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T. Le Chevalier

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    ED08 - Early-Stage NSCLC: State-of-the-Art Treatment and Perspectives (ID 276)

    • Event: WCLC 2016
    • Type: Education Session
    • Track: Early Stage NSCLC
    • Presentations: 4
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      ED08.01 - Surgery of Early-Stage NSCLC (ID 6469)

      14:30 - 14:50  |  Author(s): M.R. Mueller

      • Abstract
      • Presentation
      • Slides

      Abstract:
      General considerations Early stage lung cancer - a term in transition Generally early stage lung cancer is understood as stage I and stage II non-small lung cancer. An alternative understanding of early stage lung cancer is resectable disease. However, both definitions are imprecise and subject to development and Expertise. 1. Defining early stage lung cancer as resectable disease depends on regional philosophies and local expertise and therefore is the most unreliable and variable definition. The term resectability focuses on the T factor of the tumour and describes the ability of the surgeon to achieve radical resection. In contrast operability includes any potential regional and systemic spread and focuses more on the N and M descriptors. 2. Defining early stage lung cancer based on mediastinal nodal involvement neglects the fact, that single station N2 (N2a) is associated with the same five-year survival as multistation N1 (N1b). This touches on the term locally advanced disease, which in fact also means different things for different people. For the oncologist locally advanced disease usually means N2 involvement with the consequent call for chemotherapy. For the surgeon locally advanced disease primarily addresses the T factor and is used for T3 or T4 tumours, indicating more extended resections in the absence of N2 disease. In summary, terms like early stage, locally advanced stage or advanced stage should be avoided since they do not properly describe a clinical situation nor are they guiding therapy. If the term early stage lung cancer should be maintained for any reason, there is need for revisions. The five-year survival of stage I and stage II non-small lung cancer is a range of less than 30 to more than 90% and the survival expectedly mainly depends on nodal involvement. The estimated median five-year survival of patients with Screening detected T1N0 NSCLC is a reported 92%. Even nodal negativeT3 tumours are associated with almost 60% five year survival following radical resection. On the other hand involvement of multiple N1 lymph nodes results in a much worse prognosis of about 35%. However, for this presentation the current definition of stage I and stage II non-small lung cancer was used. Preoperative staging Resectability of lung cancer for technical reasons in general, and in early stage lung cancer in particular, very rarely is an issue. Oncological operability has to be defined preoperatively along international guidelines. The European Society of Thoracic Surgeons (ESTS) recently has ublished revised guidelines for preoperative mediastinal lymph nodes staging for non-small cell lung cancer. Only one selected group of patients with tumours of less than 3 cm in diameter (cT1) in the outer third of the lung without signs of nodal involvement at CT scan, PET scan or PET CT (cN0) may directly undergo surgical resection. All other clinical situations require invasive preoperative staging by bronchoscopy plus EBUS/EUS. If the absence of nodal involvement is verified by EBUS/EUS this patient may also directly undergo surgery. In the presence of radiologically suspect mediastinal lymph nodes and negative EBUS/EUS further confirmation is recommended using mediastinoscopy or thoracoscopy. If mediastinal nodal involvement is histologically verified by any means the patient has to undergo multimodality treatment. All clinical findings are to be discussed in an interdisciplinary tumour board for proper therapy planning. [1] Surgical therapy of early stage NSCLC Surgery remains the cornerstone of treatment of early stage non-small lung cancer for patients willing to accept the procedure-related risks. Goal of any surgical intervention for early stage lung cancer is the complete resection of the primary tumour together with regional lymphatic nodes. The standard for any resection with curative intent is defined by anatomical lung resection. In early stage lung cancer the predominant type of resection is lobectomy or bilobectomy, sometimes along with bronchoplastic or angioplastic procedures or extended resections for locally invading T3 tumours. Pneumonectomy particularly in the treatment of early stage lung cancer is rarely used. Gold standard of surgical resection for lung cancer is lobectomy. This standard is based on a prospective multi-institutional randomized trial comparing limited resection with lobectomy for peripheral T1N0 non-small cell lung cancer published in 1995. [2 ]In the absence of more recent prospective randomised trials lobectomy still must be considered the surgical procedure of choice for patients with peripheral T1N0 non-small cell lung cancer. An extensive body of literature mainly composed of retrospective studies supports the use of radical anatomical segmentectomy for peripheral cT1N0M0 non-small lung cancer with less than 2 cm in diameter, certainly for older patients with limited cardiopulmonary function. However, caution should be taken to promote a widespread indication for intentional segmentectomy in young good surgical candidates until the results of the ongoing randomised controlled trials become available.[ 3,4] The role of minimally invasive surgery Minimally invasive anatomical resection for lung cancer carried out by means of video-assisted thoracic surgery (VATS) has been increasingly carried out during the past years. A systematic review and meta-analysis of randomized and nonrandomized trials published in 2009 reported an improved five-year survival and reduced systemic recurrences in patients who received VATS lobectomy. [5 ]A multicentric propensity-matched analysis of more than 1000 patients, of which 700 had undergone VATS lobectomy confirms, that thoracoscopic lobectomy is associated with lower morbidity as compared with thoracotomy. The positive impact of minimally invasive surgery in the treatment of lung cancer particularly applies to the elderly. [6] Regarding long-term survival after video-assisted thoracoscopic lobectomy a meta- showed a survival benefit in the favour of VATS with a difference in survival of 5% at five years. The reason for this observed survival benefit may be attributed to