Segmenting the Utility of ADCs in NSCLC: How These Agents Are Affecting Second-Line Standards

Benjamin P. Levy, MD

Keeping investigators on the edge of their seats, new data from clinical trials evaluating the antibody-drug conjugates (ADCs) datopotamab deruxtecan (Dato-DXd) and fam-trastuzumab deruxtecan-nxki (T-DXd, Enhertu) continue to impress, with Dato-DXd earning acceptance from the FDA in February 2024 for a biologics license application (BLA) seeking approval of the agent for the treatment of patients with locally advanced or meta- static nonsquamous non–small cell lung cancer (NSCLC) following prior systemic therapy.¹

“These ADCs work well in patients with genomic alterations, [and] not just T-DXd but [with] Dato-DXd we’ve witnessed activity that we did not think would happen,” Benjamin P. Levy, MD, said in an episode of OncLive Insights. “It’s an exciting time, it’s a complicated time, but being vigilant in [identifying] the right mutation, doing the right testing, giving the drug—at least right now at the time of disease progression—and moni- toring for toxicities like interstitial lung disease [ILD] are critical. That is going to improve the patient journey—it’s going to improve quality of life—and we’re going to begin again to move this field forward, not just with immunotherapies or targeted therapies, but also with ADCs.”

During the program, Levy, an associate professor of oncology and clinical director of medical oncology at Johns Hopkins Sidney Kimmel Cancer Center at Sibley Memorial Hospital in Washington, DC, detailed how these ADCs are shifting the HER2-mutated NSCLC treatment paradigm and he highlighted the efficacy seen in patients with brain metastases and squamous vs nonsquamous histology. Key adverse effects (AEs) for clinicians to monitor include stomatitis with Dato-DXd and ILD for not only T-DXd, but all ADCs as well, according to Levy.

ADCs Make Waves in HER2-Mutated NSCLC

“We’ve historically done a poor job drugging HER2 mutations in lung cancer. We’ve had tyrosine kinase inhibitors [TKIs] or monoclonal antibodies that have had underwhelming results when we’ve looked at them as a single agent or even in combination with chemotherapy. Fortunately, T-DXd [came along],” Levy said.

Data from the phase 2 DESTINY-Lung01 (NCT03505710) trial revealed that patients with HER2-overexpressing disease who received T-DXd 6.4 mg/kg (n=49) achieved an objective response rate (ORR) of 26.5% (95% CI, 15.0%- 41.1%); when stratified by HER2 expression by immunohistochemistry (IHC), patients with an IHC of 3+(n=10) experienced an ORR of 20.0% (95% CI, 2.5%-55.6%) compared with 28.2% (95% CI, 15.0%-44.9%) for those with an IHC of 2+(n=39). When patients were treated with T-DXd at 5.4 mg/kg (n=41), the confirmed ORR was 34.1% (95% CI, 20.1%-50.6%) and results varied for those with IHC 3+(n=17) and 2+(n=24) disease—the ORRs were 52.9% (95% CI, 27.8%-77.0%) vs 20.8% (95% CI, 7.1%-42.2%), respectively.²

“What we learned from DESTINY-Lung01 is that overexpression doesn’t seem to predict response the way a HER2 mutation does,” Levy explained. “[Also], we need to remember that HER2 alterations come in many sizes, shapes, and forms. There’s HER2 overexpression, which is the most common alteration in lung cancer and is [identified] by IHC. There is also HER2 amplifi- cation, which can be [identified] by fluorescence in situ hybridization [FISH] or next-generation sequencing. [The third HER2 alteration is] theHER2 exon 20 insertion mutation and it’s import- ant [to note] that, for now, the HER2 exon 20 insertion mutation predicts efficacy for the ADC T-DXd—we need to make sure that patients we deliver this ADC to have that alteration. It’s not yet approved for HER2 overexpression or HER2 amplifications but is specifically approved for HER2 exon 20 insertions.”

