TROPION-LUNG01 Trial to Unveil Novel ADC Potential in Heavily Pretreated NSCLC

Preliminary research with datopotamab deruxtecan has shown a promising, unprecedented duration of response (DOR) in heavily pretreated patients with non–small cell lung cancer (NSCLC), explained Edward B. Garon, MD, who added that the ongoing TROPION-LUNG01 (NCT04656652) trial has the potential to shift the antibody-drug conjugate (ADC) into the second-line setting, replacing poorly tolerated and modestly effective single-agent chemotherapeutics. 

“If the efficacy, including the DOR data hold up, and particularly if the pulmonary toxicity can be controlled at the dose that more than half the patients on TROPION-PanTumor01 (NCT03401385) received, datopotamab deruxtecan does have the potential to change our second-line treatment approach,” said Garon, professor of medicine, David Geffen School of Medicine, and director of Thoracic Oncology, Jonsson Comprehensive Cancer Center, University of California Los Angeles.

In an interview with OncLive, Garon, who is the lead TROPION-Lung01 study author, discussed the significance of the TROPION-PanTumor01 data, the next phase of research with the ADC, and other notable advances with targeted therapy in NSCLC.

OncLive®: Has TROP2 become an important biomarker in lung cancer?

Garon: The importance of the TROP2 pathway is in some ways overshadowed by the effectiveness of the drug that we have seen to date. The reason that I say that is that datopotamab deruxtecan is a TROP2-directed ADC. The promise of an ADC is that you’re going to target your agent directly to the tumor cell via a protein of interest. The clearest example of this is with a similar compound, fam-trastuzumab deruxtecan-nxki [Enhertu] which is used in HER2-positive breast cancer, and now has a recent New England Journal of Medicine article in HER2-mutated non–small cell lung cancer [NSCLC]. TROP2 is overexpressed in lung cancers and is associated with poor prognosis, but we have had a hard time showing TROP2 to serve as a biomarker for datopotamab deruxtecan.

In fact, what has been shown at the 2021 World Conference on Lung Cancer in the overall population, which were over one-quarter of the patients in dose expansion in a heavily pretreated patient population had a benefit and over one-third of the patients with actionable genomic alterations showed benefit. It’s a little unclear how to incorporate that with the TROP2 biomarker or other factors.

What is clear is that the drug is having a very respectable response rate in heavily pretreated patients and that the DOR has also been quite good. All those things are favorable when evaluating the drug, which is currently being further evaluated in those patients with actionable genomic alterations in a single-arm study. In the patients without such mutations, there’s a randomized study of datopotamab deruxtecan vs docetaxel. That is sort of a second-line study, much earlier in the treatment paradigm compared with when patients received it as part of the [single-arm] clinical trial.

How have the TROPION-PanTumor01 data been received? 

The TROPION-PanTumor01 data are very encouraging in that in this salvage setting, with a very respectable response rate and a good DOR, which has not typically been the case with single-agent chemotherapeutics, which has been our standard approach in this setting to date. That has been encouraging. If you’re looking for a counterpoint [in terms of] what tempers enthusiasm, there were 3 patients in the study who died of interstitial lung disease that was adjudicated as being related to datopotamab deruxtecan. All those patients were [treated] at the 8-mg dose level. That dose level is no longer being evaluated as part of the program.

On one hand, it’s easy to say that perhaps we won’t be seeing that sort of toxicity now that we have gotten rid of that dose level, although we can’t have full confidence. I remain enthusiastic about the agent, because even recognizing the toxicity concern, which is real, the efficacy is particularly important in this poor prognostic group.

What are your thoughts on the ongoing TROPION-LUNG01 and TROPION-Lung05 (NCT04484142) trials?

The single-arm trial that is looking at datopotamab deruxtecan in actionable genomic alterations will guide our view of what this agent’s role is. The trial that has particularly substantial potential impact for clinical care is the TROPION-LUNG01 study, which is randomizing datopotamab deruxtecan vs docetaxel. Docetaxel has been a stubborn comparator arm; it is one that, in general, we don’t like much. The toxicity is high, and the efficacy is not that great.

Some regimens have shown improved outcomes in the United States. The addition of ramucirumab [Cyramza] to docetaxel has led to an improvement in outcomes, although it has not necessarily been included in the comparator arms of many of the studies, including the one in which second-line therapy is compared with datopotamab deruxtecan.

Looking back on the year, what has been the most notable advance in targeted therapy?

The most notable targeted therapy advance over the past year has been the approval of sotorasib [Lumakras] for KRAS G12C–mutant NSCLC care. KRAS has been a very difficult target for us to drug. To have an approval for KRAS G12C is substantial. The response rates are about 40%. The progression-free survival is certainly less than a year. It is not as efficacious as for instance osimertinib [Tagrisso] in EGFR-mutant NSCLC. That being said, the advance is notable for a couple reasons. One is this is a target that has previously not been able to be addressed and now we do have targeted therapies available for.

The other issue is that it is a substantial population, and at academic centers where we tend to have a referral bias, we certainly see more EGFR-mutant patients than KRAS G12C, particularly at a practice like mine in Southern California, where we have a large Asian population. We have had progressive smoking laws over time, but in many practices, the number of EGFR-mutant patients would be swamped by the number of KRASG12C–positive patients [because it] is a common mutation in lung cancer. The ability to have this as part of our treatment armamentarium does substantially improve outcomes for patients and will lead to improvement in the care of lung cancer patients presumably in terms of longevity, but also quality of life. The agent does have some toxicities. Compared with docetaxel, we haven’t seen randomized data there yet, although there have been studies looking at it. My anticipation is that the tolerability will be greater than docetaxel.