a less pronounced compromise of the immunocompetence after the surgical trauma. [7] The role of mediastinal lymph node dissection The rationale for a formal mediastinal lymph node dissection is multifold. The distribution pattern of mediastinal lymph node metastasis is not predictable and skip metastasis are seen in up to 30% of patients. Even small tumours may present with unexpected N2 disease with an incidence of 6-10%. The operative morbidity is not significantly influenced by a systematic mediastinal lymph node dissection. Recommended standard of mediastinal lymph node dissection is the removal of all mediastinal tissue containing lymph nodes in a systematic Approach within anatomical landmarks. The most recent randomized controlled trial published in 2011 did not find a survival benefit by complete mediastinal lymphadenectomy in patients with early stage lung cancer, but the results should not be generalized to patients staged only radiographically or those with higher stage tumours. The recommendation from this study is that a formal mediastinal en-bloc dissection may still affect survival and certainly optimally stages patients. In the subgroup analysis no difference between VATS and open lobectomy was observed for number of lymph nodes harvested and regarding long-term survival.[8] As minimally invasive surgery along with unilateral mediastinal lymphadenectomy generally prolongs operation times and the requirement of single lung ventilation the advantages for the elderly population has to be questioned and discussed individually. An alternative to thoracoscopic unilateral lymphadenectomy is offered by video-assisted mediastinal lymphadenectomy through the neck (VAMLA). The approach is similar to transcervical mediastinoscopy and allows for a radical bloc dissection of all mediastinal lymph node stations. Besides the benefit of bilateral lung ventilation during this phase of the operation a bilateral mediastinal lymphadenectomy offers improved surgical radicality. Alternatives to surgical resection and the role of primary radiotherapy In patients unfit for surgery SABR is the treatment of choice for peripherally located stage I non-small cell lung cancer. If SABR is not available a hypofractionated radiotherapy is advocated. A systematic Review comparing outcomes of SABR and surgery in patients with severe COPD revealed a higher 30 day mortality following surgery but similar overall survival at one and three years. [9] In a meta-analysis of 19 out of 318 papers with the best evidence addressing a comparison of SABR and surgical wedge resection both methods proved as reasonable alternatives to lobectomy in high risk surgical patients. In this analysis SABR was associated with reduced local recurrence compared to wedge resection and should be considered when wedge resection is planned due to anatomical location and size of the primary tumour in a patient who is high risk for surgery. [10] Although local tumour control may be comparable or even superior to extra-anatomic surgical resection a quite high rate of late radiological changes after stereotactic ablative radiotherapy for early stage lung cancer has to be considered. At one year follow-up the predicted probability of having expected or pronounced radiological changes after SABR were 65 and 22%. These changes included phenomena like mass-like appearance, radiation fibrosis, and rib fractures, which sometimes are difficult to differentiate from tumour recurrence. Summary The ACCP guidelines address the question, who had to be considered a high risk candidate for surgery. With the advent of minimally invasive resection, the criteria to classify a patient as too ill to undergo an anatomic lung resection are being redefined. Surgical resection remains the primary and preferred approach to the treatment of stage I and II NSCLC in patients with good or low surgical risk. Primary radiation therapy remains the primary curative intent approach for patients who refuse surgical resection or are determined by a multidisciplinary team to be inoperable. [11] References 1. Revised ESTS guidelines for preoperative mediastinal lymph node staging for non-small-cell lung cancer. De Leyn P, Dooms C, Kuzdzal J, Lardinois D, Passlick B, Rami-Porta R, Turna A, Van Schil P, Venuta F, Waller D, Weder W, Zielinski M. Eur J Cardiothorac Surg. 2014 May;45(5):787-98 2. Randomized trial of lobectomy versus limited resection for T1 N0 non-small cell lung cancer. Lung Cancer Study Group. Ginsberg RJ; Rubinstein LV. Ann Thorac Surg. 1995; 60(3):615-22; discussion 622-3 3. Tsutani Y, Miyata Y, Nakayama H, et al. Oncologic outcomes of segmentectomy compared with lobectomy for clinical stage IA lung adenocarcinoma: propensity score-matched analysis in a multicenter study. J Thorac Cardiovasc Surg 2013;146:358-64. 4. Zhao X, Qian L, Luo Q, et al. Segmentectomy as a safe and equally effective surgical option under complete video-assisted thoracic surgery for patients of stage I non-small cell lung cancer. J Cardiothorac Surg 2013;8:116, 5. Yan TD, Black D, Bannon PG, McCaughan BC. Systematic review and metaanalysis of randomized and non-randomized Trials on safety and efficacy of videoassisted thoracic surgery lobectomy for early-stage non-small cell lung cancer. J Clin Oncol 2009; 27: 2553–2562 6. Thoracoscopic lobectomy is associated with lower morbidity compared with thoracotomy.Villamizar NR, Darrabie MD, Burfeind WR, Petersen RP, Onaitis MW, Toloza E, Harpole DH, D'Amico TA. J Thorac Cardiovasc Surg. 2009 Aug;138(2):419-25. 7. Long-term survival in video-assisted thoracoscopic lobectomy vs open lobectomy in lung-cancer patients: a meta-analysis. Taioli E, Lee DS, Lesser M, Flores R. Eur J Cardiothorac Surg. 2013 Feb 14. 8. Darling GE, et al. Randomized trial of m diastinal lymph node sampling versus complete lymphadenectomy during pulmonary resection in the patient with N0 or N1 less than hilar) non-small cell carcinoma. J Thorac Cardiovasc Surg 011;141:662-70 9. Early and locally advanced non-small-cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, Treatment and follow-up. J. Vansteenkiste, D. De Ruysscher, W. E. E. Eberhardt, E. Lim, S. Senan, E. Felip & S. Peters, on behalf of the ESMO Guidelines Working Group 10. Mahmood S, Bilal H, Faivre-Finn C, Shah R. Is stereotactic ablative radiotherapy equivalent to sublobar resection in high-risk surgical patients with stage I non-small-cell lung cancer? Interact Cardiovasc Thorac Surg. 2013 Nov;17(5):845-53. 11. Treatment of stage I and II non-small cell lung cancer: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines.Howington JA, Blum MG, Chang AC, Balekian AA, Murthy SC. Chest. 2013 May;143(5 Suppl)

