G. Ceresoli - Lung cancer - State of the art


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  • Dear co-chair, dear colleagues, it is a pleasure for me to be here and have this lecture on the state of the art in lung cancer. I would like to thank the chairs of the course, the Scientific Committee the Euro-Arab School of Oncology for their kind invitation.
  • Lung cancer is a leading cause of cancer-related deaths worldwide, with more than a million of new cases per year, and a 5-yr survival for the overall population in the range of 15% to 20%. 4 major histology types are recognized (adenocarcinoma, squamous cell carcinoma, large cell carcinoma and small cell carcinoma). Overall, more than 80% of lung cancer cases are represented by non-small cell histologies. In my presentation, I will focus on non-small cell lung cancer only.
  • My overview will cover three topics: adjuvant therapies in resected patients, multimodality treatment in locally advanced disease and therapy of metastatic disease in NSCLC. I will not go through the details of all the trials of metastatic disease, that is the topic of Prof. Gaafar’s presentation.
  • 3 Survival in resected NSCLC with surgery alone is poor, except for stage I patients. Recurrence and death are mostly related to the occurrence of distant metastases , especially when a nodal N1 and N2 disease is found at surgery. This has been a clear rationale for the development of adjuvant strategies.
  • After more than ten years of randomized studies comparing chemotherapy with observation alone after surgery, the use of adjuvant cisplatin-based chemotherapy has been established as a standard therapy in fit patients. The LACE metanalysis based on the largest randomized studies on more than 4.500 patients has shown an absolute survival improvement of nearly 5 percent at 5 years, with an hazard ratio of 0.89 .
  • What have we learned about adjuvant chemotherapy in early-stage NSCLC patients? First, adjuvant chemotherapy should be administered to patients with stage II and IIIA , while there is still a debate regarding patients with stage IB (specially with large tumors). Second, platinum agents are important and the majority of the data supports the use of cisplatin. There are not a lot of data evaluating carboplatin, and this data come from small trials, such as the CALGB trial. Finally, the majority of the data has been shown with vinorelbine and those data have suggested that it is very effective. However, there are not enough data on other drugs with an appropriate dose of cisplatin.
  • Recently the results of a randomized phase II trial have been reported, in which the combination of cisplatin plus pemetrexed was compared to cisplatin plus vinorelbine in the adjuvant setting.
  • Efficacy results are not mature, however toxicity data showed a significant decrease of hematological toxicity , namely grade 3 and 4 neutropenia, with the pemetrexed combination. Dose delivery was higher with cisplatin/pemetrexed. Dose delivery failure in cisplatin/vinorelbine was mostly due to vinorelbine, planned on a weekly schedule.
  • Although adjuvant chemotherapy is now considered as a standard, we have to treat a large number of patients to give a survival benefit only to a minority of them. For example according to the data of LACE metanalysis, 61% of patients with resected stage III tumors will die despite adjuvant chemotherapy, while 13% only will survive due to the adjuvant treatment. Of course the next step will be to identify in advance patients who will benefit from adjuvant chemotherapy.
  • The most promising approach is a pharmacogenomic approach. Based on preliminary results in advanced disease, the role of ERCC1 (one of the several proteins involved in DNA repair) was retrospectively investigated in about seven hundreds patients enrolled in the International Adjuvant Lung Trial. Patients with negative ERCC1 benefit of adjuvant chemotherapy, with a gain of 14 months in median OS, and an hazard ratio of 0.65, that represents a decrease of 35% in the risk of death with adjuvant chemotherapy.
  • Cis, cisplatin; EGFR, epidermal growth factor receptor; ERCC1, excision repair cross-complementation group 1; gem, gemcitabine; NSCLC, non-small-cell lung cancer; RRM1, ribonucleotide reductase subunit M1; TS, thymidylate synthase.   Several prospective biomarker adjuvant trials are ongoing. The studies include a pilot trial led by the Southwest Oncology Group and 3 trials ongoing in Europe. Each trial is evaluating different biomarkers hypothesized to be predictive and focusing on the chemotherapy agents associated with those biomarkers.
  • Cis, cisplatin; DDP, platinum; EGFR, epidermal growth factor receptor; ERCC1, excision repair cross-complementation group 1; gem, gemcitabine; pem, pemetrexed; TS, thymidylate synthase.   For example, the International Tailored Chemotherapy Adjuvant Trial is a randomized trial of standard chemotherapy versus biomarker-tailored chemotherapy. The control arm receives standard chemotherapy with a platinum-based doublet selected by the investigator. Patients on the experimental arm receive treatment assignments based on ERCC1 and TS levels. Patients with high levels of ERCC1 and high levels of TS are predicted to be resistant to both platinum and pemetrexed and, therefore, receive a taxane. Patients with low levels of ERCC1 and low levels of TS are predicted to be sensitive to both cisplatin and pemetrexed and are assigned to a combination of those agents. Patients with high ERCC1 levels and low TS levels receive pemetrexed (no platinum), and patients with low ERCC1 levels but high TS levels receive cisplatin plus gemcitabine (no pemetrexed). This trial is actively accruing.  
  • Another approach to improve the results of adjuvant chemotherapy has been to add targeted therapies in the adjuvant setting. In the JBR.19 study, adjuvant gefitinib was compared to placebo in unselected stage IB-IIIA NSCLC patients, stratified by gender, stage, histology, postoperative radiation and adjuvant chemotherapy. 503 patients were enrolled. The results of the study were negative, with no improvement in overall or disease-free survival with gefitinib vs placebo.   A similar trial is ongoing with erlotinib , in patients selected based on the positivity to Epithelial Growth Factor Receptor (EGFR) as determined by immunohistochemistry or FISH.
