ED08.03 Adjuvant Chemotherapy of Completely Resected

January 2017

[Allibhai Z, 2012; Hamaji M, 2015; Verstegen N, Proc ELCC 2015].

The observed rates for a second primary lung cancer following SABR appear similar to those following surgery [Verstegen N, 2015]. In this situation, a subsequent course of SABR can generally be performed safely. Operable patients: The role of SABR in fit patients remains a topic of active debate. Indirect comparisons of outcomes following the two modalities have revealed conflicting results. The role of SABR in surgical patients is currrently being investigted in 3 prospective randomized studies (NCT02468024, NCT02629458, NCT01753414), with a fourth study (VALOR) scheduled to open shortly. Keywords: stereotactic radiotherapy, Early-stage lung cancer, follow-up, toxicity

ED08.03 Adjuvant Chemotherapy of Completely Resected Glenwood Goss Medical Oncology, The Ottawa Hospital Cancer Centre, University of Ottawa, Ottawa/ON/Canada Adjuvant Chemotherapy of Completely Resected NSCLC Glenwood D. Goss Lung cancer remains the leading cause

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of cancer death world-wide and accounts for approximately 28% of all cancer deaths.1,2 Surgical resection is the cornerstone of therapy for early stage disease, but relapse is high with 30-60% of patients with resected NSCLC still dying of their disease. Despite the results of a 1995 meta-analysis demonstrating a non-significant 5% survival advantage at five years with the addition of adjuvant cisplatin-based chemotherapy, no large randomized studies conclusively demonstrated a benefit following resection until 2003.3 Five large randomized trials were undertaken to determine if adjuvant platinum-based chemotherapy after curative surgery for NSCLC conferred a survival advantage: ALPI; IALT; JBR10; CALGB 9633; and ANITA.4-8 Three of these five trials showed statistically significant improvements in overall survival, ranging from 4% [IALT] to 15% [JBR10] at 5 years, corresponding to an absolute improvement in relapse-free survival from 49% to 61%. Of the two trials that did not demonstrate improved survival, one [ALPI] suffered from poor compliance to the treatment regimen (69%), and the second was a smaller trial (n¼344) limited to patients with stage IB disease [CALGB 9633], which was likely underpowered to detect a statistically significant improvement in overall survival. Interestingly, despite being limited to patients with stage IB disease, CALGB 9633 did demonstrate an overall survival hazard ratio comparable to the other adjuvant trials (HR¼0.8) that included patients with more advanced disease, despite not achieving statistical significance. Since the publication of original adjuvant chemotherapy trials, a number of meta-analyses have confirmed the benefit of adjuvant platinum-based chemotherapy after surgical resection for NSCLC.9,10 In these meta-analyses, all-stage (IB-IIIA) hazard ratios were in the range of HR¼0.86, corresponding to an absolute benefit for chemotherapy on overall survival of 4-5% at 5 years. The benefit, however, was demonstrated to be stage dependent (albeit using older staging criteria versions), with the benefit only reaching statistical significance for stages II and III. While the role of adjuvant chemotherapy in stage I disease is controversial11, subgroup analyses in a number of trials in highrisk patients with stage IB disease (tumors4cm) suggests that there may be an overall survival advantage with adjuvant chemotherapy in this subgroup of patients, comparable to those observed in stage II and III disease [Strauss 2008]. In 2009 the long term follow up of the IALT study (with a median follow up of 7.5 years) was reported. Results showed a beneficial effect of adjuvant chemotherapy on overall survival (hazard ratio [HR], 0.91; 95% CI, 0.81 to 1.02; P ¼ .10) and on disease-free survival (HR, 0.88; 95% CI, 0.78 to 0.98; P ¼ .02). However, there was a significant difference between the results of overall survival before and after 5

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years of follow-up (HR, 0.86; 95% CI, 0.76 to 0.97; P ¼ .01 v HR, 1.45; 95% CI, 1.02 to 2.07; P ¼ .04) with P ¼ .006 for interaction. Similar results were observed for disease-free survival. The analysis of non-lung cancer deaths for the whole period showed an HR of 1.34 (95% CI, 0.99 to 1.81; P ¼ .06) suggesting that those patients receiving adjuvant chemotherapy had a higher death rate from non- lung causes after 5 years.12 However these conclusions were not support by the findings of Butts and colleagues reporting on JBR10 with a median follow-up was 9.3 years (range, 5.8 to 13.8). Adjuvant chemotherapy continued to show a benefit (hazard ratio [HR], 0.78; 95% CI, 0.61 to 0.99; P ¼ .04). There was a trend for interaction with disease stage (P ¼ .09; HR for stage II, 0.68; 95% CI, 0.5 to 0.92; P ¼ .01; stage IB, HR, 1.03; 95% CI, 0.7 to 1.52; P ¼ .87). Adjuvant chemotherapy resulted in significantly prolonged disease specific survival (HR, 0.73; 95% CI, 0.55 to 0.97;P ¼ .03). Observation was associated with significantly higher risk of death from lung cancer (P ¼ .02), with no difference in rates of death from other causes or second primary malignancies between the arms. They concluded that prolonged follow-up of patients from the JBR.10 trial continues to show a survival benefit for adjuvant chemotherapy.13 Recently in a post hoc analysis of ECOG 1505, a trial of adjuvant chemotherapy +/bevacizumab for early stage NSCLC, Wakelee and colleagues had the opportunity to compare four different cisplatin doublet regimens namely, cisplatin with one of vinorelbine, docetaxel, gemcitabine or pemetrexed. Median follow-up time for each chemotherapy doublet was: vinorelbine 54.3 months; docetaxel 60.3 months; gemcitabine 57.0 months; and pemetrexed 40.6 months respectively. The arms were well balanced for the major prognostic factors apart from smoking where the rate was slightly lower in the pemetrexed arm. There was no difference in the median number of cycles between arms. Both in the nonsquamous and squamous subgroups there was no difference in overall survival (nonsquamous logrank p¼0.18 and squamous p¼0.99) and disease free survival (nonsquamous p¼0.54 and p¼0.83). The authors concluded that there did not appear to be a difference in outcome between cisplatin doublet regimens.14 Despite the established benefit of adjuvant chemotherapy after curative surgery for NSCLC there is still much to be done with approximately 50% of patients still dying from disease. Furthermore, not all patients with early stage disease are eligible or willing to undergo chemotherapy following complete surgical resection [Booth 2010]. As such, the long-term prognosis of patients with NSCLC, even among those with early stage disease, remains poor. Therefore it is imperative that we find new and better therapies to improve upon