When data from DESTINY-Lung01 was eval- uated in patients with HER2 mutations (n=91), most of whom had exon 20 insertions (86%), the confirmed ORR for patients treated with 6.4 mg/kg of T-DXd was 55% (95% CI, 44%-65%) and the median duration of response was 9.3 months (95% CI, 5.7-14.7).²

“This changed the game for us. The challenge with this study was that although it showed the highest response rates we’ve ever seen in HER2-mutated lung cancer, unfortunately, the 6.4 mg/kg dose led to a high rate of ILD—26% of patients had ILD at the 6.4 mg/kg dose. That led to perhaps the more important phase 2 DESTINY-Lung02 [NCT04644237] study,” Levy said. “What we’ve learned from DESTINY-Lung02 is that the dose [of T-DXd] is 5.4 mg/kg, not 6.4 mg/kg. Now we have this approved and we’re using it in clinic.”

T-DXD Takes the HER2-MUTATED Lung Cancer Field by Storm

As the first ADC approved by the FDA in lung cancer and the first drug approved by the agency in HER2-mutant NSCLC, investigators are looking to determine T-DXd’s optimal place in the treatment paradigm for patients with HER2 mutations.³

“For now, patients with this mutation should receive chemotherapy first. Currently, the drug is approved in the second line, so patients get chemotherapy first, and then once there’s disease progression, T-DXd 5.4 mg/kg in the second line [can be given]. We will have other studies coming out evaluating T-DXd vs chemotherapy in the first line because all of us believe that this drug should move first,” Levy said. “But for now, this drug is after disease progression on chemotherapy for patients with a HER2 mutation, not HER2 overexpression or HER2 amplification.”

Reinforcing the importance of genetic testing, Levy noted that finding HER2 mutations is key. HER2 dysregulations have been described as occurring in NSCLC as gene mutations (1%-4%), gene amplifications (2%-5%), and protein over-expression (2%-30%).⁴ However, as Levy explained, research has shown these should be regarded as 3 distinct subtypes of NSCLC.

He also noted that molecular testing in the advanced and early-stage settings is key as there are approvals in the adjuvant setting for targeted therapies. In addition to liquid biopsy, he stressed that tissue biopsy must be completed for patients with advanced nonsquamous NSCLC and that single-gene panels are not enough—RNA- and DNA-based testing should be performed, and clinicians should confirm that the assay they are using tests for both DNA and RNA. Ensuring an adequate sample is collected, whether it be by fine-needle aspiration or core biopsy, should also be top of mind, according to Levy.

“We know a couple of things from publications on liquid biopsies,” he explained. “Number one is there’s a high concordance rate—if you have the alteration in the blood, you’re going to have it in tissue because the DNA is the same. Number two is that if you have a positive result in the blood, you do not need to wait for the tissue to come back and you can move forward with executing a plan based on that alteration discovered in the plasma. The third thing is a negative result in plasma tells you nothing [because] if you don’t have anything in the plasma, you can still have it in the tissue. These are complementary.”

TROP2-Directed ADCs: a Class of Their Own

Dato-DXd has emerged as another promising ADC in lung cancer, as the TROP2-directed agent was the first ADC to demonstrate a statistically significant improvement in progression-free survival (PFS) vs docetaxel for patients with previously treated, locally advanced or metastatic NSCLC. Data from the phase 3 TROPION-Lung01 (NCT04656652) trial showed that patients who received Dato-DXd (n=299) achieved a median PFS of 4.4 months (95% CI, 4.2-5.6) compared with 3.7 months (95% CI, 2.9-4.2) for those treated with docetaxel (n=305; HR, 0.75; 95% CI, 0.62-0.91; P=.004). The ORRs were 26.4% (95% CI, 21.5%-31.8%) vs 12.8% (95% CI, 9.3%- 17.1%), respectively.⁵

“The phase 1 TROPION-PanTumor01 study [NCT03401385] told us a couple of things,” Levy explained. “[There were] encouraging response rates in a highly pretreated group of patients and we need to be mindful of stomati- tis. Fast forward to TROPION-Lung01—can we beat out docetaxel? We saw single-agent activity in TROPION-PanTumor01 as [the ORR] was 26% and there was durability of responses. The dose that was selected from that phase 1 study was 6 mg/kg. It made a lot of sense to look at Dato- DXd vs docetaxel in the second line given that docetaxel remains the standard of care and we need to do better.”

