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Advanced Non-Small Cell Lung Cancer: State of the Art Primo N. Lara, Jr., MD Professor of Medicine University of California Davis Cancer Center.

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Presentation on theme: "Advanced Non-Small Cell Lung Cancer: State of the Art Primo N. Lara, Jr., MD Professor of Medicine University of California Davis Cancer Center."— Presentation transcript:

1 Advanced Non-Small Cell Lung Cancer: State of the Art Primo N. Lara, Jr., MD Professor of Medicine University of California Davis Cancer Center

2 Frontline therapy of advanced NSCLC: “Back in the day” dogma (ie, 2009) Prognostic factors for survival (PS, Weight Loss, Gender) are known and clinically apparent Platinum-based chemotherapy results in prolongation of life, symptom control, & superior QOL compared with supportive care alone –Four to six cycles are sufficient Inhibitors of epidermal growth factor and angiogenesis pathways improve outcomes in select patient subsets

3 ECOG 1594: Platinum-based doublets have similar survival outcomes Cis/Gem Cis/Docetaxel Carbo/Paclitaxel Control arm: Cisplatin/paclitaxel Schiller JH, et al. N Engl J Med. 2002; 346:92–98

4 Duration of chemotherapy: 4-6 cycles are sufficient AuthorStudy designPatients Median survival (months)P value Smith JCO 2001 MVP x 31556.2 MVP x 61537 Socinski JCO 2002 Carbo/Pac x 41146.6.63 Carbo/Pac till PD1168.5 Eberhardt W, et al. (2007) ASCO

5 Bevacizumab in NSCLC (E4599) BV/PC51.0%22.0% 12.3 mo PC44.4%15.4% 10.3 mo 12 mo24 mo Median HR: 0.80, P =.013 0.0 0.2 0.4 0.6 0.8 1.0 Proportion surviving 0642481830 122436 444318101049 190365 4343403012725 216548 PC BV/PC Months Patients at risk Median 12.3 mo Median 10.3 mo Non-squamous histology, no hemoptysis, no CNS mets, no anticoagulation Sandler A, et al. N Engl J Med. 2006; 356:2542–2550

6 Months 1-year OS 47% vs 42% 10.1 Patients surviving, % ▬ Cetuximab +CT ▬ CT 11.3 HR = 0.871, 0.762–0.996 Log-rank P =.044 Cisplatin/vinorelbine + cetuximab (FLEX) in EGFR-positive* (by IHC) NSCLC * One or more IHC positive cell(s) Pirker R, et al. (2008) ASCO

7 Metastatic NSCLC: The New Issues (i.e., October 2010) Maintenance therapy –After completing platinum-based chemo, should all patients receive maintenance therapy? Tumor histology –Should we routinely use histology to select therapy? Frontline biologics –Can we abandon frontline platinum therapy in favor of single agent EGFR TKI?

8 Maintenance therapy: Considerations Continuing same chemotherapy past 4–6 cycles yields no clear benefit E4599 and FLEX trials included maintenance therapy of bevacizumab and cetuximab, respectively Maintenance therapy with non-cross resistant agents may be more efficacious

9 Maintenance pemetrexed  Stage IIIB/IV NSCLC  PS 0-1  4 prior cycles of gem, doc, or tax + cis or carb, with CR, PR, or SD Randomization factors:  gender  PS  stage  best tumor response to induction  non-platinum induction drug  brain mets Pemetrexed 500 mg/m 2 (d1,q21d) + BSC (N = 441)* Primary Endpoint = PFS Placebo (d1, q21d) + BSC (N = 222)* *B 12, folate, and dexamethasone given in both arms 2:1Randomization Double-blind, Placebo-controlled, Multicenter, Phase III Trial Ciuleanu TE, et al. (2008) ASCO; Belani CP, et al. (2009) ASCO