Journal of Thoracic Oncology

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the results of surgical resection and adjuvant chemotherapy. References: 1. American Cancer Society. Cancer Facts & Figures 2012. Atlanta: American Cancer Society; 2012. 2. Jemal A, Siegel R, Ward E et al. Cancer Statistics 2007. CA Cancer J Clin 2007;57:43-66. 3. L. A. Stewart, S. Burdett, J. F. Tierney, J. Pignon on behalf of the NSCLC Collaborative Group: Surgery and adjuvant chemotherapy (CT) compared to surgery alone in non-small cell lung cancer (NSCLC): A meta-analysis using individual patient data (IPD) from randomized clinical trials (RCT). Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings (Post-Meeting Edition).Vol 25, No 18S (June 20 Supplement), 2007:7552 4. Scagliotti GV, Fossati R, Torri V et al. Randomized study of adjuvant chemotherapy for completely resected stage I, II, or IIIA non-small-cell lung cancer. J Natl Cancer Inst 2003;95:1453-61. 5. Arriagada R, Bergman B, Dunant A et al. Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer. N Eng J Med 2004;350:351-60. 6. Winton T, Livingston R, Johnson D et al. Vinorelbine plus cisplatin vs observation in resected non-small-cell lung cancer. N Eng J Med 2005;352:2589-97. 7. Strauss GM, Herdone JE, Maddaus et al. Adjuvant paclitaxel plus carboplatin compared with observation in stage IB non-small cell lung cancer: CALGB 9633 with the Cancer and Leukemia Group B, Radiation Therapy Oncology Group, and North Central Cancer Treatment Group Study Groups. J Clin Oncol 2008;26:5043-51. 8. Douillard JY, Rosell R, De Lena M et al. Adjuvant vinorelbine plus cisplatin versus observation in patients with completely resected stage IB-IIIA non-small cell lung cancer (Adjuvant Navelbine International Trialist Association [ANITA]): a randomized controlled trial [published erratum appears in Lancet Oncol 2006;7:797]. Lancet Oncol 2006;7:719-27. 9. Pignon JP, Tribodet GV, Scagliotti G et al. Lung adjuvant cisplatin evaluation: a pooled analysis by the LACE Collaborative Group. J Clin Oncol 2008;26:3552-9. 10. NSCLC Meta-analyses Collaborative Group. Adjuvant chemotherapy, with or without postoperative radiotherapy, in operable non-small-cell lung cancer: two meta-analyses of individual patient data. Lancet 2010;375:1267-77. 11. Wakelee H, Dubey S, Gandara D et al. Optimal adjuvant therapy for non-small cell lung cancer e how to handle stage I disease. Oncologist 2007;12:331-7. 12. Arriagada R, Dunant A, Pignon JP, et al. Long-Term Results of the International Adjuvant Lung Cancer Trial Evaluating Adjuvant Cisplatin-Based Chemotherapy in Resected Lung Cancer JCO January 1, 2010 vol. 28no. 1 35-42 13. Butts C, Ding K, Seymour L,et al. Randomized Phase III Trial of Vinorelbine Plus Cisplatin Compared With Observation in Completely

January 2017

Resected Stage IB and II NoneSmall-Cell Lung Cancer: Updated Survival Analysis of JBR-10. Journal of Clinical Oncology, January 1, 2010 vol. (28) 1 29-34. 14. H.A. Wakelee1, S.E. Dahlberg2, S.M. Keller te al. E1505: Adjuvant chemotherapy +/bevacizumab for early stage NSCLC: Outcomes based on chemotherapy subsets. ASCO Annual Meeting, 2016 Abstr 8507: E1505 Chemotherapy subsets. 15. Booth CM, Shepherd FA, Peng Y et al. Adoption of adjuvant chemotherapy for NSCLC: a population-based outcome study. J Clin Oncol 2010; 28: 3472-8. Keywords: adjuvant chemotherapy, early stage nonsmall cell lung cancer

ED08.04 Perspectives of Targeted Therapies and Immunotherapy in Completely Resected NSCLC Heather Wakelee Department of Medicine, Division of Oncology, Stanford Cancer Institute/Stanford University School of Medicine, Stanford/CA/United States of America 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 ECOGACRIN 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

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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 (N¼161) DFS did favor erlotinib (HR 0.61, 95% CI ¼ 0.384-0.981, p ¼ 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