ED08.04 Perspectives of Targeted Therapies and Immunotherapy in Completely Resected NSCLC

Abstract

The use of four cycles of cisplatin-based adjuvant chemotherapy is now the standard of care for patients with resected stage II and IIIA NSCLC and is commonly used for patients with larger (at least 4 cm in size) stage IB tumors. The survival benefit with adjuvant chemotherapy though is limited with meta-analyses revealing a 4-5% absolute survival benefit at 5 years for patients receiving adjuvant cisplatin-based chemotherapy.1,2 Some recent attempts to improve outcomes with the addition of other agents to cisplatin doublets (or as longer term therapy) have been disappointing. The addition of bevacizumab to chemotherapy in the ECOG-ACRIN E1505 adjuvant trial failed to show a benefit in disease free survival (DFS) or overall survival (OS).3 The use of the MAGE-A3 vaccine in the MAGRIT trial was similarly negative.4 With knowledge about molecular drivers of NSCLC and targeted treatment options in advanced disease, multiple studies are either completed or underway to study molecularly targeted agents in earlier stages of lung cancer, particularly with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). In metastatic NSCLC the EGFR TKIs produce superior response and progression free survival (PFS) compared with platinum doublet chemotherapy in treatment naïve patients with tumors with activating EGFR mutations (EGFRmut).5,6 Similar outcomes with significant response and PFS improvements with the anaplastic lymphoma kinase (ALK) inhibitor crizotinib compared to chemotherapy have been reported in patients with tumors harboring translocations of ALK.7 Encouraging data from retrospective and non-randomized trials looking at adjuvant EGFR TKI use led to randomized trials. Earlier trials that did not select based on EGFRmut status were negative, but more recent trials have been more encouraging. The phase III RADIANT trial selected patients with resected early stage NSCLC for EGFR expression by IHC/FISH, but not by EGFR mutation status, and randomized them to adjuvant erlotinib or placebo.8 The primary end point was DFS in the full data set, with secondary analyses focused on patients with tumors harboring del19 or L858R EGFR mutations. No differences were found in DFS or OS based on treatment arm for the nearly 1000 patients who were enrolled. In the EGFRmut subset (N=161) DFS did favor erlotinib (HR 0.61, 95% CI = 0.384-0.981, p = 0.0391), but this was not considered statistically significant, as the primary endpoint of the trial was negative. The overall survival results, while still immature, were not in favor of the erlotinib arm, even in the EGFRmut subset. The conclusion from this study is that adjuvant EGFR TKI therapy requires further investigation and should not be considered a standard treatment option at this time. Multiple ongoing trials are exploring adjuvant EGFR TKI (and adjuvant ALK TKI) therapy for resected early stage NSCLC patients with tumors harboring the appropriate molecular marker. (Table 1) The ongoing trials are looking not only at whether or not an OS benefit can be obtained with adjuvant molecularly targeted therapy but also duration of therapy and the potential to use EGFR TKIs instead of chemotherapy in selected patients. The largest United States study is the NCI National Clinical Trials Network (NCTN) ALCHEMIST trial. The study is open to patients with resected early stage (IB-IIIA) NSCLC who are screened for EGFR activating mutations and ALK translocations. Patients with tumors harboring EGFR mutations or ALK translocations enter the appropriate sub-study and, after completion of all planned adjuvant chemotherapy or radiation therapy, are randomized to targeted TKI therapy or placebo for 2 years. Both sub-studies will enroll approximately 400 patients (410 EGFR; 378 ALK) and are powered for an OS endpoint. Patients without actionable mutations can enroll on the ANVIL sub-study looking at adjuvant nivolumab, a PD-1 targeted agent. (Table 1) Globally most targeted therapy adjuvant trials are being conducted in Asia, particularly China and Japan. ADJUVANT (C-TONG 1104) trial in China and IMPACT WJOG6410L in Japan are phase III trials for patients with resected stage II-IIIA EGFRmut NSCLC comparing gefitinib to cisplatin/vinorelbine using DFS as the primary endpoint. (Table 1) Other trials outlined in the Table are exploring variations on this theme using gefitinib or icotinib and either after or instead of adjuvant chemotherapy. The PD-1 inhibitors nivolumab and pembrolizumab are approved for the second line treatment of advanced stage NSCLC and will likely be utilized in first-line in the near future.9-11 Based on their promise in advanced stage NSCLC, multiple trials with PD-1 and PD-L1 agents are ongoing. Most studies are for patients who have completed adjuvant chemotherapy (though some allow chemotherapy naïve patients) and they predominantly randomize patients to approximately 1 year of PD-1 or PD-L1 inhibitor therapy. Most include testing for PD-L1 expression, but do not exclude patients with low tumor levels of PD-L1. Many are placebo controlled. (Table 1) Chemotherapy has helped improve outcomes but continued investigations with novel approaches will be necessary to continue to improve cure rates for patients with resected early stage NSCLC. The use of molecularly targeted agents for patients with tumors containing EGFRmut or ALK translocations are promising with validation studies ongoing and the hope of immunotherapy is being investigated as well in multiple global trials.TableOngoing Phase III Targeted and Immunotherapy Adjuvant TrialsTrialDescriptionPrimary Endpoint(s)C-TONG 1104 NCT01405079*gefitinib vs. cisplatin/vinorelbine3-year DFSGASTO1002 NCT01996098*Chemo then icotinib vs obs5-year DFSBD-IC-IV-59 NCT02125240*Chemo then icotinib vs. placebo2-year DFSWJOG6401L IMPACT*Gefitinib vs. cisplatin/vinorelbine5-year DFSALCHEMIST A081105/E4512*Erlotinib vs. placebo: ALKˆ crizotinib vs placeboOSALCHEMIST/ANVIL&EGFR/ALK wildtype; US NCI NCTN, Nivolumab vs obsOS/DFSImpower010Restricted to PD-L1+ Global, Atezolizumab vs. placeboDFSMEDI4736&Global, MEDI4736 vs placeboDFSKeynote-091&ETOP/EORTC, Pembrolizumab vs placeboDFSAll EGFR studies include stage II-IIIA All PD-1/PD-L1 studies open to IB (4cm) – IIIA after adjuvant chemotherapy N: Number of estimated enrollment DFS: disease-free survival; OS: overall survival *EGFR deletion 19 or exon 21 L858R mutation only ALKˆ : Positive for ALK translocation by FISH &- regardless of PD-L1 status US NCI NCTN: United States National Cancer Institute, National Clinical Trials Network Open table in a new tab All EGFR studies include stage II-IIIA All PD-1/PD-L1 studies open to IB (4cm) – IIIA after adjuvant chemotherapy N: Number of estimated enrollment DFS: disease-free survival; OS: overall survival *EGFR deletion 19 or exon 21 L858R mutation only ALKˆ : Positive for ALK translocation by FISH &- regardless of PD-L1 status US NCI NCTN: United States National Cancer Institute, National Clinical Trials Network 1. 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