CE / CME
Physician Assistants/Physician Associates: 1.50 AAPA Category 1 CME credits
Nurses: 1.50 Nursing contact hours
Physicians: maximum of 1.50 AMA PRA Category 1 Credits™
Pharmacists: 1.50 contact hours (0.15 CEUs)
Released: November 17, 2023
Expiration: November 16, 2024
DESTINY-Lung02: Fam-trastuzumab Deruxtecan-nxki in Patients With Previously Treated HER2-Mutated Metastatic NSCLC
Helena Yu, MD:
As mentioned earlier, ADCs are a burgeoning new therapy in the treatment of lung cancers, with fam-trastuzumab deruxtecan-nxki being the first approved by the FDA for NSCLC with HER2 insertion mutations. Trastuzumab deruxtecan-nxki is a HER2-targeted antibody conjugated to the camptothecin analogue deruxtecan (topoisomerase I inhibitor) with accelerated approval at a dose of 5.4 mg/kg every 3 weeks for adult patients with unresectable or metastatic NSCLC whose tumors have activating HER2 mutations and who have received a prior systemic therapy. This approval was based on preliminary data from the phase II DESTINY-Lung01 trial showing anticancer activity with fam-trastuzumab deruxtecan-nxki at the doses of 5.4 mg/kg and 6.4 mg/kg in patients with metastatic HER2-mutant NSCLC.11,45
At WCLC 2023, the primary analysis of DESTINY-Lung02 supporting this FDA approval was presented.46,47 In DESTINY-Lung02, 151 patients with previously treated metastatic HER2-mutated NSCLC were randomized 2:1 to receive fam-trastuzumab deruxtecan-nxki at a dose of 5.4 mg/kg or 6.4 mg/kg. The primary endpoint was confirmed ORR by BICR, with secondary endpoints including ORR by investigator, DoR, DCR, PFS, OS, and safety. Patients received a median of 2 prior lines of systemic therapies in both arms, and approximately three quarters of patients had received prior PD-1/PD-L1 therapy.
At a median follow-up of 11.5 and 11.8 months, fam-trastuzumab deruxtecan-nxki at 5.4 mg/kg and 6.4 mg/kg achieved a confirmed ORR of 49.0% (95% CI: 39.0%-59.1%) and 56.0% (95% CI: 41.3%-70.0%), respectively; median DoR was 16.8 months and not reached. The waterfall plot shown here indicates the antitumor activity of fam-trastuzumab deruxtecan-nxki at 5.4 mg/kg, with responses observed independent of prior treatment or presence of CNS metastases.
DESTINY-Lung02: Safety
Helena Yu, MD:
There appears to be greater toxicity with the higher dose of 6.4 mg/kg compared with 5.4 mg/kg, with more grade ≥3 TRAEs (58.0% vs 38.6%) and serious TRAEs (24.0% vs 13.9%). Some of the most common TEAEs were similar to those seen with CT, including nausea, neutropenia, fatigue, decreased appetite, and anemia. Patients receiving the higher dose also had higher rates of drug discontinuation (20.0% vs 13.9%), dose reduction (32.0% vs 16.8%), and drug interruption (48.0% vs 26.7%).
ILD/pneumonitis has emerged as a significant concern with the use of ADC therapies in the treatment of NSCLC. In DESTINY-Lung02, adjudicated drug-related ILD with trastuzumab deruxtecan-nxki was higher in the 6.4-mg/kg arm compared with the 5.4-mg/kg arm, and 1 patient on each arm died from adjudicated drug-related ILD.
DESTINY-Lung02: Clinical Implications
Helena Yu, MD:
As mentioned above, trastuzumab deruxtecan-nxki is already in clinical use at a dose of 5.4 mg/kg every 3 weeks for the treatment of adult patients with unresectable or metastatic HER2-mutated NSCLC who have received a prior systemic therapy. The standard utilization of trastuzumab deruxtecan-nxki is after first-line platinum-based CT.
The results of DESTINY-Lung02 presented at WCLC 2023 confirm that the 5.4-mg/kg dose is equally as effective as the higher dose of 6.4 mg/kg while being safer, with a lower risk of pneumonitis.
With such an active second-line drug, we are definitely interested in bringing it into the first-line setting if possible. Toward this end, the randomized phase III DESTINY-Lung04 trial (NCT05048797) is comparing first-line fam-trastuzumab deruxtecan-nxki monotherapy with SoC pembrolizumab plus platinum CT and pemetrexed in patients with treatment-naive, HER2-mutated locally advanced or metastatic NSCLC.
