TRIALS ON ADVANCED NSCLC Cesare Gridelli Division of Medical Oncology S.G. Moscati Hospital Avellino (Italy) cgridelli@libero.it
When should we suspend bevacizumab? Revascularisation following discontinuation of anti-vegf therapy Baseline After 6 weeks of treatment 3 weeks after treatment withdrawal Heavily vascularised tumour Considerable vascular regression Highly vascularised areas reform Early withdrawal of anti-vegf therapy results in rapid vessel re-growth These results provide a clinical rationale for administering anti-vegf therapy at least until disease progression 1 Vosseler, et al. Cancer Res 2005 2 Bocci, et al. Cancer Res 2004
Bevacizumab Beyond First Progression Is Associated With Prolonged Survival in Metastatic Colorectal Cancer (BRiTE) No post-therapy Post-therapy without beva Post-therapy + beva Grothey, A. et al. J Clin Oncol; 26:5326-5334 2008
Randomize 1:1 AvALL (MO22097): Study Design Primary endpoint: OS Stage IIIB/IV non-squamous NSCLC treated with platinumdoublet (4-6 cycles) + bevacizumab PLUS > 2 cycles of bevacizumab maintenance PD 1 Enroll SOC2* + bevacizumab PD 2 SOC3 + bevacizumab PD 3 SOC4 ± bevacizumab SOC2* SOC3 SOC4 *SOC2: Labelled agents for second-line treatment of NSCLC (erlotinib, pemetrexed and docetaxel) SOC3 and beyond: Choice of labelled agents is the Investigator s choice Bevacizumab dose must remain the same throughout the trial Beyond PD3, bevacizumab should be continued through subsequent lines of therapy at Investigator s discretion (in the absence of unacceptable toxicity or consent withdrawal) Confidential
MO22097: Steering Committee Dr. Gridelli, Chair (Italy) (ETOP Representative) Dr. Bennouna (France) Dr. Griesinger (Germany) Dr. Grossi (Italy) Dr. de Castro (Spain) Dr. Dingemans (NL) Prof. Thatcher (UK)
MO22097: Study Set-up Patient number (at enrollment) 600 Primary endpoint Secondary endpoints Number of participating countries Recruitment Follow-up OS from first disease progression PFS from randomization to each PD, RR for each line, safety QoL, biomarkers ~25 globally 2 years 12 months FPI Q2 2011
MO22097: Key Inclusion Criteria Non-squamous NSCLC with PD per investigator assessment following 1st-line treatment with 4-6 cycles of bevacizumab plus a platinum doublet-containing chemotherapy regimen and a minimum of 2 cycles of bevacizumab (monotherapy) maintenance treatment prior to PD1. No treatment interruption of bevacizumab treatment > 2 consecutive cycles (42 days) between the start of 1st-line treatment to Day 1 of Cycle 1 of 2nd line treatment. Randomization within 4 weeks of PD1. EGFR-mutation-positive disease according to local laboratory testing. In centers where EGFR mutation testing is not routinely done, patients with unknown EGFR mutation status are allowed to participate in this trial. > 1 unidimensionally measurable lesion meeting RECIST (v.1.1) criteria. ECOG Performance Status 0-2.
MO22097: Key Exclusion Criteria Patients with symptomatic treated brain metastases are not eligible for trial participation. To be included patients must complete treatment for brain metastases, including steroids, at least 28 days prior to randomization. Treatment with anticonvulsants at a stable dose at the time of randomization is allowed. History of hemoptysis grade 2 within 3 months of randomization. Evidence of tumor invading or abutting a major blood vessel on imaging. Radiotherapy to any site for any reason within 28 days prior to randomization. Palliative radiotherapy to bone lesions within 14 days prior to randomization is allowed. Current or recent use of aspirin, clopidogrel, or full (therapeutic)-dose of oral or parenteral anticoagulant or thrombolytic agent for therapeutic purposes. Prophylactic use of anticoagulants is allowed. Inadequately controlled hypertension within 28 days prior to randomization or history of hypertensive crisis or hypertensive encephalopathy. Clinically significant cardiovascular disease that is uncontrolled by medication.
SPLENDOUR trial Survival improvement in Lung cancer induced by DenOsUmab therapy
BONE MEATASTASES AND ZOLENDRONIC ACID
DENOSUMAB
DENOSUMAB
Solid Tumors and myeloma: study design Key Inclusion Adults with solid tumors and bone metastases (excluding breast and prostate) or multiple myeloma Key Exclusion Current or prior intravenous bisphosphonate administration N = 886 Denosumab 120 mg SC and Placebo IV* every 4 weeks Supplemental Calcium and Vitamin D N = 890 Zoledronic acid 4 mg IV* and SC placebo every 4 weeks 1 Endpoint 2 Endpoints Time to first on-study SRE (non-inferiority) Time to first on-study SRE (superiority) Time to first and subsequent on-study SRE (superiority) *IV product dose adjusted for baseline creatinine clearance and subsequent dose intervals determined by serum creatinine (per Zometa label) Henry D, et al. Eur J Can Suppl. 2009;7:11. Abstract 20LBA and Oral Presentation.
Proportion of Subjects Without Skeletal Related Event Time to First On-Study SRE 1.00 0.75 1 - HR: 0.84 (95% CI: 0.71 0.98) P = 0.0007 Noninferiority 2 - Unadjusted P = 0.03 Superiority* Adjusted P = 0.06 0.50 0.25 Denosumab Zoledronic Acid KM Estimate of Median Months 20.6 16.3 0 Subjects at Risk Zoledronic Acid 0 3 6 9 12 15 18 21 24 Study Month 890 578 376 261 194 126 86 47 Denosumab 886 582 387 266 202 134 96 55 *Due to multiplicity adjustment Henry D, et al. Eur J Can Suppl. 2009;7:11. Abstract 20LBA and Oral Presentation.
Proportion of Subjects Survived Overall Survival 1.00 0.75 HR: 0.95 (95% CI: 0.83 1.08) P = 0.43 0.50 0.25 Denosumab Zoledronic Acid 0 Subjects at Risk Zoledronic Acid Denosumab 0 3 6 9 12 15 18 21 24 27 Study Month 890 727 540 410 343 232 176 118 64 886 726 557 420 340 247 181 127 66 Henry D, et al. Eur J Can Suppl. 2009;7:11. Abstract 20LBA and Oral Presentation.
2010
2010
ETOP Study Proposal: First-line advanced NSCLC Key Inclusion Advanced NSCLC PS 0-1 No bone metastases ( PET scan or bone scan at baseline) Bevacizumab and EGFR TKI allowed Key Exclusion Previous chemotherapy (except adjuvant or neoadjuvant > 6 months) Chemotherapy* + Denosumab 120mg s.c. q 1 mos Supplemental Calcium and Vitamin D Chemotherapy*alone 1 Endpoint 2 Endpoints *Platin-based doublet Overall survival Progression free survival Bone metastasis free survival Time to first on-study SRE Time to first and subsequent on-study SRE Blood biomarkers (ctx, PTH, Vit. D,BSAP) Urinary biomarkers (NTX)