Dato-DXd Outperforms Docetaxel in Nonsquamous Lung Cancer

Aaron Lisberg, MD

In the phase 3 TROPION-Lung01 study (NCT04656652), datopotamab deruxtecan (Dato-DXd; DS-1062a), a Trop-2 directed antibody drug conjugate (ADC), induced a statistically significant improvement in progression-free survival (PFS) when given as a treatment for patients with advanced or metastatic non-small cell lung cancer (NSCLC). However, patients with squamous histology did not experience a benefit.

The phase 3 study compared Dato-DXd with docetaxel among patients with stage IIIB, IIIC, or IV NSCLC who were randomly assigned 1:1 to receive Dato-DXd 6 mg/kg every 3 weeks or docetaxel 75 mg/m2 every 3 weeks. The dual primary end points of the trial were PFS by blinded independent central review and overall survival (OS). Secondary end points of the study included overall response rate (ORR), duration of response (DOR), and safety.

In the study, patients achieved a median PFS of 4.4 months (95% CI, 4.2-5.6) with Dato-DXd compared with 3.7 months for those taking docetaxel, demonstrating a statistically significant improvement in PFS (HR, 0.75; 95% CI, 0.62-0.91; P =.004). This benefit was especially pronounced for patients with nonsquamous lung cancer, as they experienced a median PFS of 5.6 months (95% CI, 4.4-7.0) in the Dato-DXd arm (n = 229) vs 3.7 months (95% CI, 2.9-4.2) in the docetaxel arm (n = 232; HR, 0.63; 95% CI, 0.51-0.78). Additionally, Dato-DXd led to a higher ORR at 31.2% vs 12.8% in the docetaxel arm. The DOR was 7.7 months vs 5.6 months, respectively.

However, patients with squamous histology did not experience a benefit when treated with Dato-DXd vs docetaxel. The median PFS among these patients was 2.8 months (95% CI, 1.9-4.0) in the Dato-DXd arm (n = 70) vs 3.9 months (95% CI, 2.8-4.5) in the docetaxel arm (n = 73; HR, 1.38; 95% CI, 0.94-2.02). The ORR was 9.2% vs 12.7%, respectively, and the DOR was 5.9 months in the Dato-DXd arm vs 8.1 months in the docetaxel arm.

These positive results suggest Dato-DXd could be an effective treatment option for certain patients with lung cancer, particularly those with nonsquamous histology.

In an interview with Targeted Oncology^TM, Aaron Lisberg, MD, a thoracic medical oncologist at the University of California, Los Angeles (UCLA), discussed the phase 3 TROPION-Lung01 study which evaluated Dato-DXd for patients with advanced or metastatic NSCLC.

3D illustration of lungs: © Mopic - stock.adobe.com

Targeted Oncology: Can you provide some background on the phase 3 TROPION-Lung01 study?

Lisberg: The TROPION-Lung01 study was a study evaluating Dato-DXd, which is a Trop-2 directed antibody drug conjugate, vs docetaxel in patients with advanced metastatic non-small cell lung cancer eligible for second-line chemotherapy. Patients were eligible irrespective of histology, actionable genomic alteration status, or Trop-2 expression level on the tumor cell surface

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Please discuss the methods and design of the study.

Patients were randomized 1:1 to receive Dato-DXd, a Trop-2 ADC, vs docetaxel. The trial had dual primary end points of progression-free survival by blinded independent central review and overall survival. Patient characteristics were well balanced on both study arms with approximately 25% of patients evidencing squamous histology, while 17% of patients had actionable genomic alterations, the most common of which was EGFR.

What findings from the study can you highlight in regard to efficacy?

Three times more patients treated with Dato-DXd were on study at the time of data cutoff compared to those treated with docetaxel (18% vs 6%). We also saw that more than half the patients treated with docetaxel were on therapy for 3 months or less. This was in stark contrast to the Dato-DXd arm, where we saw 20% of patients were on therapy for at least 9 months, compared to less than 1 in 10 on the docetaxel arm.