  • ASCI, antigen-specific cancer immunotherapeutic; DFS, disease-free survival; ECOG, Eastern Cooperative Oncology Group; NSCLC, non-small-cell lung cancer; PS, performance score.   Another ongoing adjuvant trial is the MAGRIT trial, examining a vaccine against the MAGE-A3 protein found in about 30% of resected NSCLCs, and slightly more frequently in the squamous cell population. This trial is a randomized phase III study with the primary endpoint of disease-free survival . Patients with stage IB-IIIA disease with a good performance score who have evidence of MAGE-A3 gene expression are randomized 2:1 to receive 13 doses of an intramuscular MAGE-A3 vaccine or a placebo. Patients are allowed to receive and are stratified based on adjuvant chemotherapy . This trial will accrue more than two thousand patients.
  • Post-operative radiotherapy has been proposed in several trials to reduce the occurrence of locoregional (and maybe distant) relapse. According to the results of the PORT metanalysis , post-operative mediastinal radiotherapy was detrimental in patients with resected stage I and II disease. PORT metanalysis has been criticized because is based on old trials with old radiotherapy techniques. However, in clinical practice post-operative RT should only be considered for patients with resected stage IIIA and mediastinal node involvement .
  • To assess the real role of ajuvant radiotherapy in N2 patients, a randomized trial is running. In the Lung ART trial patients with pathologically proven N2 nodal involvement are randomized to post-operative conformal RT at the dose of 54 Gy versus control.
  • The treatment of locally advanced NSCLC, namely stage IIIA and IIIB, is highly complex due the heterogeneity of the patients populations, that makes the conduct of clinical studies and their comparison quite difficult. In particular, there is no clear consensus about the exact definition of unresectable disease , that is generally related to the invasion of mediastinal structures, to pathological N3 involvement, to the presence of bulky nodes, to multi-stational lymph-nodal involvement, and to extracapsular extension of lymph node metastases.
  • We can grossly distinguish a resectable disease, a marginally resectable disease that is candidate to induction treatments, and a truly unresectable NSCLC.
  • Several phase II and III trials have been conducted with chemotherapy alone, generally with 2 to 4 cycles of platinum-based regimens. Response rates were in the range of 60 to 70%, with a low pathological complete response rate, that is the ideal goal for a prolonged survival. Other trials have explored neoadjuvant chemoradiotherapy , with a dose of 40 to 45 Gy, and platinum-based regimens, the most classical being the combination of cisplatin and etoposide . With CT/RT higher rates of pathological complete remission can be achieved, but with higher surgical morbidity and mortality.
  • This slide shows the results of a meta-analysis of randomized trials of neoadjuvant chemotherapy followed by surgery versus surgery alone. As you can see, the overall result is a marginal improvement in OS, with an hazard ratio of 0.88 .
  • The strategy of neoadjuvant chemoradiotherapy was studied in a large intergroup trial in which technically resectable pts with pathologically-proven N2 disease, not progressing after 45 Gy and 2 cycles of concomitant cisplatin and etoposide, were randomized to continue RT to 61 Gy versus surgical resection.
  • No survival improvement was observed in the surgical arm, with an excess of mortality for surgical patients in the first part of the curve .
  • The detrimental effect of surgery in this trial was limited, according to a post-hoc analysis, to patients who underwent pneumonectomy (especially right pneumonectomy) after the induction treatment.
  • For unresectable stage III NSCLC patients in good clinical conditions the standard treatment is concurrent CT/RT , as demonstrated in several randomized trial versus sequential chemo-radiotherapy. With the concomitant treatment, median survival was of about seventeen to eighteen months, with a small but definite proportion of patients surviving at 5 years .
  • The problem with the concurrent treatment is the high rate of severe toxicities, particularly esophageal toxicity . These treatment therefore should be performed to selected patients only, in experienced centers able to guarantee an adequate supportive care.
  • Most patients with locally advanced NSCLC recur with distant metastases. Therefore a rationale approach was to give more chemotherapy, as induction before concomitant CT/RT or as consolidation after combined treatment.
  • The obvious potential advantage of induction chemotherapy is not only the treatment of micro-metastatic disease but also a tumor shrinkage with smaller radiotherapy fields.
  • I will show just the results of one classical trial published nearly 10 years ago, in which patients were randomized to receive induction chemotherapy for 2 cycles according to 3 different cisplatin-based regimens, and than the same regimens at reduced doses for two more cycles with concomitant RT. As you can see in the lower section of the slide, the addition of induction chemotherapy worsened esophageal toxicity to unaccetable rates.
  • The second strategy of consolidation chemotherapy after concurrent CT/RT was explored in two main studies. In the first study patients not progressing after concomitant CT/RT were randomized to observation versus consolidation chemotherapy with docetaxel at full doses for 3 cycles.
  • No survival improvement was observed, in spite of an increased toxicity in the docetaxel arm.
  • In the second trial all patients received concomitant CT/RT followed by docetaxel for 3 cycles. Non-progressing patients were then randomized to placebo or maintenance gefitinib for a maximum of 5 years. The primary endpoint of the study was overall survival.