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      ED08.02 - The Role of Radiotherapy in Early-Stage NSCLC (ID 6470)

      14:50 - 15:10  |  Author(s): S. Senan

      • Abstract
      • Presentation
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      Abstract:
      Radiotherapy is a curative treatment for early-stage NSCLC. Following hypofractionated radiotherapy in 15 once-daily fractions of 4 Gy to biopsy-proven tumors, a prospective multicenter study reported a 3-year local control rate of 82.7% (95% CI = 69.7% to 90.5%) [Cheung PC, 2014]. In the past decade, stereotactic ablative radiotherapy (SABR or SBRT) has become established as the guideline-recommended standard of care for medically inoperable patients with a peripheral early-stage NSCLC, as 5-year local control rates of 90% have been reported [Louie AV, 2015]. SABR is usually delivered in 3-8 fractions, utilizes small margins for positional uncertainty, 4-dimensional computed tomography (4DCT) for treatment planning, multiple conformal beams or arcs for delivery, and cone-bean CT scans for daily setup. Where facilities for SABR are unavailable, hypofractionated radiotherapy delivered using 4DCT planning remains an acceptable curative treatment. Diagnosis Population studies reveal that a significant proportion of elderly patients, as well as those with severe co-morbidities, do not receive any treatment. Guidelines recommend that a tissue diagnosis be obtained before initiating treatment for early-stage NSCLC, but also permit the use of SABR following review by an expert tumor board, in tumors where the calculated probability of malignancy is high [Vansteenkiste J, 2014; Callister ME, 2015]. However, any decision to proceed to a FDG-PET directed SABR approach in less fit patients must take into account the likelihood of benign disease. Given a high incidence of pulmonary tuberculosis, guidelines for Asia have recommended performing early non-surgical biopsies in Asian patients [Bai C, 2016]. Toxicity Treatment-related grades 3-4 toxicity are uncommon following SABR to peripheral lung tumors, while local control rates are approximately 90% [Louie AV 2015]. Commonly reported toxicities are chest wall pain, rib fractures, and except in patients who have pre-existing interstitial lung disease (ILD), the incidence of high-grade radiation pneumonitis is low. A systematic literature review of SABR in patients with ILD reported a treatment-related mortality in 15% [Chen H, Proc ASTRO 2016]. Follow-up Guidelines recommend 6-monthly CT scans for up to 3 years following SABR, followed by annual scans thereafter. The assessment of radiological changes can be challenging in a sub-group of patients during long-term follow-op, and the so-called high-risk radiological features [HRF] can identify patients in whom a biopsy is warranted [Figure 1, Huang K, 2014]. The HRF’s identified in the literature are an enlarging opacity at primary site, a sequential enlarging opacity, enlarging opacity after 12-months, a bulging margin, loss of linear margin, loss of air bronchogram and cranio-caudal growth [Huang K, 2014]. Initial reports on surgery for local failures following SABR indicate that this salvage procedure can be performed safely [Allibhai Z, 2012; Hamaji M, 2015; Verstegen N, Proc ELCC 2015]. Figure 1 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.