10 adverse events Drug-related adverse events Pemetrexed n = 441 Placebo n = 222P value Drug-related deaths* 0.0% 1.000 ≥ 1 serious AE (SAE) 4.3% 0.0%.001 ≥ 1 grade 3/4 AE14.3% 3.6%<.001 Drug-related CTCAE grade 3/4 toxicity (≥ 2% of pts) Anemia 2.7%0.5%.070 Neutropenia 2.7%0.0%.011 Fatigue 4.3%0.5%.004 * on-study or within 30 days post-study Ciuleanu TE, et al. (2008) ASCO

11 Pemetrexed 4.0 mos Placebo 2.0 mos Progression-free Probability Time (months) HR = 0.60 (95% CI: 0.49-0.73) P <0.00001 Pemetrexed 13.4 mos Placebo 10.6 mos Survival Probability Time (months) HR = 0.79 (95% CI: 0.65-0.95) P = 0.012 JMEN: “Maintenance” Pemetrexed vs Placebo After Platinum-based Chemotherapy Progression-free Survival Overall Survival Belani CP, et al. ASCO 2009. CRA8000. 03691215182124 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 036912151821242730333639424548 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0

12 Pemetrexed N = 309 Placebo N = 178 Any systemic therapy51%67% Docetaxel22%29% Erlotinib22%21% Gefitinib13%10% Pemetrexed 1%19% Post-study therapy was not balanced between the arms 51% of patients on the pemetrexed arm received further therapy (equates to third-line therapy) Only 19% of placebo-arm patients received pemetrexed Would survival benefits have been preserved if more patients on the placebo arm received pemetrexed? Belani CP, et al. ASCO 2009. CRA8000. JMEN: “Maintenance” Pemetrexed vs Placebo After Platinum-based Chemotherapy

13 JMEN: “Maintenance” Pemetrexed vs Placebo: Survival by Histology Pemetrexed 15.5 mosPemetrexed 9.9 mos Placebo 10.3 mos Placebo 10.8 mos Non-squamous (n = 481)Squamous (n = 182) Survival Probability Time (months) HR = 0.70 (95% CI: 0.56-0.88); P = 0.002 HR = 1.07 (95% CI: 0.49–0.73); P = 0.678 Belani CP, et al. ASCO 2009. CRA8000. 036912151821242730333639424548 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 036912151821242730333639424548 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0

14 Maintenance chemotherapy: Points to Ponder Definition of “maintenance” variesDefinition of “maintenance” varies Benefit for pemetrexed confined to non- squamous histologyBenefit for pemetrexed confined to non- squamous histology Many patients never received second- line therapy!Many patients never received second- line therapy! –Survival in control arms may have diminished due to lack of life-prolonging second line therapy Difficult to reconcile with maintenance bevacizumab, cetuximab, and erlotinibDifficult to reconcile with maintenance bevacizumab, cetuximab, and erlotinib

15 Maintenance chemotherapy: Is it time for routine clinical use? Issues of cost, convenience, toxicity, and QOL need to be weighed against (modest) PFS benefit in the palliative care settingIssues of cost, convenience, toxicity, and QOL need to be weighed against (modest) PFS benefit in the palliative care setting –Many patients desire a “drug holiday” Maintenance chemotherapy can be considered only for selected, highly motivated patientsMaintenance chemotherapy can be considered only for selected, highly motivated patients –Bottom line: It’s not for everyone

16 SATURN trial (N = 889) –Phase III erlotinib vs. placebo following initial treatment with platinum-based chemotherapy ATLAS trial (N = 1157) –Phase III bevacizumab ± erlotinib following initial treatment with chemo + bevacizumab –Brain mets, non-centrally located squamous, anticoagulation allowed Maintenance biologics 1. Cappuzzo F, et al. (2009) ASCO; 2. Miller VA, et al. (2009) ASCO

