CME
Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™
Released: May 27, 2025
Expiration: November 26, 2025
ORCHARD Module 10: Osimertinib Plus Datopotamab Deruxtecan (Dato-DXd) in Advanced EGFR-Mutated NSCLC After First-line Osimertinib
After first-line osimertinib, it is unclear what treatment should be used in the second line for patients with advanced EGFR-mutated NSCLC.17-19 Dato-DXd is a TROP2-directed antibody–drug conjugate (ADC) that has shown promising efficacy for treating NSCLC, particularly in patients with EGFR mutations in the phase III TROPION-Lung01 and phase II TROPION-Lung05 trials.20-22 It has been granted Breakthrough Therapy designation and priority review status by the FDA for the treatment of adults with locally advanced or metastatic EGFR-mutated NSCLC after systemic therapies, including EGFR-targeted treatments, with approval decision expected by July 12, 2025.
So, the phase II ORCHARD trial is testing several new treatment combinations in this setting, including osimertinib plus Dato-DXd after progression on first-line osimertinib.23 Module 10 of the study (N = 69) compares 2 different dose levels of Dato-DXd, either 4 mg/kg every 3 weeks or 6 mg/kg every 3 weeks, combined with standard administrations of osimertinib 80 mg daily. The goal was to determine the dose of Dato-DXd with the best efficacy and safety in combination with osimertinib with a primary endpoint of ORR and secondary endpoints of DoR, PFS, OS, and safety.
ORCHARD Module 10: Baseline Characteristics
Again, this study enrolled a classic EGFR-mutated NSCLC patient population with a median age of 62-64 years and a significant proportion with central nervous system metastases (46% in the 4-mg/kg Dato-DXd arm and 32% in the 6-mg/kg arm).23 All patients had WHO performance status of 0 or 1. There was a slightly higher proportion of women (69% and 65%). Of note, this was a small study with 35 patients in the arm with 4-mg/kg Dato-DXd and 34 patients in the 6-mg/kg Dato-DXd arm.
ORCHARD Module 10: ORR
The ORR was similar between the 2 doses with an ORR of 43% and 36% for the 4-mg/kg and 6-mg/kg Dato-DXd plus osimertinib arms.23 The 6-mg/kg arm also had a shorter median time to onset of response of 1.4 months vs 2.7 months for the 4-mg/kg arm.
ORCHARD Module 10: PFS, DoR, and OS
The PFS data were promising with both dose levels, but slightly favored the 6 mg/kg.23 Median PFS was 11.7 months vs 9.5 months for the 6-mg/kg and 4-mg/kg arms, respectively, and PFS rate was higher for the higher dose at 6, 9, and 12 months after randomization. The 6-mg/kg Dato-DXd dose also had a better DoR of 20.5 months vs 6.3 months with 4-mg/kg Dato-DXd.
ORCHARD Module 10: Treatment Exposure
Treatment exposure duration was comparable between the 2 arms at 9.0 months for the 4-mg/kg dose and 9.8 months for the 6-mg/kg dose.23 The rate of dose reduction of Dato-DXd was higher with the higher dose (23% vs 62%). No dose reductions of osimertinib were observed in the 6-mg/kg Dato-DXd arm, which is promising because it is important to not reduce the dose level of osimertinib, which is a very effective agent for these patients. In addition, osimertinib dose interruptions and discontinuations occurred at lower rates in the 6-mg/kg arm.
ORCHARD Module 10: Safety
The most frequent AEs of the Dato-DXd plus osimertinib combination are gastrointestinal, such as nausea and stomatitis or oral mucositis, which are well-known adverse effects of Dato-DXd.23 The AE rates are similar between the 2 study arms. Prophylactic measures, like performing daily oral hygiene and using steroid-containing mouthwash, should be taken to prevent these events.24,25
Other study AEs of interest include ocular surface events and some interstitial lung disease, both of which had slightly higher rates in the 6-mg/kg arm.23
ORCHARD Module 10: Safety Summary
The safety profiles of these combinations were as expected, with mostly grade ≥3 AEs (34% and 56% in the 4-mg/kg and 6-mg/kg dose arms, respectively).23 Again, we see that there were no AEs leading to dose reduction of osimertinib in the 6-mg/kg arm and AEs leading to dose interruption and discontinuation were similar in both arms. In general, the safety profiles of both Dato-DXd doses with osimertinib were comparable, which supports choosing to continue studying the dose arm that showed better efficacy.
ORCHARD Module 10: Conclusions
The phase II ORCHARD trial has shown a potential benefit of Dato-DXd with osimertinib treatment for patients with EGFR-mutated NSCLC after progression on first-line osimertinib.23 The ORR was comparable between the 2 dose levels of Dato-DXd, but the 6-mg/kg dose arm showed a favorable DoR and median PFS. No unexpected or new safety concerns were observed with the Dato-DXd plus osimertinib combination, and safety profiles were similar for both arms.