EVOKE-02: Phase II Study of First-line Sacituzumab Govitecan + Pembrolizumab in Metastatic NSCLC
Helena Yu, MD:
ADCs targeting TROP-2 also are under investigation in the treatment of advanced NSCLC, including sacituzumab govitecan-hziy, which has FDA-approved indications in breast and urothelial cancers, and datopotamab deruxtecan.
Sacituzumab govitecan-hziy and datopotamab deruxtecan have demonstrated antitumor activity as monotherapy in heavily pretreated metastatic NSCLC48-50 and are now both being evaluated in combination with IO to improve patient outcomes. The idea is that ADCs may enhance the efficacy of IO by stimulating antibody-dependent cellular toxicity, in which natural killer cells are recruited to the tumor.51 Moreover, an immune system that has been stimulated by IO can more easily recognize neoantigens released by ADC-induced tumor cell lysis.
At WCLC 2023, a preliminary analysis of the phase II EVOKE-02 trial evaluating first-line sacituzumab govitecan-hziy (until progression or unacceptable toxicity) plus up to 35 cycles of pembrolizumab in patients with untreated metastatic NSCLC without actionable genomic alterations was reported.52 This analysis focused on patients in cohort A (n = 30) with a PD-L1 TPS ≥50% and cohort B (n = 33) with PD-L1 TPS <50%. The primary endpoint was ORR, with secondary endpoints including DCR, DoR, PFS, OS, and safety.
EVOKE-02: Efficacy Summary
Helena Yu, MD:
The reported efficacy data for EVOKE-02 included patients with ≥13 weeks of follow-up at data cutoff (June 16, 2023). In cohort A of patients with PD-L1 ≥50%, the ORR was 69%, with a DCR of 86%. In cohort B of patients with PD-L1 <50%, the ORR was 44%, with a DCR of 78%. The ORR result of 69% with first-line sacituzumab govitecan-hziy plus pembrolizumab in patients with PD-L1 ≥50% compared favorably with the historical ORR of 44.8% with pembrolizumab monotherapy in this patient population.53
EVOKE-02: Antitumor Activity
Helena Yu, MD:
The waterfall plot shows that a majority of patients in both cohorts had tumor shrinkage with combination therapy.52
EVOKE-02: Safety Summary
Helena Yu, MD:
Regarding the safety of sacituzumab govitecan-hziy plus pembrolizumab, any-grade and grade ≥3 TRAEs were observed in 90% and 38% of patients, respectively. TRAEs led to the death of 1 patient. TEAEs leading to discontinuation of any therapy or to discontinuation of sacituzumab govitecan occurred in 18% and 14% of patients, respectively.
For comparison, any-grade and grade ≥3 AEs related to pembrolizumab were observed in 73.4% and 26.6% of patients, respectively, in the phase III KEYNOTE-024 trial evaluating pembrolizumab monotherapy in patients with advanced NSCLC and PD-L1 ≥50%.53 TRAEs with pembrolizumab led to discontinuation in 7.1% of patients and to the death of 1 patient.
EVOKE-02: TEAEs
Helena Yu, MD:
Immune-mediated TEAEs observed with combination therapy were consistent with the known immune-related safety profile of pembrolizumab and did not appear appreciably higher than what we see with PD-1/PD-L1 monotherapy.52
TROPION-Lung04: Phase Ib Study of Datopotamab Deruxtecan + Durvalumab ± Carboplatin in Advanced/Metastatic NSCLC
Helena Yu, MD:
Before we discuss the clinical implications of EVOKE-02, let’s look at data for the other TROP-2–directed ADC, datopotamab deruxtecan, in combination with IO.
Previous reports of the phase Ib TROPION-Lung02 trial suggested efficacy and a manageable safety profile of datopotamab deruxtecan plus the PD-1 inhibitor pembrolizumab with or without platinum-based CT in advanced/metastatic NSCLC, including in the first-line setting, where ORRs of 50% and 57% were achieved with first-line doublet and triplet therapy, respectively.54
At WCLC 2023, data from the TROPION-Lung04 trial evaluating datopotamab deruxtecan plus durvalumab with or without carboplatin in patients with advanced or metastatic NSCLC with no actionable genomic alterations were reported (NCT04612751). The PD-L1 inhibitor durvalumab is approved in combination with the CTLA-4 inhibitor tremelimumab plus platinum-based CT for the treatment of adult patients with metastatic NSCLC with no sensitizing EGFR mutations or ALK genomic aberrations.55 The current analysis focused on the dose-expansion cohorts that received the higher dose of datopotamab deruxtecan (6 mg/kg), including cohort 2 of the doublet of datopotamab deruxtecan plus durvalumab (n = 19) and cohort 4 of the triplet of datopotamab deruxtecan plus durvalumab plus carboplatin (n = 14).56 The primary endpoint was safety and tolerability, with key secondary endpoints including ORR and DCR by investigator.