The reason for treatment discontinuation was similar on both arms of the trial and median study follow-up was ~13 months for both arms. During my ESMO 2023 plenary presentation, I shared data from the trial’s two efficacy end points. For progression-free survival in the intention-to-treat population we saw a statistically significant improvement in progression-free survival in favor of Dato-DXd over docetaxel with a hazard ratio of 0.75. We also saw that the objective response rate was more than doubled in the Dato-DXd treated patients and the duration response was longer for Dato-DXd.

When look at the forest plot, we found that the vast majority of characteristics favored Dato-DXd from a PFS perspective over docetaxel. However, when we looked at histology, we saw a clear divergence in terms of that benefit, where the patients with nonsquamous disease clearly had a PFS benefit with Dato-DXd, while those patients with squamous disease did not. We also saw that the patient population with the greatest benefit from Dato-DXd were the patients with actionable genomic alterations with a PFS hazard ratio of 0.38 in favor of Dato-DXd. It is important to note that all but 3 of those patients with actionable genomic adulterations had nonsquamous histology.

We then took a deeper dive into this dichotomy in terms of PFS benefit based on histology by looking at two Kaplan-Meier curves. What we saw is that in the nonsquamous population a clear separation in the Kaplan-Meier curves for PFS in favor of Dato-DXd was observed with a hazard ratio 0.63, a median progression-free survival improvement for Dato-DXd vs docetaxel of 1.9 months, objective response rate almost 3 times higher in a Dato-DXd-treated patients than docetaxel treated patients, and a longer duration of response. We saw the exact opposite in squamous patients, suggesting that in an unselected manner, Dato-DXd does not appear to be a superior therapy with respect to PFS over docetaxel for our patients with squamous disease.

What questions arose following the release of these data?

One important question that arose was whether the Dato-DXd efficacy benefit seen in the nonsquamous population was entirely driven by the actionable genomic alteration population and the data suggests this was not the case. Specifically, we showed that the progression-free survival hazard ratio for patients with nonsquamous disease that did not have actual genomic alterations was of 0.71, suggesting that nonsquamous patients, both with and without actionable genomic alteration, are deriving a PFS benefit from Dato-DXd over docetaxel. We then looked at the second efficacy end point, which was overall survival. There were 2 overall survival analyses planned on trial. I presented the intention-to-treat overall survival analysis at the interim time point and there is a final overall survival analysis that has not occurred yet and will be presented at a future meeting.

What were the overall survival results observed?

In terms of the interim overall survival analysis in the intention-to-treat population, what we saw was a trend in favor of Dato-DXd over docetaxel. This did not cross the prespecified boundary for statistical significance. However, when we looked a little closer at the histologic breakdown, since we knew it was so informative in the PFS data, we saw the same thing. We saw the OS benefit in favor of Dato-DXd appears to be primarily driven by the nonsquamous patients where the hazard ratio was 0.77. Again, squamous patients do not appear to be deriving an overall survival benefit from Dato-DXd as the hazard ratio was greater than 1.

What were the safety findings from the study?

From a high level, it appears the Dato-DXd is better tolerated than docetaxel. Grade 3 or higher treatment-related adverse events occurred at a lower rate in the Dato-DXd arm compared with docetaxel, 25% of patients compared with 41%. This was despite a longer duration of therapy in the Dato-DXd-treated patients.

We then looked at specific treatment-related adverse events on trial. The most common treatment-related adverse events experienced by patients treated with Dato-DXd were stomatitis and nausea. We do know that bone marrow suppression is problematic with docetaxel, and we found that febrile neutropenia and neutropenia, which are very common with docetaxel, were much less common with Dato-DXd. Importantly, the safety data that I presented did not show any new safety signals with Dato-DXd.