In addition to TROPION-PanTumor01 and TROPION-Lung01, the phase 1 TROPION-Lung02 (NCT04526691) and phase 2 TROPION-Lung05 (NCT04484142) studies were initiated to further evaluate Dato-DXd.6,7 The agent is exam- ined as monotherapy in TROPION-Lung05 and in combination with immunotherapy with or without platinum-based chemotherapy in TROPION-Lung02.

“These drugs [have] activity in the second line and we’ll see what happens if they get approved, but we’re going to start moving them up to the front line to see if they can replace platinum, even,” Levy said. “We’ll have to see how this plays out in the future, and how these TROP2 ADCs may work in patients [because] we don’t have the right biomarker yet. [Based on the data] from TROPION-PanTumor01 [and TROPION-Lung01], TROP2 overexpression doesn’t seem to matter—the higher the expression, it doesn’t seem to matter in its ability for that to predict response. As it stands now, we don’t have a biomarker for Dato-DXd and it may be an all-comer approach. TROP2 expression does not seem to predict efficacy from [these] studies.”

Breaking it Down by Histology: TROPION-LUNG01

Although benefit was observed in the intention- to-treat (ITT) population of TROPION-Lung01 with Dato-DXd vs docetaxel, the PFS benefit
was mainly driven by patients with nonsqua- mous histology. Among patients with and without actionable gene alterations, those with nonsqua- mous histology who received Dato-DXd (n=229) achieved a median PFS of 5.6 months (95%CI, 4.4-7.0) vs 3.7 months (95% CI, 2.9-4.2) for those given docetaxel (n=232; HR, 0.63; 95% CI, 0.51-0.78).⁵

In the group of patients with squamous histology, those who received Dato-DXd (n=70) experienced a median PFS of 2.8 months (95% CI, 1.9-4.0) compared with 3.9 months (95% CI, 2.8-4.5) for patients treated with docetaxel (n=73; HR, 1.38; 95% CI, 0.94-2.02). Further, for patients without actionable genomic alterations and nonsquamous histology, benefit was also observed with Dato-DXd vs docetaxel (HR, 0.71; 95% CI, 0.56-0.91).

“When we look specifically at the patients with squamous disease, there didn’t seem to be a bene- fit at all. In fact, if you look at the Kaplan-Meier curves, [patients who received] docetaxel seemed to do better than those treated with Dato-DXd. This was a new signal and a new finding for us. When we looked at the OS in the ITT analysis, the HR was 0.90 and, once again, it seemed like when you broke down the HR by histology, the benefit was restricted to the patients with nonsquamous disease, not squamous. We still have a lot of work to do to try to understand this,” Levy said.

The interim OS findings favor the ADC over docetaxel, but OS data are still immature. However, the FDA accepted a BLA for Dato-DXd in patients with previously treated advanced nonsquamous NSCLC who received prior systemic therapy based on data from TROPION- Lung01, and the Prescription Drug User Fee Act date is set for the fourth quarter of 2024.¹

“Right now, the only second-line drug that we have approved is docetaxel and that is not good enough, we need to do better, and there are a lot of efforts to do so. Looking at these data, if there is an OS advantage [shown by] more mature data specifically in the nonsquamous patient population, it’s a no-brainer this drug will get approved. If there’s a trend in OS and a benefit and PFS in the nonsquamous population, I think it still will get approved and we’ll see if that happens,” Levy said.

Searching for Agents to Cross the Blood-Brain Barrier

Patients with brain metastases enrolled in the phase 3 TROPION-Breast01 trial (NCT05104866) and DESTINY-Lung01 and DESTINY-Lung02 trials experienced benefit when treated with either Dato-DXd or T-DXd. In TROPION-Breast01, patients with previously treated, hormone receptor–positive/HER2-negative inoperable or metastatic breast cancer experienced benefit when treated with Dato-DXd (n=35) vs chemotherapy (n=23); the median PFS was 5.6 months (95% CI, 3.0-8.1) vs 4.4 months (95% CI, 1.4-5.7), respectively (HR, 0.73; 95% CI, 0.39-1.42).⁸

