The Role of Antiangiogenic Agents - PowerPoint Presentation

The Role of Antiangiogenic Agents in the Changing Treatment Paradigm of NSCLC: Expert Perspectives Moderator Solange Peters, MD, PhD Chair, Medical Oncology Department of Oncology Centre Hospitalier Universitaire Vaudois (CHUV) Lausanne, Switzerland

Panelists Edward Garon, MDAssociate Professor of MedicineDavid Geffen School of MedicineUniversity of California, Los Angeles Los Angeles, California Keunchil Park, MD, PhD Professor/Director Division of Hematology/Oncology Innovative Cancer Medicine Institute Samsung Medical Center Sungkyankwan University School of Medicine Seoul, South Korea

Villaruz LC, Socinski MA. Curr Oncol Rep. 2015;17:26.Rationale for Antiangiogenic Therapy in NSCLC Angiogenesis is central to tumor growth and metastasisVEGF/VEGF receptor pathway is major regulator of angiogenesis; controls vascular distribution to tumor VEGF signaling may indirectly affect tumor proliferation VEGF inhibition may improve distribution of chemotherapy to the tumor

a. Avastin® (bevacizumab) PI 2019; b. Tecentriq® (atezolizumab) PI 2019; c. Cyramza® (ramucirumab) PI 2019.Antiangiogenic Agents Used in NSCLC: US FDA Approvals Bevacizumab [a] With carboplatin and paclitaxel in patients with advanced nonsquamous NSCLC, for first-line treatment [a] With atezolizumab, carboplatin, and paclitaxel in patients with m etastatic nonsquamous NSCLC with no EGFR or ALK genomic tumor aberrations, for first-line treatment[b] Ramucirumab[c] With docetaxel in patients with metastatic NSCLC with progression on/after platinum-based chemotherapy. Patients with EGFR or ALK aberrations should have progression on FDA-approved targeted therapy prior to ramucirumab

a. Patel JD, et al. J Clin Oncol. 2013;31:4349-4357; b. Reck M, et al. Ann Oncol. 2010;21:1804-1809. Other Bevacizumab-Containing Combinations Have Not Yielded OS BenefitPointBreak trial [a] No significant OS benefit with bevacizumab, carboplatin, pemetrexed vs bevacizumab, carboplatin, paclitaxel AVAiL trial [b] No significant OS benefit with addition of bevacizumab to cisplatin and gemcitabine Given these outcomes, taxane-based combinations remain standard of care

*After targeted therapy in patients with targetable mutations. Antiangiogenic Agents Used in NSCLC: Asia Agent Regimen Population China Japan Korea Singapore Taiwan Bevacizumab + carboplatin and paclitaxel Nonsquamous X X X X X + erlotinib EGFR-mutated X X X X Ramucirumab + docetaxel With progression on/after platinum-based chemotherapy* X X X X Nintedanib + docetaxel Adenocarcinoma after first-line chemotherapy X

European Medicines Agency. Medicines. 2019. Antiangiogenic Agents Used in NSCLC: EMA Approvals Bevacizumab With platinum-based chemotherapy in patients with advanced nonsquamous NSCLC With erlotinib in patients with advanced NSCLC with activating mutations in EGFR With atezolizumab, paclitaxel, and carboplatin as first-line therapy (patients with targetable mutations should have targeted therapy first) Ramucirumab With docetaxel in patients with metastatic NSCLC with progression on/after platinum-based chemotherapy Nintedanib With docetaxel in patients with previously treated advanced adenocarcinoma

Use of Antiangiogenic Agents in Europe 2 antiangiogenic agents approved in second-line setting in EuropeNintedanib offers an oral antiangiogenic agent option However, regimen still requires docetaxel administration Ramucirumab is more widely available than nintedanib and is more commonly used Toxicity profiles of nintedanib and ramucirumab differ

Antiangiogenic Agents in Patients Without Targetable Mutations: A Case Study Frontline therapy with carboplatin, pemetrexed, and pembrolizumab induced SD after 9 wk End of chemotherapy scan indicates PD Additional cycles of pemetrexed and pembrolizumab not effective Second-line docetaxel and ramucirumab induced a PR

Antiangiogenic Agents in Patients Without Targetable Mutations: A Case Study a. Herbst RS, et al. Lancet Oncol. 2019;20:1109-1123. Might there be an opportunity to give an antiangiogenic drug here, after frontline triplet with immunotherapy ? Existing second-line data evaluate regimens after initial platinum-based chemotherapy, not immunotherapy Possible increased toxicity after immune checkpoint inhibitor Recent data do suggest feasibility of pembrolizumab + ramucirumab [a] Frontline therapy with carboplatin, pemetrexed, and pembrolizumab induced SD after 9 wkEnd of chemotherapy scan indicates PD Additional cycles of pemetrexed and pembrolizumab not effective Second-line docetaxel and ramucirumab induced a PR