17 SATURN study design Cappuzzo et al, ASCO 2009, # 8001 1:1 Chemonaïve advanced NSCLC n=1,949 Non-PD n=889 4 cycles of first- line platinum doublet chemotherapy* Placebo PD Erlotinib 150mg/day PD Mandatory tumour sampling Stratification factors: EGFR IHC (positive vs negative vs indeterminate)EGFR IHC (positive vs negative vs indeterminate) Stage (IIIB vs IV)Stage (IIIB vs IV) ECOG PS (0 vs 1)ECOG PS (0 vs 1) CT regimen (cis/gem vs carbo/doc vs others)CT regimen (cis/gem vs carbo/doc vs others) Smoking history (current vs former vs never)Smoking history (current vs former vs never) RegionRegion Co-primary endpoints: PFS in all patientsPFS in all patients PFS in patients with EGFR IHC+ tumoursPFS in patients with EGFR IHC+ tumours Secondary endpoints: OS in all patients and those with EGFR IHC+ tumours, OS and PFS in EGFR IHC– tumours; biomarker analyses; safety; time to symptom progression; QoLOS in all patients and those with EGFR IHC+ tumours, OS and PFS in EGFR IHC– tumours; biomarker analyses; safety; time to symptom progression; QoL *Cisplatin/paclitaxel; cisplatin/gemcitabine; cisplatin/docetaxel cisplatin/vinorelbine; carboplatin/gemcitabine; carboplatin/docetaxel carboplatin/paclitaxel

18 Erlotinib (n = 438) Placebo (n = 451) HRP Value PFS (n = 437)(n = 447) 0.71<.0001 PFS at 12 weeks 53%40% PFS at 24 weeks 31%17% Median PFS 12.3 weeks11.1 weeks Median OS 12 months11 months 0.81.0088 (n = 436)(n = 445) ORR 12%5%NA.0006 DCR 61%51%NA.0035 SATURN Trial: Efficacy Summary PFS benefit with erlotinib observed regardless of gender, race, histology or smoking history Cappuzzo et al. J Thorac Oncol 2009; 4(suppl 1):S289 (abstract A2.1).

19 PFS in EGFR wild-type tumors 1.0 0.8 0.6 0.4 0.2 0 081624324048566472808896 Time (weeks) Erlotinib (n=199) Placebo (n=189) HR=0.78 (0.63–0.96) Log-rank p=0.0185 PFS probability Capuzzo, ASCO 2009

20 HR=0.10 (0.04–0.25) Log-rank p<0.0001 PFS in EGFR mutation+ tumors* 1.0 0.8 0.6 0.4 0.2 0 081624324048566472808896 Time (weeks) Erlotinib (n=22) Placebo (n=27) PFS probability *60% censored Capuzzo, ASCO 2009

21 SATURN: Post-study Treatment Erlotinib* (n = 438) Placebo* (n = 451) All classes55%64% Taxanes (including docetaxel)26%27% Antimetabolites (including pemetrexed)18%20% Antineoplastic agents11%15% Tyrosine-kinase inhibitors 5%16% Platinum compounds 8%11% *% receiving ≥1 treatment Cappuzzo F, et al. ASCO 2009. Abstract 8001.

22 ATLAS Phase III Study Design Miller et al, ASCO 2009, #8002 1:1 *Carbo/paclitaxel; cis/vinorelbine; carbo or cis/gemcitabine; carbo or cis/docetaxel. Unblind at PD Bevacizumab (15mg/kg) + erlotinib (150mg) to PD Chemo-naïve advanced NSCLC N=1,160 4 cycles of 1st-line chemotherapy* + bevacizumab Non-PD n=768 (66%) Post progression therapy Bevacizumab + placebo to PD Primary endpoint PFS in all randomized pts Secondary endpoints Overall survival Safety Exploratory endpoints Biomarker analyses (IHC, FISH, EGFR & K-Ras mutation) Eligibility Stage IIIB**/IV NSCLC ECOG performance status 0-1 Stratification factors Gender Smoking history (never vs former/current) ECOG performance status (0 v >1) Chemotherapy regimen **IIIB with pleural effusion

23 Progression-Free Survival 03691215 1821 0.0 0.2 0.4 0.6 0.8 1.0 Proportion Without Event HR=0.722 (0.592-0.881) Log-rank P=0.0012 Progression-Free Survival (months) Bev + Placebo (n=373) Bev + Erlotinib (n=370) Bev + Erlotinib (n=370) Miller et al, ASCO 2009, #8002