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      ED08.03 - Adjuvant Chemotherapy of Completely Resected (ID 6471)

      15:10 - 15:30  |  Author(s): G. Goss

      • Abstract
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      Abstract:
      Adjuvant Chemotherapy of Completely Resected NSCLC Glenwood D. Goss Lung cancer remains the leading cause 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 (4,5,6,7,8). 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 (n=344) 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 (HR=0.8) 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 HR=0.86, 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 controversial (11), subgroup analyses in a number of trials in high-risk patients with stage IB disease (tumours≥4cm) 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 = .10) and on disease-free survival (HR, 0.88; 95% CI, 0.78 to 0.98; P = .02). However, there was a significant difference between the results of overall survival before and after 5 years of follow-up (HR, 0.86; 95% CI, 0.76 to 0.97; P = .01 v HR, 1.45; 95% CI, 1.02 to 2.07; P = .04) with P = .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 = .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 = .04). There was a trend for interaction with disease stage (P = .09; HR for stage II, 0.68; 95% CI, 0.5 to 0.92; P = .01; stage IB, HR, 1.03; 95% CI, 0.7 to 1.52; P = .87). Adjuvant chemotherapy resulted in significantly prolonged disease specific survival (HR, 0.73; 95% CI, 0.55 to 0.97;P = .03). Observation was associated with significantly higher risk of death from lung cancer (P = .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 p=0.18 and squamous p=0.99) and disease free survival (nonsquamous p=0.54 and p=0.83). 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 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 GroupSurgery 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 – 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 Resected Stage IB and II Non–Small-Cell Lung Cancer: Updated Survival Analysis of JBR-10. Journal of Clinical Oncology, January 1, 2010 vol. (28) 1 29-34. 14. H.A. Wakelee[1], S.E. Dahlberg[2], 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.

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      ED08.04 - Perspectives of Targeted Therapies and Immunotherapy in Completely Resected NSCLC (ID 6472)

      15:30 - 15:45  |  Author(s): H. Wakelee

      • Abstract
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      • Slides

      Abstract:
      Perspectives of Targeted Therapies and Immunotherapy in Completely Resected NSCLC - Heather Wakelee, USA 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 Table 1 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. Table 1. Ongoing Phase III Targeted and Immunotherapy Adjuvant Trials