a. Sandler A, et al. N Engl J Med. 2006;355:2542-2550; b. Reck M, et al. J Clin Oncol. 2009;10:1227-1234; c. Garon EB, et al. Lancet. 2014;384:665-673; d. Reck M, et al. Lancet Oncol . 2014;15:143-155. Evidence for Antiangiogenic Agents in Nonmutated NSCLC Trial Study Design Efficacy Outcomes With vs Without Antiangiogenic Agent ECOG 4599 [a] Paclitaxel and carboplatin +/- bevacizumab in recurrent/advanced NSCLC (N = 878)mOS 12.3 mo vs 10.3 mo (HR, 0.79; P = .003)mPFS 6.2 vs 4.5 mo (HR, 0.66; P < .001)AVAiL[b]Cisplatin and gemcitabine +/- bevacizumab in previously untreated patients (N = 1043)Low dose: mPFS 6.7 vs 6.1 mo (HR, 0.75; P = .003) High dose : mPFS 6.5 vs 6.1 mo (HR, 0.82; P = .03) No OS difference REVEL [c] Docetaxel +/- ramucirumab after platinum-based frontline therapy (N = 1253) mOS: 10.5 vs 9.1 mo (HR, 0.86; P = .023)mPFS: 4.5 vs 3.0 mo (HR, 0.76; P < .0001) LUME-Lung1 [d] Docetaxel +/- nintedanib as second line after chemotherapy (N = 1341) m PFS: 3.4 vs 2.7 mo (HR, 0.79; P = .0019) mOS in adenocarcinoma: 12.6 vs 10.3 mo ( HR, 0.83; P = .0359)

Reck M, et al. WCLC 2017. Abstract MA 03.06.Patient Selection Factors: Rapid Progression on First-Line Therapy Exploratory subset analysis of REVEL study showed similar outcomes with ramucirumab in those with rapid progression on first-line therapy vs the ITT population Suggests that even patients with rapid progression on first-line therapy may benefit from second-line therapy Outcome ITT Population (N = 1253) Pts With TTP ≤ 9 Wk (n = 133) Pts With TTP ≤ 12 Wk (n = 209) Pts With TTP ≤ 18 Wk (n = 354) HR for OS with RAM + DOC vs placebo + DOC (95% CI) 0.86 ( 0.75, 0.98 ) 0.69 ( 0.47, 1.01 ) 0.74 ( 0.54, 1.00 ) 0.80 ( 0.63, 1.01 ) HR for PFS with RAM + DOC vs placebo + DOC (95% CI) 0.76 (0.68, 0.86 ) 0.69 ( 0.48, 0.98 ) 0.73 ( 0.55, 0.97 ) 0.72 ( 0.58, 0.89 )

a. Langer CJ, et al. Am J Clin Oncol. 2016;39:441-447; b. Sandler A, et al. N Engl J Med. 2006;355:2542-2550; c. Garon EB, et al. Lancet. 2014;384:665-673; d. Besse B, et al. Clin Cancer Res. 2015;21:1896-1903. Other Patient Selection Factors Older patients (≥ 75 yr) Meta-analysis of patients in ECOG 4599 and PointBreak studies showed no significant OS benefit with bevacizumab in patients ≥ 75 yr [a ] Patients with brain metastases Excluded from randomized trials [b,c] but data suggest benefit of bevacizumab[d]Availability of these agents varies geographically

Kurzrock R, Stewart DJ. Clin Cancer Res. 2017;23:1137-1148.Toxicity Profiles of Antiangiogenic Agents Selected class effectsHypertensionBleeding, including severe and fatal hemorrhage Proteinuria Nintedanib, an oral multitargeted tyrosine kinase inhibitor, has unique toxicities Alanine and aspartate aminotransferase elevations Diarrhea In early bevacizumab studies, risk of pulmonary hemorrhage in patients with squamous cell NSCLC was prohibitive Led to development in nonsquamous NSCLC

a. Garon EB, et al. Lancet. 2014;384:665-673.Ramucirumab and Bleeding Risk: Expert PerspectivesREVEL trial excluded patients with central tumors [a] Ramucirumab was not associated with an increased risk of pulmonary hemorrhage despite included patients with squamous cell NSCLC [a] In general, a patient meeting criteria for REVEL trial would be a candidate for ramucirumab

a. Reck M, et al. Lancet Oncol. 2014;15:143-155. Safety Considerations with Antiangiogenic Agents: Bleeding and Nintedanib LUME-Lung1 trial excluded patients with [a ] : Central tumor with local invasion of major blood vessel Recent clinically significant hemoptysis Recent major thrombotic or clinically relevant major bleeding event Bleeding rates in LUME-Lung1 were similar between arms[a]