  • Overall survival from the time of randomization was 23 months for gefitinib compared to 35 months for placebo. The detrimental effect of gefitinib was probably related to an excess of pulmonary toxicity and also to the fact that concomitant CT/RT probably select a cell population highly resistant to EGFR inhibitors .
  • Real improvements in these patients are expected with a better patient selection that can be achieved with PET staging . Furthermore, the use of PET scanning before RT treatment allows a more accurate definition of treatment volumes .
  • The major improvements are expected from the extraordinary progress of RT techniques . The use of involved field RT and of intensity-modulated RT has the potential to reduce toxicity and to increase local control by delivering higher doses.
  • The last part of my presentation will cover metastatic disease. As I have mentioned before, metastatic disease will be the topic of Prof. Gaafar’s presentation. I will just give an overview of the treatment paradigm in these patients. In stage IV NSCLC, 10 years ago the results of several phase III studies comparing different platinum-based doublets in fit patients had clearly shown that we had reached a survival plateau of about 10 months . In the last 10 years there has been a tremendous effort to move forward to a better understanding of tumor biology .
  • It has become clear that patients that were grouped once under the same diagnosis of stage IV NSCLC have often completely different diseases, and should be treated with different therapies.
  • Besides clinical factors such as age and PS, also histological factors and molecular factors have emerged as potential drivers of personalized therapy in advanced NSCLC.
  • In a pivotal trial published 3 years ago, patients with non squamous histology achieved a significantly longer survival when treated with the combination of cisplatin and pemetrexed, while patients with squamous histology had a better outcome if treated with another combination of cisplatin and gemcitabine.
  • In reality the histological factors are a surrogate of molecular differences between the two groups of tumor. This molecular profile shows that the levels of expression of thymidilate synthase , that is the main target of pemetrexed, are lower in adenocarcinoma, in comparison to small cell and squamous cell carcinoma. That would be one explanation for why squamous cell patients respond less well to pemetrexed than adenocarcinoma patients.
  • Molecular factors in NSCLC have been studied in the clinical setting mainly for two pathways: the VEGF and the EGFR pathways.
  • Bevacizumab and cetuximab, two monoclonal antibodies targeting VEGF and EGFR, have been studied in large phase III trials in combination with chemotherapy. The details of these trials will be discussed by Prof. Gaafar. No clear predictive factor has been identified for these drugs. Survival improvement is modest (in one trial only for bevacizumab, one month only for cetuximab), with relevant toxicities and high costs.
  • Tyrosine kinase inhibitors gefitinib and erlotinib have been studied in a number of phase I, II and III studies, as single agents or in combination with chemotherapy, in unselected patients. All these trials were negative, except for BR21 study.
  • In this study, erlotinib was superior to placebo as second or third line treatment in terms of PFS and OS, with a gain of 2.0 mos in median survival. In all these EGFR-TKIs trials, response were higher in Asian patients, in female, never smokers, adenocarcinoma patients.
  • The turning point of the treatment of advanced non small cell lung cancer was the identification of EGFR mutations in the tyrosine kinase domain of the receptor. Mutations in the exons 18,19 and 21 are predictors of sensitivity to 1 st generation of EGFR TKIs (gefitinib and erlotinib), while mutations in exon 20 were identified as predictors of acquired resistance to these drugs. The most frequent activating mutations are deletions in the exon 19 and point mutation in exon 21; T790M mutation is the most frequent mutation in exon 20 associated with resistance. Activating mutations are more frequent in Asian patients, females, never smokers, and in adenocarcinoma patients.
  • The incidence of activating mutations in Asian patients with lung adenocarcinoma is over 30%, while it is about 10% in the Caucasian population. Therefore most trials with TKIs as first line treatment in selected patients were conducted in Asian patients . In all these trials gefitinib and erlotinib had a significantly longer PFS as compared to chemotherapy. No advantage in OS was observed due to the cross-over effect (second-line treatment with EGFR TKIs in the control arms).
  • A similar European trial with erlotinib has been recently presented at last ASCO meeting, confirming these data.
  • Other mutations have been identified in NSCLC patients. In a study conducted on 516 lung adenocarcinoma pts, mutations were found in 54% of tumors. In this study, patientswere referred to appropriate biomarker driven clinical trials, based on the specific analysis.
  • One of the recently identified gene alteration is re-arrangement of the ALK gene . Similar to EGFR mutations, the frequency of EML4 - ALK fusions is increased in pts with adenocarcinomas, in young adult pts, and in people who have never smoked (<100 cigarettes in a lifetime) or who are light smokers (≤15 pack-years). In a phase II trial, response rate of more than 60% was achieved with an oral ALK inhibitor, crizotinib.
  • Two confirmatory trials with crizotinib are ongoing, one phase III in the second line setting following platinum-based chemotherapy, and one single arm phase II study in third line of treatment.
  • Another example of molecular-driven therapies are represented by the treatment strategies in patients that develop resistance to EGFR TKIs . Resistance to these drugs is due in about half cases to the presence in the tumor of an acquired EGFR mutation, frequently the T790M in exon 20; in 20% of cases the resistance is due to MET amplification .
  • Afatinib is an oral irreversible inhibitor of EGFR and HER2. In preclinical models, afatinib was active in tumors with the T790M mutation . In the clinical setting, it has been studied versus placebo in a large randomized trial
  • A modest improvement was observed in PFS , while no advantage versus placebo was seen as regards overall survival .
  • In another preclinical study, it was shown that cetuximab could enhance the activity of afatinib, in the presence of the resistance mutation T790M.