      Trial Description Primary Endpoint(s)
      C-TONG 1104 NCT01405079 *gefitinib vs. cisplatin/vinorelbine 3-year DFS
      GASTO1002 NCT01996098 *Chemo then icotinib vs obs 5-year DFS
      BD-IC-IV-59 NCT02125240 *Chemo then icotinib vs. placebo 2-year DFS
      WJOG6401L IMPACT *Gefitinib vs. cisplatin/vinorelbine 5-year DFS
      ALCHEMIST A081105/E4512 *Erlotinib vs. placebo: ALK^ crizotinib vs placebo OS
      ALCHEMIST/ANVIL &EGFR/ALK wildtype; US NCI NCTN, Nivolumab vs obs OS/DFS
      Impower010 Restricted to PD-L1+ Global, Atezolizumab vs. placebo DFS
      MEDI4736 &Global, MEDI4736 vs placebo DFS
      Keynote-091 &ETOP/EORTC, Pembrolizumab vs placebo DFS
      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 ALK^ : Positive for ALK translocation by FISH &- regardless of PD-L1 status US NCI NCTN: United States National Cancer Institute, National Clinical Trials Network References: 1. Pignon JP, Tribodet H, Scagliotti GV, et al: Lung Adjuvant Cisplatin Evaluation: A Pooled Analysis by the LACE Collaborative Group. J Clin Oncol, 2008 2. Group NM-aC, Arriagada R, Auperin A, et al: Adjuvant chemotherapy, with or without postoperative radiotherapy, in operable non-small-cell lung cancer: two meta-analyses of individual patient data. Lancet 375:1267-77, 2010 3. Wakelee HA, Dahlberg SE, Keller SM, et al: Randomized phase III trial of adjuvant chemotherapy with or without bevacizumab in resected non-small cell lung cancer (NSCLC): Results of E1505. Journal of Thoracic Oncology Proceedings WCLC 2015:Abstr: Plen04.03, 2015 4. Vansteenkiste JF, Cho BC, Vanakesa T, et al: Efficacy of the MAGE-A3 cancer immunotherapeutic as adjuvant therapy in patients with resected MAGE-A3-positive non-small-cell lung cancer (MAGRIT): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 17:822-835, 2016 5. Mok TS, Wu YL, Thongprasert S, et al: Gefitinib or Carboplatin-Paclitaxel in Pulmonary Adenocarcinoma. N Engl J Med, 2009 6. Sequist LV, Yang JC, Yamamoto N, et al: Phase III Study of Afatinib or Cisplatin Plus Pemetrexed in Patients With Metastatic Lung Adenocarcinoma With EGFR Mutations. J Clin Oncol, 2013 7. Solomon BJ, Mok T, Kim DW, et al: First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med 371:2167-77, 2014 8. Kelly K, Altorki NK, Eberhardt WE, et al: Adjuvant Erlotinib Versus Placebo in Patients With Stage IB-IIIA Non-Small-Cell Lung Cancer (RADIANT): A Randomized, Double-Blind, Phase III Trial. J Clin Oncol 33:4007-14, 2015 9. Brahmer J, Reckamp KL, Baas P, et al: Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer. N Engl J Med 373:123-35, 2015 10. Borghaei H, Paz-Ares L, Horn L, et al: Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer. N Engl J Med 373:1627-39, 2015 11. Herbst RS, Baas P, Kim DW, et al: Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet 387:1540-50, 2016

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    PL05 - Closing Plenary Session: A Life in Thoracic Oncology - Reflections from Giants on Milestones in the Treatment Advances in Lung Cancer (ID 433)

    • Event: WCLC 2016
    • Type: Plenary
    • Track:
    • Presentations: 1
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      PL05.05 - Chemotherapy (ID 6918)

