Breakthrough Clinical Results
HUTCHMED announced that new data from several clinical studies of its compounds, including savolitinib, ranosidenib, fruquintinib, and surufatinib, will be presented at the 2025 ASCO Annual Meeting. Key highlights include positive Phase III data for savolitinib in combination with osimertinib for EGFR-mutant, MET-amplified non-small cell lung cancer (NSCLC), showing improved progression-free survival. Data from Phase I ranosidenib trials in solid tumors with IDH mutations demonstrated good tolerability and efficacy signals in lower-grade gliomas. Subgroup analyses of fruquintinib in endometrial cancer and colorectal cancer showed promising efficacy and safety profiles. Multiple presentations will cover various aspects of these drugs, including safety, efficacy, and combination therapies.
Key Highlights
- Positive Phase III data for savolitinib + osimertinib in EGFR-mutant, MET-amplified NSCLC.
- Phase I ranosidenib data showed good tolerability and efficacy signals in lower-grade gliomas.
- Subgroup analyses of fruquintinib demonstrated promising efficacy and safety in endometrial and colorectal cancers.
- Multiple presentations covering various aspects of savolitinib, ranosidenib, fruquintinib, and surufatinib.
Emerging Mechanism of Action
Emerging Mechanisms of Action for Non-small Cell Lung Cancer
Over the past few years, several key mechanisms of action have emerged in the treatment of Non-small cell lung cancer (NSCLC):
Immune Checkpoint Inhibitors
- Play an important role in NSCLC management
- Include anti-CTL4 and anti-PD1 antibodies
- PD-1 and PD-1 ligand inhibitors (nivolumab, MK3475, MPDL3280) have demonstrated clinical efficacy in advanced/metastatic NSCLC
- Pembrolizumab combined with chemotherapy shows anti-tumor activity in advanced LCC and LCNEC (rare NSCLC subtypes)
- Treatment-naïve LCC patients receiving this combination showed 44.4% overall response rate and 88.9% disease control rate
- Treatment-naïve LCNEC patients showed 70% overall response rate and 90% disease control rate
Tyrosine Kinase Inhibitors
- Three can be used as first-line treatment for EGFR-positive adenocarcinoma: gefitinib, erlotinib, and afatinib
- Erlotinib is used against NSCLC but can develop drug resistance
- Dosage can be modified for erlotinib and afatinib in case of severe adverse effects
- When disease relapses, T790M mutation testing is required for potential osimertinib treatment
MET Inhibitors
- Capmatinib (Tabrecta™) targets and selectively binds to MET, including mutant variants
- Received FDA approval in May 2020 for metastatic NSCLC with MET exon 14 skipping mutations
PKCa Expression Inhibitors
- ISIS-3521 is a 20-mer antisense phosphorothioate oligonucleotide under development
- Used in combination with carboplatin and paclitaxel for NSCLC treatment
- Received FDA Fast Track review status for NSCLC in November 2000
Taxanes
- Paclitaxel and docetaxel work by promoting assembly of microtubules and preventing depolymerization
- Phase II studies showed 21-24% response rates for paclitaxel in advanced NSCLC
- Docetaxel showed 28-38% response rates, including in cisplatin-pretreated patients
Novel Combination Approaches
- Co-delivery of erlotinib (ELT) and resveratrol (RES) using nanostructured lipid carriers (NLCs)
- This approach shows augmented cytotoxic performance against NSCLC
Emerging Adjuvant and Neoadjuvant Treatments
- European Medicines Agency (EMA) recently approved adjuvant osimertinib, adjuvant atezolizumab, adjuvant pembrolizumab, and neoadjuvant nivolumab combined with chemotherapy.