  • These data have generated a clinical trial of this combination of afatinib and cetuximab in patients with acquired resistance to first generation TKIs. The preliminary results of this study have been presented recently at the last World Conference on Lung Cancer. The great majority of patients had tumor shrinkage, with a substantial number having RECIST partial response , or even complete response. What was surprising, is that the patients who benefited included not only the patients with T790M mutation, but also patients without that mutation . These data are very provocative for the use of the monoclonal antibody, cetuximab, in reversing resistance to a TKI.
  • Another interesting trial with molecular-driven therapy is a phase II trial of the combination of erlotinib plus MetMAb , a monoclonal antibody directed against the Met receptor. Patients in second or third line of treatment were randomized to receive erlotinib plus MetMAb versus erlotinib plus placebo. A Met IHC score was developed and applied to patient samples after randomization.
  • In the Met diagnostic positive group, the combination of the two drugs achieved a substantial improvement in progression-free survival and overall survival . This is another example of molecular-driven treatment.
  • In conclusion: Adjuvant chemotherapy is standard in N1 and N2 resected pts. Mediastinal RT should be considered in N2 pts only. Ongoing pharmacogenomic-oriented trials will hopefully help to properly select chemotherapy regimens for adjuvant treatment. Multimodality treatments (concomitant ChT/RT) is the standard treatment in unresectable stage III pts. Major improvements (reduced toxicity, improved local control) are awaited from new RT techniques. . 3. Treatment in stage IV should be personalized, as much as possible, based on clinical, histological and molecular factors. Targeted therapies should be ideally used only in selected patients with predictive biomarkers.
  • G. Ceresoli - Lung cancer - State of the art

    1. 1. LUNG CANCER: state of the art Giovanni Luca Ceresoli Thoracic and GU Oncology Unit Humanitas Gavazzeni Clinic – Bergamo, Italy 27/10/2011 - 29/10/2011, Amman, Jordan 3rd EASO Masterclass in Clinical Oncology
    2. 2. Lung Cancer Subtypes <ul><li>The WHO classification for primary lung cancer recognizes 4 major histology types </li></ul>Small cell carcinoma 13.0% Large cell carcinoma 5.0% Adenocarcinoma 38.3% 19.7% Squamous cell carcinoma Others 24.0% Percent distribution by histology among histologically confirmed lung cancer cases, 2001-2004 SEER Database. Lung and Bronchus Cancer (Invasive), 1975-2004.
    3. 3. Non-small cell lung cancer <ul><li>Adjuvant therapies in resected pts </li></ul><ul><li>Multimodality treatments in stage III pts </li></ul><ul><li>Metastatic disease [Guidelines, R. Gaafar] </li></ul>
    4. 4. RATIONALE FOR ADJUVANT CT IN NSCLC <ul><li>Survival with surgery alone is poor in some stages </li></ul><ul><li>Recurrence and death are most commonly related to distant mets </li></ul>Relapse % Surgical Stage 5-Year Surv. (%) Local Distant IA T1N0M0 67 10 15 IB T2N0M0 57 10 30 IIA T1N1M0 55 IIB T2N1M0 T3N0M0 39 38 12 40 IIIA T3N1M0 T1-3N2M0 25 23 15 60
    5. 5. JL Pignon et al, JCO 2008
    6. 6. Adjuvant Chemotherapy: Lessons Learned <ul><li>Stages </li></ul><ul><ul><li>II-IIIA </li></ul></ul><ul><ul><li>IB a question </li></ul></ul><ul><li>Agents </li></ul><ul><ul><li>Platinum agents important (cisplatin) </li></ul></ul><ul><ul><li>Vinorelbine effective </li></ul></ul><ul><ul><li>Not enough data on other drugs </li></ul></ul>
    7. 7. TREAT Design R0 Winton et al., N Engl J Med (2005) 352: 258 Inclusion • NSCLC stages IB, IIA, IIB, T3N1M0 • ≤ 42 Tage postoperatively, R0, systematic LN-dissection • ECOG 0, 1 • amenable to Cisplatin treatment Stratification • Center • Nodal status (N0 versus N1) • Surgical procedure (lobectomy versus pneumonectomy) Kreuter et al., ASCO 2011 Randomized phase II study Cisplatin / Vinorelbine (CVrb) Cisplatin / Pemetrexed (CPx) 50 mg/m 2 d1+8 / 25 mg/m 2 d1, 8, 15, 22 q d 29 x 4 75 mg/m 2 d1 / 500 mg/m 2 d1 q d 22 x 4