      17:10 - 17:25  |  Author(s): T. Le Chevalier

      • Abstract
      • Presentation
      • Slides

      Abstract:
      Chemotherapy has long been the only available systemic treatment for Non-Small Cell lung Cancer. In the late 70’s, there were a multitude of triplets and quadruplets with response rates ranging from 20-35% in patients with stage IV disease. In 1980, cisplatin, a cytotoxic agent initially developed for germ-cell tumors, showed some activity, mostly when combined with a vinca-alkaloïd or with etoposide. At the time Vinorelbine was registered by the FDA in 1994, alone or in combination with cisplatin, only 3 drugs were approved for NSCLC, nitrogen mustard, methotrexate and doxorubicin! Metastatic Disease The individual data-based meta-analysis published in 1995 established the superiority of chemotherapy over supportive care in patients with advanced NSCLC. These results have been recently updated and confirmed in 2714 patients from 16 trials with an overall survival benefit of 9% at 1 year. Chemotherapy also improves quality of life and symptom control in patients with good performance status. It is classically recommended to use platin compounds (mostly cisplatin and carboplatin) in combination with third generation agents including vinorelbine, gemcitabine, taxanes (paclitaxel, docetaxel, nab-paclitaxel) or pemetrexed (in non-squamous NSCLC). Integrating palliative care at an early stage of the treatment also prolongs survival and improves quality of life. Second line chemotherapy with docetaxel or pemetrexed has also been demonstrated active even if the benefit on overall survival remains modest. The use of biological markers such as ERCC1, RRM1, beta-tubulin or thymidilate synthase has not yet proven efficacy on the choice of cytotoxic agents. Maintenance: Up to 2009, it was generally accepted that 4 to 6 cycles of induction chemotherapy followed by a rest till progression were the standard. The switch to a new drug as maintenance after 4 cycles of a platin-based doublet showed a benefit for PFS and OS. Maintenance is now considered a standard in the management of metastatic NSCLC. Chemo-radiotherapy for locally advanced disease: The benefit obtained with radiotherapy and chemotherapy given sequentially in locally advanced inoperable NSCLC is modest but significant and well established. Several randomized trials comparing radiotherapy-chemotherapy given sequentially or concomitantly have suggested a better outcome when both modalities were given early and simultaneously. A meta-analysis based on individual patient data from published and unpublished randomised trials which compared radiotherapy alone with the same radiotherapy combined with concomitant cisplatin- or carboplatin-based chemotherapy was recently performed. The analysis was based on 9 trials including 1764 patients. The hazard ratio of death among patients treated with radio-chemotherapy compared to radiotherapy alone was 0.89 (CI 95%: 0.81-0.98; P = 0.02) corresponding to an absolute benefit of chemotherapy of 4% at 2 years. There was some evidence of heterogeneity among trials and sensitivity analyses did not lead to consistent results. The available data are insufficient to accurately define the size of such a potential treatment benefit and the optimal schedule of chemotherapy in combination with radiotherapy. Adjuvant chemotherapy: In the meta-analysis published in 1995, a 13% reduction in the risk of death was observed, suggesting an absolute benefit of 5% at 5 years with adjuvant chemotherapy. These results constituted the rationale for a new generation of randomized studies with platinum-based regimens. The LACE meta-analysis, which was reported at ASCO 2006, pooled a total of 4584 patients accrued in the five largest cisplatin-based adjuvant trials launched after the results of the meta-analysis. It confirmed the benefit of adjuvant chemotherapy with a 5.3% improvement of survival at 5 years (p=0.0043). Disease-free survival was also improved (5.2% at 5 years, p<0.0001). There was a negative effect of adjuvant chemotherapy for stage IA. The risk reduction was 8% for stage IB, 17% for stages II and III. The effect of chemotherapy did not vary according to age, gender, PS, type of surgery and histology. In parallel, the adjuvant UFT meta-analysis also confirmed a significant advantage of the drug compared to control in 2003 Japanese patients (p<0.001). The individual-data-based meta-analysis was updated in 2007. It confirmed the significant effect of postoperative chemotherapy, with or without postoperative radiotherapy. Neoadjuvant chemotherapy : Several phase II trials have been carried out in the 80’s to evaluate the benefit of preoperative chemotherapy in operable NSCLC with encouraging results. In the mid 90’s, two randomized phase III trials had a significant impact on the medical community due to their impressive results. Both trials randomized 60 stage IIIA patients and were interrupted after positive interim results were observed. Only two published randomized phase III studies comparing front-line surgery to pre-operative chemotherapy followed by surgery accrued the number of patients that were initially planned: a French study that included 373 patients and the Medical Research Council LU22 trial that included 519 patients. None of the large randomized studies could demonstrate a significant advantage in favor of pre-operative chemotherapy. A recent individual patient data-based meta-analysis of pre-operative chemotherapy trials has included 2385 patients from 15 trials. A HR of 0.87 (CI 95%: 0.7_–0.96, p=0.007) was observed, equivalent to an absolute improvement in survival of 5% at five years, similar to the benefit observed with postoperative chemotherapy. Preoperative or postoperative chemotherapy? A comparison of preoperative versus postoperative chemotherapy has been did not show any difference. In fact, the key issue may be to determine which patients should be treated with adjuvant and/or neo-adjuvant therapy. The neo-adjuvant approach offers a unique opportunity to test new drugs and to compare the tumor characteristics prior to and following induction therapy. Developing molecular based therapeutic strategies will certainly be one of the major challenges over the next few years. Several randomized adjuvant studies have recently been initiated in Europe and in America, based on the molecular characteristics of patients tumor. In conclusion, chemotherapy remains the main systemic treatment for most patients with lung cancer and the only one able to increase the cure rate. Unfortunately, very few drugs have been developed in the last decade in spite of a clear unmet medical need. A better individual selection of drugs/drug combinations according to pharmacogenomic data might encourage the community to optimize the use of cytotoxic agents.

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