Antiangiogenic Agents in Patients With EGFR-Mutated NSCLC: A Case Study 64-year-old woman with metastatic adenocarcinoma of the lung with asymptomatic brain metastases EGFR mutation-positive (exon 19 deletion) Local standard of care is erlotinib She was enrolled in trial of erlotinib + bevacizumab

a. Seto T, et al. Lancet Oncol. 2014;15:1236-1244; b. Saito H, et al. Lancet Oncol. 2019;20:625-635; c. Nakagawa K, et al. ASCO® 2019. Abstract 9000 . Evidence for Antiangiogenic Agents in EGFR-Mutated NSCLC Trial Study Arms mPFS With vs Without Antiangiogenic Agent , mo JO25567 [a] (N = 154) Erlotinib +/- bevacizumab16.0 vs 9.7 (HR, 0.54; P = .0015) NEJ026[b](N = 228)Erlotinib +/- bevacizumab16.9 vs 13.3 (HR, 0.605; P = .016) RELAY [c] (N = 449) Erlotinib +/- ramucirumab 19.4 vs 12.4 (HR, 0.591; P < .0001 )

Nakagawa K, et al. ASCO® 2019. Abstract 9000. Points to Consider From RELAY Trial of Erlotinib + Ramucirumab Trial excluded patients with brain metastases Median PFS was similar in patients with EGFR deletion 19 and in those with exon 21 mutations: Ex19del: 19.6 vs 12.5 mo ( HR, 0.651; 95% CI, 0.469; 0.903 ) Ex21.L858R: 19.4 vs 11.2 mo (HR, 0.618; 95% CI, 0.437; 0.874)This differs from the typical observation that deletion 19 is associated with better outcomes than exon 21

Antiangiogenic Agents in Patients With EGFR-Mutated NSCLC: A Case Study (cont) Erlotinib + bevacizumab induced response including in brain after 2 cycles Toxicities were well managed 18 months later, she returned with disease progression Repeat molecular profiling of tumor tissue and circulating tumor DNA showed T790M Patient started on third-generation EGFR TKI osimertinib, which induced a PR She remains in PR after 1 additional year on osimertinib

a. Akamatsu H, et al. Clin Lung Cancer. 2019;20:e492-e494; b. Akamatsu H, et al. Clin Lung Cancer. 2018;19:e871-e874; c. Nakahara Y, et al. J Clin Oncol. 2019;37(suppl):TPS9120.Trials Are Evaluating Antiangiogenic Agents With Third-Generation EGFR TKI Phase 1/2 WJOG8715L trial [a] : Osimertinib +/- bevacizumab in patients with EGFR -mutated, T790M-positive NSCLC with progression on EGFR TKI Brain metastases allowed if patient is asymptomatic; ≥ 14 days between last RT to brain and study treatment Phase 1b study[b]:Osimertinib + ramucirumab in EGFR-mutated, T790M-positive NSCLC with progression on EGFR TKIExcludes patients with leptomeningeal carcinomatosisPhase 2 TORG1833 trial[c]:Osimertinib +/- ramucirumab in patients with previously untreated EGFR mutation-positive NSCLCSymptomatic brain metastases excludedToxicity of combinations will be important to assess

a. Campesato LF, Merghoub T. Ann Transl Med. 2017;5:497; b. Socinski MA, et al. N Engl J Med. 2018;378:2288-2301. Future Directions: Role of Antiangiogenic Therapy in Immunotherapy Era Preclinical data suggest that VEGF pathway has downregulatory effects on the immune system [a] Might VEGF inhibition promote immunotherapy? The role of combining antiangiogenic therapy with immunotherapy is an open question The IMpower150 regimen (atezolizumab, bevacizumab, carboplatin, and paclitaxel [ABCP]) had notable benefit in patients with EGFR mutations or ALK rearrangements[b]Outcome ITT Population (N = 800)Patients With EGFR or ALK Alterations (n = 108)ABCP BCP ABCP BPC mPFS, mo 8.3 6.8 9.7 6.1 HR (95% CI) 0.61 ( 0.52, 0.72 ) 0.59 ( 0.37, 0.94 )

Future Directions and Ongoing Considerations The potential for a chemotherapy-free regimen is being evaluated in ongoing trialsIn Europe, there is particular interest in using the IMpower150 regimen in patients with EGFR mutation Cost, resources, and lack of significant clinical benefit may limit uptake of this type of regimen Would sequencing available agents provide greater benefit? (eg, starting with immunotherapy)

Key Takeaways Antiangiogenic therapy can be used in both the frontline and second-line treatment of NSCLC Bevacizumab as a component of frontline therapy Ramucirumab and docetaxel as standard second-line option Nintedanib and docetaxel is a second-line option in some countries Ongoing research is determining the optimal use of these agents

AbbreviationsABCP = atezolizumab, bevacizumab, carboplatin, and paclitaxel ALK = anaplastic lymphoma kinaseCI = confidence intervalDOC = docetaxelECOG = Eastern Cooperative Oncology GroupEGFR = epidermal growth factor receptor EMA = European Medicines Agency HR = hazard ratio ITT = intention to treat mOS = median overall survival mPFS = median progression-free survival NSCLC = non-small cell lung cancer OS = overall survival PD = progressive disease PR = partial responseRAM = ramucirumabSD = stable diseaseTKI = tyrosine kinase inhibitorTTP = time to progressionVEGF = vascular endothelial growth factor