In the doublet cohort, 73.7% of treatment was given in the first-line setting, and 68.4% of patients had some degree of PD-L1 expression (31.6% with PD-L1 1%-49%; 36.8% with PD-L1 ≥50%). In the triplet cohort, 92.9% of treatment was given in the first-line setting, and 57.1% of patients were PD-L1 positive (21.4% with PD-L1 1%-49%; 35.7% with PD-L1 ≥50%).
TROPION-Lung04: Safety
Helena Yu, MD:
No serious safety signals emerged, but this study included a relatively small number of patients. Perhaps unsurprisingly, there were more grade ≥3 TRAEs in the triplet cohort compared with the doublet cohort (57.1% vs 31.6%). Dose-limiting toxicity was reported in 2 patients (14.3%) in the triplet cohort, including 1 grade 3 febrile neutropenia and 1 grade 3 stomatitis/grade 3 maculopapular rash.
In both cohorts, the rate of discontinuation of any drug was relatively high (~21%), and adjudicated ILD reached 15.8% in the doublet cohort and 7.1% in the triplet cohort. As more patients are treated with these combinations, we will need to see more granular data regarding ILD risk and reasons for treatment discontinuation.
TROPION-Lung04: TEAEs in ≥15% of Patients
Helena Yu, MD:
Regarding the type of AEs seen, again, no new safety signals emerged. As expected with ADCs, there were AEs typically associated with CT. We also saw a significant incidence of stomatitis with both the doublet and the triplet therapy, which is an important emerging AE with datopotamab deruxtecan that is somewhat unique compared with the other in class ADCs.
TROPION-Lung04: Antitumor Activity in First-line Setting
Helena Yu, MD:
Regarding efficacy, patients receiving doublet therapy had a confirmed ORR of 50.0%, with a DCR of 92.9%. Patients receiving triplet therapy had a confirmed ORR of 76.9%, with a DCR of 92.3%.
TROPION-Lung04: Best Overall Tumor Change From Baseline in First-line Setting
Helena Yu, MD:
TROPION-Lung04 was an all-comers study in regard to PD-L1 expression, and responses were seen regardless of PD-L1 expression levels.
TROP-2 ADCs + IO: Clinical Implications
Helena Yu, MD:
We are seeing a tsunami of studies looking at combination therapies with ADCs for the treatment of advanced NSCLC. At WCLC 2023, we saw very early data showing the feasibility of combining the TROP-2 ADCs sacituzumab govitecan or datopotamab deruxtecan with IO and even with carboplatin. Dr Gubens, what was your take on the EVOKE-02 and TROPION-Lung04 studies?
Matthew Gubens, MD, MS:
These trials are not changing practice at this point. Rather, they are whetting our appetite for the more rigorous phase III trials that are forthcoming. The patient populations are still quite small, particularly for TROPION-Lung04, which also had a heterogeneous population, including patients who had received prior CT and those who had not, making it a bit challenging to interpret.
Furthermore, the first-line setting of advanced NSCLC is not quite an unmet need; we have immune checkpoint inhibitor (ICI) therapy in combination with CT, which is relatively efficacious and tolerable, and we are comfortable with managing associated adverse events. I cannot help but wonder, are we just trading one CT for another with a new name? To embrace ADCs, I will need to see considerably better efficacy in the phase III trials than would be expected from IO plus CT or, for our patients with high PD-L1 expression, IO alone. Of course, I am open to whatever the best treatment regimen is shown to be, and these ADCs have demonstrated reasonable efficacy and safety when given in clinic, with some caveats.
Helena Yu, MD:
It seems to me that there is this kind of urge to replace CT with ADCs without much thought as to why. I also wonder whether there is actual synergy or rather it is just adding active agents together.
As you said, IO plus CT is relatively well tolerated too, so we will need to consider all of the different potential partners for IO once we have the phase III data. It also will be very important to understand which criteria are useful for patient selection to improve outcomes beyond those of CT as the combination partner for IO.
Matthew Gubens, MD, MS:
Where I am more interested to see some benefit for these TROP-2 ADCs is after IO or IO plus CT, a setting where our only current option is docetaxel and there is a huge unmet need for new therapies.
Helena Yu, MD:
I agree that the greater need is in the later-line setting, and there are ongoing phase III trials evaluating both TROP-2 ADCs vs docetaxel for pretreated advanced NSCLC: EVOKE-01 for sacituzumab govitecan (NCT05089734) and TROPION-Lung01 for datopotamab deruxtecan (NCT04656652).
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