    8. 8. TREAT Toxicity p<0.0001 p=0.7988 Higher dose delivery in CPx. Dose delivery failure mostly due to Vb (schedule). Kreuter et al., ASCO 2011 Toxicity CPx CVb Hematologic Toxicity G3/4 (%) 10.5 76.5 Non-hematologic Toxicity G3/4 (%) 33 31 Hematologic Toxicity (%) G3/4 G3/4 Anemia 0 1.5 Thrombocytopenia 0 0 Neutropenia 9 69 Febrile Neutropenia 1.5 6
    10. 10. EARLY STAGE NSCLC & ADJUVANT CT ERCC1 Role (Bio-IALT) Olaussen KA et al, NEJM 2006 <ul><li>ERCC1- : benefit of adjuvant chemotherapy (HR for death 0.65, CI95% 0.50-0.86, p=0.002). MS=56 vs 42 mos.5yS= 47 vs 39%. </li></ul>
    11. 11. Prospective Biomarker Adjuvant Trials for NSCLC <ul><li>ClinicalTrials.gov. NCT00792701. 2. Scagliotti G, et al. The Oncologist. 2009. </li></ul><ul><li>3. ClinicalTrials.gov. NCT00775385. 4. ClinicalTrials.gov. NCT00478699. </li></ul>EGFR, epidermal growth factor receptor; ERCC1, excision repair cross-complementation group 1; RRM1, ribonucleotide reductase subunit M1; TS, thymidylate synthase. Trial Stage Therapy Marker SWOG 0720 [1] I ± Chemotherapy (cis/gem) ERCC1/RRM1 ITACA [2] II-III Cisplatin/pemetrexed ERCC1/TS TASTE [3] II-IIIA Cisplatin/erlotinib ERCC1/EGFR mut SCAT [4] II-IIIA Platinum/docetaxel BRCA1
    12. 12. <ul><li>Tumors tested for ERCC1 and TS </li></ul><ul><li>High/Low ERCC1 and TS selected according to median level of mRNA expression in historical series </li></ul>International Tailored Chemotherapy Adjuvant Trial (ITACA) Scagliotti G, et al. The Oncologist. 2009;14:253-263. *Control arm: investigator choice of a DDP-based doublet. Control* ERCC1 (Planned N = 700) High Low TS TS Low Low High High Profile 4 Profile 3 Profile 2 Profile 1 Taxane Pemetrexed Cis/Gem Cis/Pem Control* Control* Control*
    13. 13. JBR.19: Adjuvant Gefitinib in Resected Stage I-IIIA NSCLC Gefitinib 250 mg/day (n = 251) Placebo (n = 252) Patients with completely resected stage IB-IIIA NSCLC (N = 503) Stratified by stage, histology, postoperative radiotherapy, sex, adjuvant chemotherapy* Yr 2 *Protocol amended in January 2003 to permit adjuvant chemotherapy. Goss GD, et al. ASCO 2010. Abstract LBA7005. No improvement in overall or disease-free survival with gefitinib vs placebo.
    14. 14. MAGRIT: MAGE-A3 ASCI Adjuvant Therapy for Stage I-IIIA NSCLC <ul><li>MAGE-A3: tumor-specific antigen observed almost exclusively on cancer cells (expressed in about 30% of NSCLC) </li></ul><ul><li>Randomized, multicenter phase III trial </li></ul><ul><li>Primary endpoint: DFS </li></ul>Patients with stage IB-IIIA NSCLC; ECOG PS ≤ 2; MAGE-A3 gene expression; chemotherapy optional (Planned N = 2270) Recombinant MAGE-A3 x 13 doses intramuscularly Placebo x 13 doses intramuscularly ClinicalTrials.gov. NCT00480025. SURGERY Postoperative randomization 2:1 ASCI:placebo Stratified by adjuvant chemotherapy
    15. 15. PORT Group, Lancet 1998; updated in Lung Cancer 2005 Post-operative RT in radically resected NSCLC
    16. 16. Lung ART (Adjuvant Radiotherapy Trial) Phase III Trial Completely resected NSCLC with mediastinal histo-cytologically proven nodal involvement (N2) R Control Post-operative conformal RT (54 Gy) Possibility of Adjuvant CT Pre-op and/or Post-op CT Stratification factors : Center, Administration of CT (no CT vs Pre-op CT vs Post-op CT alone), Histology (SCC vs others), Extent of lymph node involvement (0 vs 1 vs 2+), use of pretreatment PET-scan (yes/no)
    17. 17. Stage III NSCLC <ul><li>Highly heterogeneous </li></ul><ul><li>Definition of “unresectable” disease </li></ul><ul><ul><li>Invasion of mediastinal structures (T4) </li></ul></ul><ul><ul><li>pN3 </li></ul></ul><ul><ul><li>Bulky nodes </li></ul></ul><ul><ul><li>Multi-stational involvement </li></ul></ul><ul><ul><li>Extracapsular extension </li></ul></ul>
    19. 19. MARGINALLY RESECTABLE STAGE III NSCLC <ul><li>Chemotherapy </li></ul><ul><ul><li>Platinum-based </li></ul></ul><ul><ul><li>Radiographic response rates: up to 60-70% </li></ul></ul><ul><ul><li>Low rate of pathologic CR: ~ 10% </li></ul></ul><ul><li>Chemoradiotherapy </li></ul><ul><ul><li>Radiation dose: ~ 40-45 Gy </li></ul></ul><ul><ul><li>Platinum-based chemotherapy </li></ul></ul><ul><ul><li>Higher pathologic CR: ~ 20-30% </li></ul></ul><ul><ul><li>Higher surgical morbidity </li></ul></ul>Neoadjuvant Therapy of NSCLC: CT vs CT/RT