24 ATLAS: Toxicity Bev + Placebo, n (%) (n=368) Bev + Erlotinib, n (%) (n=367) Any Grade AE 313 (85.1%) 349 (95.1%) Grade 3–4 AE 112 (30.4%) 162 (44.1%) Grade 5 AE 4 (1.1%) 8 (2.2%) SAE 60 (16.3%) 84 (22.9%) Formal statistical comparison testing between treatment arms was not done. The most common adverse events were rash and diarrhea Miller et al, ASCO 2009, #8002

25 Take Home Points: SATURN and ATLAS trials Trials confirm that erlotinib is an active agent in NSCLC (duh!)Trials confirm that erlotinib is an active agent in NSCLC (duh!) Patients on maintenance erlotinib had more toxicities than those on placeboPatients on maintenance erlotinib had more toxicities than those on placebo Only a minority (16% in SATURN, 40% in ATLAS) of placebo patients ever received subsequent EGFR TKI therapy!!!Only a minority (16% in SATURN, 40% in ATLAS) of placebo patients ever received subsequent EGFR TKI therapy!!! As expected, PFS benefit was best in patients with EGFR-mutated tumorsAs expected, PFS benefit was best in patients with EGFR-mutated tumors Need to balance consequences of increased toxicity and cost in the context of modest PFS benefitNeed to balance consequences of increased toxicity and cost in the context of modest PFS benefit

26 Metastatic NSCLC: The New Issues (i.e., October 2010) Maintenance therapy –After completing platinum-based chemo, should all patients receive maintenance therapy? Tumor histology –Should we routinely use histology to select therapy? Frontline biologics –Can we abandon frontline platinum therapy in favor of single agent EGFR TKI?

27 Complexities of lung cancer pathogenesis result in diverse histologic subtypes Squamous Cell Ca (~25%) SCLC (~15%) BAC (~5-10%) Adenocarcinoma (~45%) Large Cell (~5-10%) NOS (Not Otherwise Specified (~10-30%) Sun S, et al. Nat Rev Cancer. 2007; 7:778–790

28 NSCLC histology: Treatment Considerations Bevacizumab is FDA-approved for non-squamous histology due to SAFETY issues –Severe hemoptysis Pemetrexed is FDA-approved for non-squamous histology due to EFFICACY issues –PFS and OS benefit confined to non-squamous EGFR TKIs traditionally viewed as more efficacious in adenocarcinoma –Likely due to higher rate of EGFR mutants in adeno

29 Cisplatin 75 mg/m 2 day 1 plus Gemcitabine 1250 mg/m 2 days 1 & 8 Randomization Factors StageStage PSPS GenderGender Histo vs cyto dxHisto vs cyto dx Brain mets hxBrain mets hx R Cisplatin 75 mg/m 2 day 1 plus Pemetrexed 500 mg/m 2 day 1 Vitamin B 12, folate, and dexamethasone given in both arms JMDB trial: Cisplatin/pemextexed (CP) vs cisplatin/gemcitabine (CG) in Adv NSCLC Scagliotti GV, et al. J Clin Oncol. 2008; 26:3543–3551

30 Cisplatin/pemetrexed (CP) vs cisplatin/gemcitabine (CG) in NSCLC No difference in PFS or OS CP improves survival over CG in non-SCCA (HR 0.81, P =.005) in non-SCCA (HR 0.81, P =.005) CG improves survival over CP in SCCA (HR 1.23, P =.05) in SCCA (HR 1.23, P =.05) Scagliotti GV, et al. J Clin Oncol. 2008; 26:3543–3551

31 Pemetrexed: Influence of histology on efficacy Scagliotti GV, et al. J Clin Oncol. 2008; 26:3543–3551 In two other phase III trials (docetaxel vs. pemetrexed; maintenance pemetrexed vs. placebo), benefit was confined to patients with non-squamous histology

32 Take Home Points: Histology-based therapy NSCLC histology is now a consideration in therapeutic selection for chemotherapy This is but one (primitive) step in the direction of “personalized therapy” Still unclear how “NSCLC NOS” or cytologic diagnoses (by FNA) should be treated True personalized therapy will rely on molecular profiling rather than histology

33 Metastatic NSCLC: The New Issues (i.e., October 2010) Maintenance therapy –After completing platinum-based chemo, should all patients receive maintenance therapy? Tumor histology –Should we routinely use histology to select therapy? Frontline biologics –Can we abandon frontline platinum therapy in favor of single agent EGFR TKI?