All those things being said, there certainly are some unique toxicities we need to be aware of with Dato-DXd. I talked about the adverse events of special interest during my [European Society of Medican Oncology 2023 Annual Congress] presentation, and their 4 categories, the first of which was an umbrella term for stomatitis or oral mucositis, and 54% of patients treated with Dato-DXd had an event associated with stomatitis or oral mucositis. That said, the vast majority [of] these events were low-grade, as only 6% were grade 3 or higher. Most importantly, when we are thinking about these events, they did not interfere with the investigators’ ability to administer the drug effectively to patients, as less than 1% of these events were associated with dose discontinuation.

Ocular toxicities do occur with Dato-DXd. They occurred in 19% of patients treated with Dato-DXd, but again, typically low-grade, 2 or lower, increased dry eyes.

One of the big toxicities that I focused on, because I think it is relevant to our patients with lung cancer, is [interstitial lung disease (ILD)]. We know that ADCs with the DXd payload, such as trastuzumab, do have ILD associated with them. What we found on this trial was there was an independent adjudication committee that looked at all potential ILD events found that 8% of patients treated with Dato-DXd had an any-grade ILD event and that 3% of those events were grade 3 or higher. There were 7 events that were grade 5. To contextualize those 7 grade 5 ILD-adjudicated events with Dato-DXd, in 4 of those 7 patients, the primary cause of death assessed on site by the investigator was attributed to disease progression. Finally, infusion-related reactions do occur with Dato-DXd. They occurred in 8% of patients treated with Dato-DXd and 8% of the patients treated with docetaxel. The majority were grade 2 or less, with the exception of 1 grade 3 event.

What are the main takeaway messages from this study?

This was a positive trial and Dato-DXd is the first ADC in advanced/metastatic NSCLC to show a statistically significant improvement in PFS over docetaxel. That said, when we looked at the data a little closer, it was clear that histology informs that benefit. The PFS benefit we observed was primarily driven by patients with nonsquamous disease both with and without actionable genomic alterations. The patients with squamous disease clearly are not benefiting from Dato-DXd over docetaxel. The toxicity profile appeared to be globally better for Dato-DXd, but there are specific adverse events of special interest to be monitored for, especially ILD. That is something to be aware of.

The overall survival data showed a trend in favor of Dato-DXd over docetaxel on the intention-to-treat population, but again, what we saw was that it was primarily driven by the non-squamous patients. There is a final overall survival analysis that we will see at a future time point. The take home here was the Dato-DXd was a better tolerated drug from a global perspective than docetaxel, although there are some clear differences in terms of toxicity profile, and it appears to be a potential new meaningful therapy for patients with nonsquamous metastatic advanced non-small cell lung cancer eligible for second-line chemotherapy.

What do you think is important for a community oncologist to know about these data?

I suspect that anyone who treats advanced metastatic non-small cell lung cancer uses docetaxel with or without ramucirumab [Cyramza] at a pretty high rate. After progression on chemotherapy and immunotherapy, docetaxel is our standard of care. Each provider’s experience with docetaxel will be a little different, but historically it is associated with limited efficacy and substantial toxicity. For several decades now we have been trying to do better for our patients. I think the takeaway here is that it appears that we have.

Dato-DXd appears to have superior progression-free survival over docetaxel in advanced/metastatic NSCLC. That magnitude of benefit in the overall study population is probably not enough to move the needle. However, when we look at the nonsquamous population, I believe it is, and I think that this is a potential new therapy for our nonsquamous patients.

Within that context, getting familiar with these drugs. In community oncology, the antibody-drug conjugate paradigm is not a new one, and neither [are] Trop-2 directed antibody-drug conjugates. I suspect that many community colleagues already have experience with Trop-2 ADCs, and likely good experience. These drugs are well-tolerated. I think that having more options for our patients with metastatic non-small cell lung cancer is a good thing and hopefully will lead to better outcomes in the long term.

REFERENCE:

Ahn MJ, Lisberg A, Paz-Ares L, et al. Datopotamab deruxtecan (Dato-DXd) vs docetaxel in previously treated advanced/metastatic (adv/met) non-small cell lung cancer (NSCLC): results of the randomized phase 3 study TROPION-Lung01. Ann Oncol. 2023;34(suppl 2):S1305-S1306. doi:10.1016/j.annon