years) who were randomized to Dato-DXd or an investigator's choice of chemotherapy.

PFS by investigator assessment was 6.9 months with Dato-DXd compared with 4.5 months with chemotherapy (HR 0.64, 95% CI 0.53-0.76). Objective response rates (ORRs) were 36.4% and 22.9%, respectively.

Overall survival (OS) results were not mature at the time of the analysis, but at a median follow-up of 9.7 months, there was a trend favoring Dato-DXd (HR 0.84, 95% CI 0.62-1.14), Bardia reported.

Median treatment duration was 6.7 months with Dato-DXd and 4.1 months with chemotherapy.

While there were more treatment-related adverse events (TRAEs) in the Dato-DXd arm versus the chemotherapy arm (94% vs 86%), the rate of grade ≥3 TRAEs was lower in the Dato-DXd arm (21% vs 45%). The same held true for the rates of dose interruption (12% vs 25%) and dose reduction (21% vs 30%).

The most common TRAEs in the Dato-DXd arm were stomatitis, nausea, and dry eye, most of which were low grade. In the chemotherapy arm, the most common TRAEs were neutropenia and anemia.

There were nine cases of interstitial lung disease (ILD) in the Dato-DXd arm, two of which were grade ≥3.

Chandarlapaty said that while the results of the study would lead him to prescribe Dato-DXd rather than more chemotherapy after one to two prior lines in unselected metastatic HR-positive/HER2-negative breast cancer, "it leaves several unanswered questions."

He noted there are two ADCs -- sacituzumab govitecan and trastuzumab deruxtecan -- approved for HR-positive breast cancer, adding that he had no answer as to whether he would use Dato-DXd over one of those drugs.

"Moreover, can I give these drugs in sequence?" he asked. "And would I rather prescribe Dato-DXd or some small molecule that might work in this context?"

TROPION-Lung01

included 604 patients (median age 63-64 years, 61-69% men) with advanced NSCLC who had been previously treated and were eligible for second-line therapy.

The ORR was substantially higher in patients treated with Dato-DXd compared with those treated with docetaxel (26.4% vs 12.8%). Median duration of response was 7.1 months and 5.6 months, respectively.

The ORR in patients with non-squamous NSCLC was 31.2% with Dato-DXd versus 12.8% with docetaxel, while those with squamous NSCLC had ORRs of 9.2% versus 12.7%.

The interim OS analysis showed a trend in favor of Dato-DXd in the entire study population (12.4 months vs 11.0 months; HR 0.90, 95% CI 0.72-1.13), but this had not crossed the prespecified boundary for statistical significance at the time of data cutoff.

Again, it was the non-squamous patients who were driving the greatest OS benefit (HR 0.77, 95% CI 0.59-1.01), compared with squamous NSCLC (HR 1.32, 95% CI 0.87-2.00).

The median treatment duration was 4.2 months with Dato-DXd and 2.8 months with docetaxel.

"Despite the longer treatment duration for the Dato-DXd patients, we can see a lower rate of grade 3 or higher treatment-related AEs, with the Dato-DXd patients at 25% compared with 41% for the docetaxel-treated patients," Lisberg said. In addition, there were fewer TRAEs leading to dose reductions and discontinuations in the Dato-DXd arm.

Stomatitis and nausea were the most frequent TRAEs observed with Dato-DXd, with most being grade 1 or 2, while neutropenia was more common with docetaxel.

ILD was observed in 8% of patients in the Dato-DXd arm, and 4% in the docetaxel arm. In the Dato-DXd arm, 3% of patients had grade ≥3 ILD, and there were seven adjudicated grade 5 ILD events (four of which were attributed to disease progression).

As with the breast cancer study, Chandarlapaty noted that while the results favored Dato-DXd, he was left with unanswered questions. For example, he said docetaxel plus ramucirumab (Cyramza) could be a standard in this space and it isn't known whether Dato-DXd would be comparable or superior to that combination.

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    Mike Bassett is a staff writer focusing on oncology and hematology. He is based in Massachusetts.

Disclosures

The studies were funded by Daiichi Sankyo and AstraZeneca.

Bardia reported relationships with Pfizer, Novartis, Genentech, Merck, Radius Health/Menarini, Immunomedics/Gilead, Sanofi, Daiichi Pharma/AstraZeneca, Phillips, Eli Lilly, Mersana, Foundation Medicine, and Natera.

Lisberg reported relationships with Bayer, Calithera, Daiichi Sankyo, AstraZeneca, Novocure, Eli Lilly, Oncocyte, Novartis, Regeneron, Janssen Oncology, MorphoSys, Sanofi, Molecular Axiom, Amgen, IQVIA, G1 Therapeutics, Bristol Myers Squibb, Leica Biosystems, Jazz Pharmaceuticals, Pfizer, PlatformQ, HMP Global, MJH Associates, Med Learning Group, Clinical Care Options, Physicians' Education Resource, Curio Science, Vaniam Group, Medscape, Projects in Knowledge, Aptitude Health, Dracen, WindMIL, Duality Biologics, eFFECTOR Therapeutics, LUNGevity Foundation, the Medical Oncology Association of Southern California, the Society for Immunotherapy of Cancer, and the National Cancer Institute.

Chandarlapaty reported relationships with AstraZeneca, Boxer Capital, Daiichi Sankyo, Nuvalent, SAGA Diagnostics, NeoGenomics, Lilly, eFFECTOR Therapeutics, Genesis Therapeutics, Prelude Therapeutics, Casdin Capital, Blueprint, Novartis, Totus Medicines, and Odyssey Therapeutics.

Primary Source

European Society for Medical Oncology

Bardia A, et al "Datopotamab deruxtecan (Dato-DXd) vs chemotherapy in previously-treated inoperable or metastatic hormone receptor-positive, HER2-negative (HR+/HER2-) breast cancer: Primary results from the randomized phase 3 TROPION-Breast01 trial" ESMO 2023; Abstract LBA 11.

Secondary Source

European Society for Medical Oncology

Ahn MJ, et al "Datopotamab deruxtecan (Dato-DXd) vs docetaxel in previously treated advanced/metastatic non-small cell lung cancer (NSCLC): Results of the randomized phase 3 study TROPION-Lung01" ESMO 2023; Abstract LBA 12.