Study Design Parameters
Study Design Parameters and Endpoints in Key Trials for Non-small Cell Lung Cancer
Study 1: Spanish Lung Cancer Group Trial on Pembrolizumab
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Design Parameters:
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Phase II, single-arm, open-label clinical trial
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Conducted between February 2018 and November 2019 at ten sites in Spain
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Included patients ≥70 years with stage IIIB or IV advanced NSCLC and PD-L1 expression ≥1%
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Treatment: 200 mg IV pembrolizumab every three weeks for maximum two years
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Endpoints:
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Primary endpoint: Overall survival at one year
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Secondary endpoints: Progression-free survival, disease-specific survival, response rate, tolerability, quality of life changes, geriatric assessments
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Results: 61.7% OS at one year, median OS 19.2 months
Study 2: TRUST Trial on Erlotinib
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Design Parameters:
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Phase IV, open-label, single-arm global trial
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Included stage IIIB/IV NSCLC patients who failed prior therapy or were unsuitable for chemo/radiotherapy
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Treatment: Erlotinib 150 mg/day orally until disease progression or unacceptable toxicity
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Endpoints:
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Progression-free survival, 1-year survival, overall survival, tumor response rates
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Results: Median PFS 2.7 months, 1-year survival 35%, median OS 6.9 months, disease control rate 58%
Study 3: Neoadjuvant Pembrolizumab Trial
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Design Parameters:
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Phase II study (NCT02818920)
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Included untreated clinical stage IB to IIIA NSCLC patients
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Treatment: Two cycles of pembrolizumab (200 mg) before surgery, four cycles adjuvant
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Endpoints:
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Primary endpoint: safety
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Secondary endpoints: efficacy
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Results: Major pathologic response observed in 28% of patients, R0 resection in 88%
Study 4: German National Network Study on KRAS/TP53 Mutations
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Design Parameters:
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Retrospective cohort analysis of 696 patients with PD-L1-high (≥50%) nonsquamous NSCLC
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Patients received pembrolizumab as first-line palliative treatment
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Endpoints:
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Mutation status correlation with outcomes
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Results: G12C/TP53mut patients experienced longest PFS and OS (33.7 and 65.3 months)
Study 5: Docetaxel Trials
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Design Parameters:
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Multiple phase II studies evaluating docetaxel 100 mg/m² every 3 weeks in chemotherapy-naïve patients
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Endpoints:
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Overall response rate, median survival
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Results: Response rate 23-38% (first-line), 16-22% (second-line)
IDEAL-1 and IDEAL-2 Trials
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Design Parameters:
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IDEAL-1: Double-blind, randomized, dose-comparative study in 210 NSCLC patients across Europe, Japan, South Africa, and Australia
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IDEAL-2: US-based study at 30 trial centers enrolling 221 NSCLC patients for third-line or greater therapy
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Endpoints:
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IDEAL-1: Tumor response rates, disease control rates, progression-free survival, improvements in NSCLC-related symptoms
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IDEAL-2: Symptom improvement rate (primary), objective tumor response rates
Additional Studies
- Colombian retrospective study of 209 metastatic NSCLC patients (2013-2018)
- KRAS mutations study using RNA purification from archived tissues
- KLT plus EGFR-TKI study with 12 RCTs recruiting 1,046 patients with stage III/IV NSCLC
- Ki67 study analyzing 190 patients with resected stage I to III NSCLC using tissue microarrays
Drug used in other indications
Based on the provided context, I can address the following information about indications and intervention models for osimertinib beyond Non-small cell lung cancer (NSCLC):
Osimertinib Additional Indications
Osimertinib is being trialled for: - Treatment of EGFR-mutated NSCLC with malignant pleural or pericardial effusion (MPE) in combination with bevacizumab - Adjuvant therapy in patients with NSCLC whose tumors have EGFR exon 19 deletions or exon 21 (L858R) mutations - Treatment of osimertinib-resistant patients with EGFR exon 19 deletion mutations in combination with bevacizumab - Urothelial carcinoma (UC) - mentioned in a trial that enrolled previously treated patients with advanced NSCLC or untreated, cisplatin-ineligible patients with advanced or metastatic UC, though this was testing avelumab plus axitinib, not osimertinib
Intervention Models
For the combination of savolitinib and osimertinib, the only clinical trial specifically mentioned is the TATTON study, which is a phase 1b study focused on NSCLC patients with MET-amplified, EGFR mutation-positive disease who progressed on EGFR TKIs.
The intervention model described in the TATTON study included two expansion cohorts (parts B and D) with specific dosing regimens for NSCLC patients.