34 IPASS Study design *Never smokers, <100 cigarettes in lifetime; ex-light smokers, stopped  15 years ago and smoked  10 pack years; # limited to a maximum of 6 cycles. Carboplatin/paclitaxel was offered to gefitinib patients upon progression WHO, World Health Organization; PS, performance status; AUC, area under the curve; EGFR, epidermal growth factor receptor Carboplatin (AUC 5 or 6) / paclitaxel (200 mg / m 2 ) 3 weekly # 1:1 randomization Patients Chemo-naïve Age ≥18 years Adenocarcinoma histology Never or ex-light smokers* Life expectancy ≥12 weeks WHO PS 0-2 Measurable stage IIIB / IV disease Primary Progression-free survival (non-inferiority) Secondary Objective response rate Overall survival Quality of life Disease-related symptoms Safety and tolerability Exploratory Biomarkers ─ EGFR mutation ─ EGFR-gene-copy number ─ EGFR protein expression End points Conducted in China, Japan, Thailand, Taiwan, Indonesia, Malaysia, Philippines, Hong Kong and Singapore Randomization period: March 2006 – October 2007 Mok et al 2008 Gefitinib (250 mg / day)

35 Progression-free survival 609 453 (74.4%) 608 497 (81.7%) N Events HR (95% CI) = 0.74 (0.65, 0.85) p<0.0001 Gefitinib Gefitinib demonstrated superiority relative to carboplatin/paclitaxel in terms of PFS Primary Cox analysis with covariates; HR <1 implies a lower risk of progression on gefitinib; ITT population PFS, progression-free survival; ITT, intent-to-treat; HR, hazard ratio; CI, confidence interval; C/P, carboplatin/paclitaxel Carboplatin / paclitaxel C/P Gefitinib Median PFS (months) 4 months progression-free 6 months progression-free 12 months progression-free 5.7 61% 48% 25% 5.8 74% 48% 7% 609 212 762450 60811822310 363 412 04812162024Months 0.0 0.2 0.4 0.6 0.8 1.0Probability of PFS Patients at risk : Mok et al 2008

36 IPASS: EGFR mutation positive status and clinical characteristics Overall EGFR mutation positive rate = 59.7% (261 / 437) MaleFemalePS 0/1PS 0/2Never smoked Light ex- smoker Locally advanced MetastaticAge <65 yrs Age >65 yrs % of samples EGFR mutation positive 49.0 63.0 60.0 57.1 60.7 46.9 57.8 60.2 56.7 68.5

37 Progression-free survival in EGFR mutation positive and negative patients Cox analysis with covariates; HR <1 implies a lower risk of progression on gefitinib; ITT population EGFR mutation positiveEGFR mutation negative Treatment by EGFR mutation status interaction test, p<0.0001 HR (95% CI) = 0.48 (0.36, 0.64) p<0.0001 No. events gefitinib, 97 (73.5%) No. events C/P, 111 (86.0%) Median PFS G, 9.5 months Median PFS C/P, 6.3 months HR (95% CI) = 2.85 (2.05, 3.98) p<0.0001 No. events gefitinib, 88 (96.7%) No. events C/P, 70 (82.4%) Median PFS G, 1.5 months Median PFS C/P, 5.5 months 132 71 311130 129377210 108 103 04812162024 Gefitinib C/P 0.0 0.2 0.4 0.6 0.8 1.0 Probability of progression-free survival Patients at risk : 91 4 2100 85141000 21 58 04812162024 0.0 0.2 0.4 0.6 0.8 1.0 Probability of progression-free survival Gefitinib (n=91) Carboplatin/paclitaxel (n=85) Months Mok et al 2008 Gefitinib (n=132) Carboplatin/paclitaxel (n=129)