In a pooled analyses of DESTINY-Lung01 and DESTINY-Lung02, the intracranial confirmed ORR (IC-cORR) was 50.0% (95% CI, 15.7%-84.3%) for patients who received T-DXd 5.4 mg/kg and underwent prior treatment (n=8) and was also 50.0% (95% CI, 11.8%-88.2%) for those who did not receive prior therapy (n=6). Among patients who received the 6.4 mg/kg dose of T-DXd, the IC-cORR was 21.4% (95% CI, 4.7%-50.8%) for patients who received prior therapy (n=14) and 37.5% (95% CI, 15.2%-64.6%) for those who did not (n=16).⁹

Regarding this patient population with NSCLC from DESTINY-Lung01 and DESTINY-Lung02, Levy said that perhaps “this [data] can be viewed through the prism of a truly targeted therapy like a TKI where we don’t have to refer [patients] to radiation; maybe we can just give the drug and have confidence that the drug will cross the blood-brain barrier. This is remarkable, [but] we need more data—these are small numbers of patients, but very exciting.”

Balancing the Scales of Efficacy and Safety

Although ILD remains a common AE with T-DXd, stomatitis is an AE to watch with Dato-DXd, according to Levy (Figure 2).2,5 When discuss- ing TROPION-Lung01, he explained, “More than half of patients had stomatitis in the Dato-DXd arm. Most of these were grade 1 and 2 AEs, but we need to be mindful of that and how to treat, mitigate, and be proactive to prevent it from happening. If this drug gets approved, there are a lot of ways we may be able to do that—steroid mouth rinses may work for patients and ice chips during the infusion may work. We have our work cut out for us to try to understand how to mitigate these toxicities, but they can be done, and it can be manageable. Having participated in many of the trials with Dato-DXd, we have been able to get patients through [who have] done very well symp- tomatically from this standpoint of stomatitis.”

In TROPION-Lung01, any-grade stomatitis was observed in 47% of the patients in the Dato- DXd arm compared with 16% of patients in the docetaxel arm. Grade 3 stomatitis occurred in 6% vs 1% of patients, respectively. Additionally, grade 3 or higher treatment-related AEs (TRAEs) occurred in 25% of patients in the Dato-DXd arm vs 41% of patients in the docetaxel arm; 3 and 2 patients died due to TRAEs in the respective arms. TRAEs were associated with dose reduction (20% vs 29%), delay (17% vs 11%), and discontinua- tion (8% vs 12%) as well.⁵

“It’s important to take 10 steps back and think about dose reductions, dose delays, and dose discontinuations—there were more dose reduc- tions and dose discontinuations in the docetaxel arm. Counterintuitively, there were more dose delays in the Dato-DXd arm. Bottom line is that it seemed like docetaxel was not as well tolerated as Dato-DXd, and that’s important to remem- ber,” Levy explained. “But this trial also did give us a nice snapshot of AEs that we need to be mindful of.”

Moreover, another notable AE that often accom- panies treatment with ADCs is ILD occurring during treatment with T-DXd. In DESTINY- Lung01, any-grade adjudicated drug-related ILD occurred in 20.4% of those given the 6.4-mg/kg dose, with 6.1% of patients experiencing a grade 5 event. Rates were lower in the 5.4-mg/kg dose group, at 4.9% and 2.4%, respectively.²

“We need to be vigilant about monitoring for ILD with these ADCs. We see ILD with other ADCs such as TROP2-[directed] ADCs. Be mind- ful of that when you’re seeing these patients—you want to screen [as well as scan patients and] talk to them about some of the symptoms they may have that suggest ILD. If you suspect that, you want to work in a multidisciplinary way. If patients have ILD, you want to suspend the treat- ment and start steroids, [but with] a grade 1 ILD with an ADC the rule is to stop treatment with the ADC. We don’t necessarily stop immunotherapy with a grade 1 ILD, [however], so this is important. The bottom line is that we are witnessing a seismic therapeutic paradigm shift in all patients with lung cancer—clearly targeted therapies and immunotherapies have been a part of that story front and center, and now ADCs are doing the same,” Levy said.