Therefore, this combination appears to have good efficacy and tolerability in this setting, and the 6-mg/kg Dato-DXd dose should be the preferred dose for future study. There are 2 phase III trials underway to further test 6-mg/kg Dato-DXd with osimertinib in patients with EGFR-mutated NSCLC. The TROPION-Lung14 study is examining this combination vs osimertinib monotherapy as first-line therapy for patients with locally advanced or metastatic EGFR-mutated NSCLC (NCT06350097). The TROPION-Lung15 trial is testing Dato-DXd with or without osimertinib vs platinum-based doublet chemotherapy for this patient population after progression on osimertinib monotherapy (NCT06417814).
SAVANNAH: Savolitinib Plus Osimertinib for Advanced EGFR-Mutated NSCLC With MET Amplification or Overexpression After Progression on Osimertinib
Resistance to the SoC first-line osimertinib treatment for patients with EGFR-mutated advanced NSCLC is most commonly mediated by amplification of the MET gene, occurring in 7% to 50% of patients.26-29 One possible strategy to overcome this resistance is to treat patients previously exposed to osimertinib and who have MET amplification or overexpression with a MET inhibitor and to continue osimertinib therapy. The SAVANNAH trial aims to test this strategy with savolitinib, a MET-specific inhibitor, and osimertinib.30
The SAVANNAH trial enrolled adults with locally advanced or metastatic EGFR-mutated NSCLC with progression on previous osimertinib treatment and MET-overexpression (confirmed by immunohistochemistry [IHC]) or amplification (confirmed by fluorescence in situ hybridization [FISH]).30,31 The study design was changed regarding how MET overexpression and amplification were measured. The latest version of the protocol, version 7, selected patients with very high thresholds of overexpression (IHC3 positive and ≥90% of positive tumor cells by IHC) and amplification (FISH10 positive or 10% tumor cell positivity by FISH) to ensure that it observes patients with activated MET pathways. These patients were randomized to 300-mg twice-daily savolitinib with 80-mg once-daily osimertinib or with placebo. Previous study versions had lower thresholds for MET overexpression and amplification (IHC3 positive/≥50% and FISH5 positive) and tested 3 doses of savolitinib with 80-mg once-daily osimertinib: 300 mg once daily, 300 mg twice daily, and 600 mg once daily.
The primary endpoint of SAVANNAH was ORR by investigator of the patients given 300-mg twice-daily savolitinib with osimertinib in the version 7 protocol with secondary endpoints of ORR by blinded independent central review (BICR), PFS, DoR, OS, and safety. The analysis presented at ELCC 2025 examined the combined patient groups that received 300-mg twice-daily savolitinib with osimertinib from all study versions.31 Specifically, the efficacy analysis was performed with patients who met the version 7 protocol inclusion requirements (primary efficacy population; n = 80) whereas the safety analysis was done with the entire combined patient set (N = 101).
SAVANNAH: Baseline Characteristics
Similar to the previous studies discussed, the study population represented typical patients with EGFR-mutated NSCLC.31 As expected, a significant proportion of patients had brain metastases (39%).
SAVANNAH: ORR and DoR
The ORR by investigator of the primary efficacy population was a promising 56%, which is a good rate in this patient population after progression postosimertinib treatment.31 The DoR was relatively long at 7.1 months, and the median time to onset of response was 6.1 weeks. The data evaluated by BICR were similar.
SAVANNAH: Subgroup Analysis of ORR by Investigator
The subpopulation analysis suggests that the combination of savolitinib with osimertinib has a significant ORR for patients of different ethnicity, sex, age, presence of brain metastases, EGFR mutation type, and whether patients were tested for MET overexpression by IHC or for MET amplification by FISH.31
SAVANNAH: PFS and Duration of Treatment
In addition to ORR and DoR, PFS is also important to analyze and was promising in this study. The median PFS by investigator of the primary efficacy population was 7.4 months with similar results by BICR.31 This further supports a potential benefit of savolitinib with osimertinib for this patient population postosimertinib.
SAVANNAH: Safety
However, AEs resulting from the EGFR and MET inhibition are expected. The most frequent AE is peripheral edema, which occurred in 59% of patients and is commonly associated with MET inhibitors.31,32 Gastrointestinal AEs, including nausea (45%), diarrhea (33%), and vomiting (21%), are also common with this type of treatment but were primarily grade 1/2. Although this treatment combination has some toxicity, AEs were generally expected and of low grade, so it appears reasonably tolerable.
SAVANNAH: Conclusions
In conclusion, the SAVANNAH study offers promising data to support the feasibility of using savolitinib with osimertinib in the second line for patients with EGFR-mutated advanced NSCLC with MET overexpression or amplification after progression on osimertinib.31 The ORR, DoR, and PFS data show promising efficacy for this chemotherapy-free therapy combination and could become a new SoC in this setting.
The randomized phase III SAFFRON trial is ongoing and comparing savolitinib plus osimertinib with the SoC chemotherapy in this patient population with advanced EGFR-mutated NSCLC and progression on osimertinib with MET overexpression or amplification (NCT05261399).
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