38 NSCLC with sensitive EGFR mutations Stage IIIb/ IV No prior chemo. PS 0-1 age of 20-75 y.o Gefitinib n=160 CBDCA+TXL n=160 Primary endpoint PFS 2ndary endpoints OS Response Side-effects QOL R balanced : Institution sex stage The sample size was calculated to be 320 in total (alpha=5%, power=80%) to confirm the superiority of Arm A (hazard ratio = 0.69). An interim analysis to investigate PFS was planned 4 months after 200 pts were entered. First line gefinitib vs. chemotherapy in EGFR mutated NSCLC North East Japan (NEJ) Gefitinib Study Group North East Japan (NEJ) Gefitinib Study Group

39 Memondo, NEJM 2010 PFSOS

40 Memondo, NEJM 2010

41 Potential Oncogenic “Drivers” in Non-small Cell Lung Cancer (NSCLC) ALK (~5%) Other Adenocarcinoma Massachusetts General Hospital, data on file. [AT Shaw, personal communication] ALK = anaplastic lymphoma kinase; EGFR = epidermal growth factor receptor; Her2 = human epidermal growth factor receptor 2; PIK3CA = phosphoinositide-3-kinase, catalytic, alpha polypeptide

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44 60 40 20 0 –20 –40 –60 –80 –100 Progressive disease Stable disease Confirmed partial response Confirmed complete response Maximum change in tumor size (%) –30% Tumor Responses to Crizotinib for Patients with ALK -positive NSCLC (N=82) *Partial response patients with 100% change have non-target disease present *

45 77% of Patients with ALK -positive NSCLC Remain on Crizotinib Treatment 036912151821 Treatment duration (months) N=82; red bars represent discontinued patients Individual patients Duration of treatment (median: 5.7 months) 0–3 mo 13 pts >3–6 mo29 pts >6–9 mo 24 pts >9–12 mo 9 pts >12–18 mo 4 pts >18 mo 3 pts Reasons for discontinuation –Related AEs1 – Non-related AEs1 – Unrelated death 2 – Other2 – Progression 13

46 Clinical Activity of Crizotinib in Patients with ALK- positive NSCLC Objective response rate (ORR): 57% (95% CI: 46, 68%) – –63% including 5 as yet unconfirmed PRs – –57% (8/14) for patients with performance status 2 or 3 No. prior regimens* ORR % (n/N) 080 (4/5) 152 (14/27) 267 (10/15) ≥356 (19/34) * Unknown for 1 patient ●Response duration: 1 to 15 months ●DCR † (CR/PR/SD at 8 weeks): 87% (95% CI: 77, 93%) † Disease control rate

47 Median PFS has Not been Reached 70% of Patients in Follow-up for PFS 1.00 0.75 0.50 0.25 0.00 Progression-free survival probability 02.55.07.510.012.515.017.5 Progression-free survival (months) PFS probability at 6 months: 72% (95% CI: 61, 83%) Median follow-up for PFS: 6.4 months (25–75% percentile: 3.5–10 months) 95% Hall–Wellner confidence bands

48 Treatment-related Adverse Events in ALK -positive NSCLC (≥10%) Adverse event Grade 1 n (%) Grade 2 n (%) Grade 3 n (%) Grade 4 n (%) Total n (%) Nausea43 (52)1 (1)0044 (54) Diarrhea38 (46)1 (1)0039 (48) Vomiting35 (43)1 (1)00 36 (44) Visual disturbance*34 (42)000 Constipation18 (22) 2 (2) 0020 (24) Peripheral edema13 (16)000 Dizziness 12 (15) 000 Decreased appetite11 (13)000 Fatigue8 (10)000 *Changes in light/dark accommodation (no abnormalities on ophthalmologic exam) N=82

49 Conclusions: Frontline NSCLC therapy Optimal therapy is rapidly evolving Maintenance therapy is an option for highly motivated patients Clinical, histologic, and molecular biomarkers are now important considerations for therapy selection Future advances in NSCLC outcomes will likely be due to molecular selection Support for clinical trials testing this paradigm is essential


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