Early first-line lung cancer data mined for datopotamab gold
The search is on for signals in front-line use, where Daiichi Sankyo and Astrazeneca have already bet big with the Trop2-targeted project.
Amy Brown
6 June, 2023
Datopotamab deruxtecan’s second-line NSCLC study Tropion-Lung01 is one of biopharma’s most keenly awaited datasets, but Daiichi Sankyo and Astrazeneca are already thinking bigger. Today Asco saw presentation of data on the antibody-drug conjugate in the first-line setting, where analysts are already talking about multi-blockbuster potential.
The partners have three large pivotal first-line trials under way already, so emerging results from the phase 1b Tropion-Lung02 Keytruda combo trial are being closely scrutinised for signs of early efficacy. Response rates are encouraging, but the dataset is still relatively early and has deteriorated slightly from the Asco abstract, which concerned an earlier cut.
The trial recruited 136 metastatic patients into first and second-line settings, who were given either datopotamab plus Keytruda or a triplet therapy that added in chemotherapy. All eyes are on that treatment-naïve cohort, where the meeting saw updated response rates of 50% with the doublet and 57% with the triplet.
An earlier abstract reported ORR of 55% and 60% respectively.
The triplet dataset is a little more mature than that for the doublet, Susan Galbraith, Astrazenca’s head of oncology, told analysts at an Asco event yesterday, adding that the data were "supportive of the pivotal phase 3s ongoing”.
The vast majority of patients have had some tumour shrinkage, she said, with good durability of response across different levels of PD-L1 expression. Median duration of response has yet to be reached.
Albeit with relatively short follow-up median progression-free survival across all patients, treated in both first and second lines, is coming in at 8.3 months for the doublet and 7.8 months for the triplet.
Ketyruda's results generated specifically in a first-line setting provide a bar to beat here. In Keynote-189 the Merck & Co drug plus chemo generated 9.4 months of mPFS in a subgroup of patients with PD-L1 expression 1-49%. In Keynote-042 Keytruda monotherapy generated mPFS of 6.9 months in patients with PD-L1 expression >50%.
It is far too soon for cross-trial comparisons, but these latest datopotamab results will help support some huge expectations for the project. Jefferies analysts have said the peak first-line opportunity for datapotamab sits at around $14bn, although the ADC would have to double PFS versus Keytruda for these sort of numbers to come into play.
Toxicity is something to watch, with interstitial lung disease – the same issue that plagues Enhertu – also seen. A 10% rate, albeit mostly mild cases and only 3% at grade 3, was seen in Tropion-Lung02. Astra maintains that ILD is more of an issue in heavily pretreated patients, something that if true should translate into manageable rates in the ongoing pivotal trials.
Safety was a concern for Massachusetts General Hospital's Dr Rebecca Heist, who discussed the Lung02 data for Asco. She questioned whether these levels of ILD and pneumonitis would be acceptable in a first-line setting. And in the absence of a runaway win on efficacy and safety in the confirmatory pivotal trials, a biomarker strategy might be important, she suggested.
Does Trop2 matter?
The ongoing pivotal trials might help answer that biomarker question. It is currently unclear whether Trop2 expression makes a difference in these patients. The protein is thought to be expressed in more than 90% of NSCLC tumours.
Daiichi confirmed to Evaluate Vantage that Tropion-Lung02 patients were not stratified by biomarker status; however, pretreatment tumour biopsies were collected for patients enrolling in the study.
Galbraith also revealed that Astra was "actively working to assess the predictive value of Trop2 biomarkers". A Trop2 diagnostic test developed by Astra is being explored in the phase 3 Avanzar study; the company told Vantage that the trial design will enable the evaluation of a Trop2 biomarker regardless of a patient's level of PD-L1 expression or tumour histology.
Otherwise, Trop2’s relevance is a work in progress. Asco saw a presentation that suggested some power at predicting a response in breast cancer, but in lung cancer it is probably up to Daiichi and Astra’s pivotal programme to provide some answers. Those are unlikely to emerge for several more years, with Astra confirming yesterday that headline readouts were not expected until at least 2024.