    20. 20. Meta-Analysis of neoadjuvant ChT trials Gilligan D, Lancet 2007 Dautzenberg 1990 13 13 1.03 [0.37, 2.93] Roth 1994 28 32 0.89 [0.42, 1.88] Rosell 1994 30 30 0.63 [0.32, 1.24] Depierre 2002 179 176 0.83 [0.64, 1.07] JCOG9209 2003 31 31 0.75 [0.43, 1.30] Sorensen 2005 44 46 0.89 [0.49, 1.63] SWOG9900 2005 168 167 0.84 [0.60, 1.18] Current trial 258 261 1.02 [0.80, 1.31] Total 751 756 0.88 [0.76, 1.01] 0.1 0.2 0.5 1 2 5 10 Favours CT+S Favours S Trial CT + S S Hazard Ratio HR (95% CI) Number of patients
    21. 21. Int 0139/RTOG9309: Study design Cisplatin 50 mg/m 2 Days 1,8,29,36 Etoposide 50 mg/m 2 Days 1-5, 29-33 TRT, 45 Gy (1.8 Gy/d) begin day 1 RE-EVALUATE 7 days before completion of RT. If No PD continue TRT to 61 Gy without interruption RE-EVALUATE 2-4 wks after completion of RT. If No PD Surgical resection CONSOLIDATION Cisplatin + Etoposide R A N D O M I Z E Albain KS, Lancet 2009
    22. 22. Albain KS, Lancet 2009 Treatment-related deaths: 8% vs 2%
    23. 23. Int 0139: CT/RT + lobectomy vs pneumonectomy CT/RT  Pneumonectomy vs CT/RT CT/RT  Lobectomy vs CT/RT Albain KS, Lancet 2009 Pts matched with those in non-surgical group according to age, sex, KPS, clinical T stage
    24. 24. Survival comparison between sequential and concurrent CT/RT P < 0.05 CONCURRENT CT/RT: mOS 17-18 mos; 5-yr OS 15% UNRESECTABLE STAGE IIIA/B NSCLC 14 (n=716) 17 (n=709)
    25. 25. SEQUENTIAL vs CONCURRENT CT+RT Esophageal Toxicity Comparison P < 0.05 (Kruskal-Wallis Test) H Choy, WCLC 2003 23% 4%
    26. 26. Designs for optimal chemoradiotherapy <ul><li>Induction Chemotherapy  Concurrent Chemoradiotherapy </li></ul><ul><li>Concurrent Chemoradiotherapy  Consolidation Chemotherapy </li></ul>
    27. 27. REGIONAL ADVANCED UNRESECTABLE NSCLC Advantage for Induction  CT/RT At diagnosis After CT Induction
    28. 28. CALGB 9431: Randomized Phase II Study Design CIS 80mg/m 2 d1 VNB 25mg/m 2 d1,8,15 Q 21 x 2 CIS 80mg/m 2 d 1 TAX 225 mg/m 2 d 1 Q 21 x 2 CIS 80mg/m 2 d 1 GEM 1250 mg/m 2 d 1&8 Q 21 x 2 RANDOM NSCLC IIIB PS<1 CIS 80mg/m 2 d1 VNB 15mg/m 2 d1,8 Q 21 x 2 CIS 80mg/m 2 d 1 TAX 135 mg/m 2 d 1 Q 21 x 2 CIS 80mg/m 2 d 1 GEM 600 mg/m 2 d 1&8 Q 21 x 2 RT 60 Gy 2 Gy/d + Vokes EE, JCO 2002 G3/4 ESOPHAGEAL TOXICITY 39% CIS/TAX 52% 25% CIS/GEM CIS/VNB
    29. 29. HOG LUN 01-24/USO 02-033 (Phase III) <ul><li>ChemoRT </li></ul><ul><li>Cisplatin 50 mg/m2 IV d 1,8,29,36 </li></ul><ul><li>Etoposide 50 mg/m2 IV d 1-5 & 29-33 </li></ul><ul><li>Concurrent RT 59.4 Gy (1.8 Gy/fr) </li></ul>Stratification Variables: PS 0-1 vs 2 IIIA vs IIIB CR vs. non-CR Docetaxel 75 mg/m 2 q 3 wk  3 Observation Randomize Hanna N, JCO 2008 CT/RT + Consolidation in Stage III NSCLC: docetaxel
    30. 30. Overall Survival (ITT) Randomized Patients (n=147) Months since registration 0 10 20 30 40 50 60 Percent of patients surviving 0% 25% 50% 75% 100% Observation Docetaxel Consolidation Observation: Median: 24.1 months (18.0-34.2) 3 year survival rate: 27.6% Docetaxel: Median: 21.5 months (17.-34.8) 3 year survival rate: 27.2% P-value: 0.940 Hanna N, JCO 2008
    31. 31. SWOG 0023: Design CDDP 50 mg/m 2 d 1,8,29,36 VP-16 50 mg/m 2 d1-5, 29-33 XRT 1.8- 2 Gy/d 61 Gy DOCETAXEL 75 mg/m 2 x 3 cycles 1 st Endpoint: Overall Survival; 2 nd Endpoint: PFS, toxicity and correlative science Maintenance therapy could continue for a maximum of 5 years PLACEBO GEFITINIB 250 mg/day Maintenance R A N D O M I Z E Kelly K, JCO 2008 Definitive TX Consolidation
    32. 32. SWOG 0023: OS Kelly K, JCO 2008
    33. 33. 2011 Precise definition of the cancer’s anatomical extent is crucial for accurate placement and shaping of the radiotherapy beams. The use of ¹⁸ F-FDG PET/CT scanning in the radiotherapy treatment position allows for accurate definition of the gross tumour volume on the treatment-planning computer. PATIENT SELECTION: BETTER STAGING AND STRATIFICATION
    34. 34. 2010 IFRT : no increase in nodal failure rates in clinically uninvolved nodal stations; significantly lower esophageal toxicity. IMPROVEMENTS IN RADIOTHERAPY 2011 IMRT has the potential to improve dose delivery in NSCLC, especially in large node-positive tumors in close proximity to the organs at risk.
    35. 35. 3rd GENERATION DOUBLETS P-BASED NO Difference in Survival METASTATIC NSCLC
    36. 36. Transition From Empiric to Rationally Selected & Individualized Cancer Therapy Patients with the same diagnosis: Stage IV NSCLC Modified from Gandara, CCO 2011 65-yr-old male smoker Squamous 39-yr-old female never-smoker Adenoca
    37. 37. Factors to Guide Personalized Therapy in NSCLC Clinical Factors Histological Factors Molecular Factors Adapted from Gandara DR, et al. Clin Lung Cancer 2009
    38. 38. GV Scagliotti et al, J Clin Oncol 2008 Histological Factors CP: cisplatin/pemetrexed; CG: cisplatin/gemcitabine
    39. 39. Thymidylate Synthetase Expression in Lung Cancer Squamous Small Cell Adenocarcinoma Normal lung <ul><li>SCLC: high TS </li></ul><ul><li>Squamous: high TS </li></ul><ul><li>Adeno: low TS </li></ul>Bhattacharjee A, et al. Proc Natl Acad Sci U S A. 2001. TS
    41. 41. “ UNTARGETED” USE OF TARGETED THERAPIES TOXICITY * In pts with non-squamous histology HR 0.87 P=0.044 + 1.2 mos 11.3 mos Vs 10.1 mos Cis/Vnr/Cetux FLEX Pirker Lancet 2009 Cetuximab HR 1.03 P=0.76 + 0.3 mos 13.4 mos Vs 13.1 mos Cis/Gem/Beva Vs Cis/Gem AVAIL Manegold JCO 2009 Bevacizumab* HR 0.79 P=0.003 + 2.0 mos 12.3 mos Vs 10.3 mos Carbo/Tax/Beva Vs Carbo/Tax ECOG 4599 Sandler NEJM 2006 Bevacizumab* Statistics OS gain OS Design Study Drug G3-4 febrile neutropenia 22% (vs 15%, p=0.0086) G3 skin toxicity 10% Cetuximab 8% of G ≥ 3 thromboembolism, and 6% of G ≥ 3 hypertension Bevacizumab
    42. 42. 1 st /2 nd /3 rd -Line TKIs TRIALS for Unselected Patients Phase I IDEAL I & II BR.21 P hase II ISEL Phase I GEFITINIB ERLOTINIB INTACT 1&2 TALENT&TRIBUTE INVITE INTEREST TRUST 2001 2002 2003 2004 2005 2007 2008
    43. 43. FA Shepherd et al, NEJM 2005 MPFS= + 0.4 ms (2.2 vs 1.8 ms) MST = + 2.0 ms (6.7 vs 4.7 ms) 1-yS = + 9 % (31 vs 22%) Overall Survival Progression Free Survival BR.21 STUDY SURVIVAL
    45. 45. TKIs 1st-line Asian Phase III R Trials Country Study Pts Agents PFS IPASS T Mok NEJM 2009 ADC Never smoker Gefitinib vs Carbo-Pac 9.5 vs 6.3 mos First-SIGNAL JS Lee WCLC 2009 ADC Never smoker Gefitinib vs Cis-Gem 8.4 vs 6.7 mos NEJ 002 M Maemondo NEJM 2010 EGFR MUT +ve Gefitinib vs Carbo-Pac 10.8 vs 5.4 mos WJTOG 3405 T Mitsudomi Lancet 2010 EGFR Mut +ve Gefitinib vs Cis-Doc 9.2 vs 6.3 mos OPTIMAL C Zhou ESMO 2010 EGFR Mut +ve Erlotinib vs Carbo-Gem 13.1 vs 4.6 mos
    46. 46. EURTAC: study design <ul><li>Primary endpoint </li></ul><ul><li>Progression-free survival (PFS) </li></ul><ul><li>Chemona ї ve </li></ul><ul><li>Stage IIIB/IV NSCLC </li></ul><ul><li>EGFR exon 19 deletion or exon 21 L858R mutation </li></ul><ul><li>ECOG PS 0–2 </li></ul><ul><li>(n=174) </li></ul>R Platinum-based doublet chemotherapy q3wks x 4 cycles* PD Erlotinib 150mg/day PD <ul><li>Stratification </li></ul><ul><li>Mutation type </li></ul><ul><li>ECOG PS (0 vs 1 vs 2) </li></ul>Rosell et al. ASCO 2011
    47. 47. Lung Cancer Molecular Consortium Analysis in Lung Adenocarcinomas Kris MG, et al. ASCO 2011. <ul><li>Mutations found in 54% (280/516) of tumors </li></ul><ul><li>97% of mutations mutually exclusive </li></ul>No Mutation Detected KRAS 22% EGFR 17% EML4-AKL 7% Double Mutants 3% BRAF 2% PIK3CA 2% HER2 MET AMP MEK1 NRAS AKT1
    48. 48. Crizotinib for Patients With ALK -Positive NSCLC Kwak EL, et al. N Engl J Med. 2010. Percent Change From Baseline Patient No. 60 40 20 -40 -100 10 20 40 50 60 70 79 30 0 -20 -60 -80 -30% PD SD PR CR FISH IHC N = 79 pts
    49. 49. Current Crizotinib Clinical Trials <ul><li>Key entry criteria </li></ul><ul><li>Positive for ALK by central laboratory </li></ul><ul><li>1 previous chemotherapy (platinum based) </li></ul>Phase III PROFILE 1007 [1] <ul><ul><ul><li>Crizotinib 250 mg BID </li></ul></ul></ul><ul><ul><ul><li>administered on a continuous </li></ul></ul></ul><ul><ul><ul><li>dosing schedule (n = 159) </li></ul></ul></ul><ul><li>Pemetrexed 500 mg/m 2 or </li></ul><ul><ul><ul><li>Docetaxel 75 mg/m 2 infused on Day 1 of a 21-day cycle (n = 159) </li></ul></ul></ul>1. ClinicalTrials.gov. NCT00932893. 2. ClinicalTrials.gov. NCT00932451. <ul><ul><li>Crizotinib 250 mg BID </li></ul></ul><ul><ul><ul><li>administered on a continuous </li></ul></ul></ul><ul><ul><ul><li>dosing schedule (N = 250) </li></ul></ul></ul><ul><li>Key entry criteria </li></ul><ul><li>Positive for ALK by central laboratory </li></ul><ul><li>Progressive disease in PD arm of PROFILE 1007 or </li></ul><ul><li>≥ 1 previous chemotherapy </li></ul>Phase II PROFILE 1005 [2] (Planned N = 400)
    50. 50. Resistance to EGFR-TKIs <ul><li>50% acquired EGFR mutation </li></ul><ul><ul><li>T790M in exon 20 </li></ul></ul><ul><li>20% MET amplification </li></ul>
    51. 51. <ul><li>Adenocarcinoma of the lung </li></ul><ul><li>Stage IIIB/IV </li></ul><ul><li>Progressed after 1 or 2 lines of CTx and 12 wks of erlotinib or gefitinib treatment </li></ul><ul><li>ECOG 0–2 </li></ul>Randomization (n=585) Oral AFATINIB 50 mg once-daily + BSC Oral placebo once-daily + BSC 2 : 1 Primary endpoint : Overall Survival (OS) V Miller et al, P ESMO 2010 AFATINIB (irreversible inhibitor of EGFR and HER-2) AFATINIB active in tumors with T790M EGFR mutation in preclinical models
    52. 52. Afatinib: PFS and OS V Miller et al, P ESMO 2010 PFS OS
    53. 53. Rationale for Afatinib (BIBW2992) + Cetuximab in the presence of T790M MT Regales L, et al. J Clin Invest. 2009;119:3000-3010. 0 500 1000 1500 2000 2500 14 10 17 21 24 31 Days Tumor Volume (mm 3 ) H1975 Cells (L858R/T790M) Control BIBW Cetux Cetux/BIBW
    54. 54. Afatinib (BIBW2992) + Cetuximab Horn L, et al. IASLC WCLC 2011. Abstract O19.07 Note: Preliminary efficacy appears equivalent in T790M- cancers Maximum Decrease From Baseline (%) Patient Index Sorted by Maximum % Decrease 70 20 0 -50 -100 4 8 32 40 48 56 69 12 -20 -30 -60 -80 T790M+ T790M- No mutation Uninformative 60 50 40 30 -10 -40 -70 -90 52 44 36 28 24 20 16 0 10
    55. 55. Randomized Phase II Trial of Erlotinib ± MetMAb in Advanced NSCLC <ul><li>Stratification factors </li></ul><ul><li>Tobacco history </li></ul><ul><li>PS </li></ul><ul><li>Histology </li></ul>Arm B Erlotinib 150 daily + Placebo IV q3w Arm A Erlotinib 150 mg daily) + MetMAb 15 mg/kg IV q3w <ul><li>Key eligibility: </li></ul><ul><li>Stage IIIB/IV NSCLC </li></ul><ul><li>2nd/3rd-line NSCLC </li></ul><ul><li>Tissue required </li></ul><ul><li>PS 0-2 </li></ul>Spigel DR, et al. ASCO 2011. Primary endpoint PFS in ITT and in Met positive population Met ICH score majority (≥ 50%) of tumor cells with moderate or strong staining intensity Met + 52% patients enrolled were Met positive
    56. 56. Erlotinib + MetMAb in Met positive pts The addition of MetMAb to erlotinib doubled PFS and nearly tripled OS in this population. Detrimental in Met-negative pts. Placebo + Erlotinib 3.8 26 MetMAb + Erlotinib 12.6 0.37 (0.19-0.72) .002 16 Median, mos HR (95% CI) Log-rank P value Events, n Placebo + Erlotinib 1.5 27 MetMAb + Erlotinib 2.9 0.53 (0.28-0.99) .04 20 Median, mos HR (95% CI) Log-rank P value Events, n PFS: HR = 0.53 OS: HR = 0.37 Spigel DR, et al. ASCO 2011. Abstract 7505. 0 3 6 9 12 15 18 Probability of Progression Free 0 0.2 0.4 0.6 0.8 1.0 0 3 6 9 12 15 18 21 Probability of Survival 0 0.2 0.4 0.6 0.8 1.0 TTP (Mos) OS (Mos)
    57. 57. Conclusions <ul><li>Adjuvant chemotherapy standard in N1 and N2 resected pts. RT to be considered in N2 pts only. Ongoing pharmacogenomic-oriented trials. </li></ul><ul><li>Multimodality treatments (concomitant ChT/RT) in stage III pts. Major improvements (reduced toxicity, improved local control) from new RT techniques. </li></ul><ul><li>Individualized treatment in stage IV disease, based on clinical, histological and molecular factors. Targeted therapies in selected patients with predictive biomarkers. </li></ul>INDIVIDUALIZED CANCER THERAPY !