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Advanced Non-Small Cell Lung Cancer: State of the Art

Advanced Non-Small Cell Lung Cancer: State of the Art. Primo N. Lara, Jr., MD Professor of Medicine University of California Davis Cancer Center. Frontline therapy of advanced NSCLC: “Back in the day” dogma (ie, 2009).

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Advanced Non-Small Cell Lung Cancer: State of the Art

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  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 pathwaysimprove 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 Eberhardt W, et al. (2007) ASCO

  5. 12 mo 24 mo Median PC 44.4% 15.4% 10.3 mo BV/PC 51.0% 22.0% 12.3 mo Bevacizumab in NSCLC (E4599) 1.0 0.8 Median 12.3 mo 0.6 HR: 0.80, P = .013 Proportion surviving Median 10.3 mo 0.4 0.2 0.0 12 24 36 0 6 18 30 42 48 Patients at risk PC 190 36 5 444 318 104 9 1 0 BV/PC 216 54 8 434 340 127 25 3 0 Months Non-squamous histology, no hemoptysis, no CNS mets, no anticoagulation Sandler A, et al. N Engl J Med. 2006; 356:2542–2550

  6. Cisplatin/vinorelbine + cetuximab (FLEX) in EGFR-positive* (by IHC) NSCLC • Cetuximab +CT • CT HR = 0.871, 0.762–0.996 Log-rank P =.044 11.3 Patients surviving, % 10.1 1-year OS47% vs 42% Months Pirker R, et al. (2008) ASCO * One or more IHC positive cell(s)

  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 Double-blind, Placebo-controlled, Multicenter, Phase III Trial • 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/m2(d1,q21d) + BSC (N = 441)* 2:1 Randomization Primary Endpoint = PFS Placebo (d1, q21d) + BSC (N = 222)* *B12, folate, and dexamethasone given in both arms Ciuleanu TE, et al. (2008) ASCO; Belani CP, et al. (2009) ASCO

  10. Drug-related adverse events * on-study or within 30 days post-study Ciuleanu TE, et al. (2008) ASCO

  11. JMEN: “Maintenance” Pemetrexed vs Placebo After Platinum-based Chemotherapy Pemetrexed 4.0 mos Placebo 10.6 mos Placebo 2.0 mos 1.0 0.9 0.8 HR = 0.60 (95% CI: 0.49-0.73)P <0.00001 0.7 Progression-free Survival Progression-free Probability 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0 3 6 9 12 15 18 21 24 Time (months) 1.0 0.9 HR = 0.79 (95% CI: 0.65-0.95) P = 0.012 0.8 0.7 Overall Survival Survival Probability 0.6 Pemetrexed 13.4 mos 0.5 0.4 0.3 0.2 0.1 0.0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 Belani CP, et al. ASCO 2009. CRA8000. Time (months)

  12. 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? JMEN: “Maintenance” Pemetrexed vs Placebo After Platinum-based Chemotherapy Belani CP, et al. ASCO 2009. CRA8000.

  13. JMEN: “Maintenance” Pemetrexed vs Placebo: Survival by Histology Pemetrexed 15.5 mos Pemetrexed 9.9 mos Placebo 10.3 mos Placebo 10.8 mos Non-squamous (n = 481) Squamous (n = 182) HR = 0.70 (95% CI: 0.56-0.88); P = 0.002 HR = 1.07 (95% CI: 0.49–0.73); P = 0.678 1.0 1.0 0.9 0.9 0.8 0.8 0.7 0.7 0.6 0.6 Survival Probability 0.5 0.5 0.4 0.4 0.3 0.3 0.2 0.2 0.1 0.1 0.0 0.0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 Time (months) Time (months) Belani CP, et al. ASCO 2009. CRA8000.

  14. Maintenance chemotherapy: Points to Ponder • Definition of “maintenance” varies • Benefit for pemetrexed confined to non-squamous histology • Many patients never received second-linetherapy! • Survival in control arms may have diminished due to lack of life-prolonging second line therapy • Difficult 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 setting • Many patients desire a “drug holiday” • Maintenance chemotherapy can be considered only for selected, highly motivated patients • Bottom line: It’s not for everyone

  16. Maintenance biologics • 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 1. Cappuzzo F, et al. (2009) ASCO; 2. Miller VA, et al. (2009) ASCO

  17. SATURN study designCappuzzo et al, ASCO 2009, # 8001 Erlotinib 150mg/day PD Chemonaïve advanced NSCLC n=1,949 4 cycles of first-line platinum doublet chemotherapy* Stratification factors: • EGFR IHC (positive vs negative vs indeterminate) • Stage (IIIB vs IV) • ECOG PS (0 vs 1) • CT regimen (cis/gem vs carbo/doc vs others) • Smoking history (current vs former vs never) • Region Non-PD n=889 1:1 Placebo PD Mandatory tumour sampling • Co-primary endpoints: • PFS in all patients • PFS 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; QoL *Cisplatin/paclitaxel; cisplatin/gemcitabine; cisplatin/docetaxel cisplatin/vinorelbine; carboplatin/gemcitabine; carboplatin/docetaxel carboplatin/paclitaxel

  18. SATURN Trial: Efficacy Summary Cappuzzo et al. J Thorac Oncol 2009; 4(suppl 1):S289 (abstract A2.1). • PFS benefit with erlotinib observed regardless of gender, race, histology or smoking history

  19. PFS in EGFR wild-type tumors PFS probability 1.0 0.8 0.6 0.4 0.2 0 Erlotinib (n=199) Placebo (n=189) HR=0.78 (0.63–0.96) Log-rank p=0.0185 0 8 16 24 32 40 48 56 64 72 80 88 96 Time (weeks) Capuzzo, ASCO 2009

  20. PFS in EGFR mutation+ tumors* PFS probability 1.0 0.8 0.6 0.4 0.2 0 Erlotinib (n=22) Placebo (n=27) HR=0.10 (0.04–0.25) Log-rank p<0.0001 0 8 16 24 32 40 48 56 64 72 80 88 96 Time (weeks) *60% censored Capuzzo, ASCO 2009

  21. SATURN: Post-study Treatment *% receiving ≥1 treatment Cappuzzo F, et al. ASCO 2009. Abstract 8001.

  22. ATLAS Phase III Study DesignMiller et al, ASCO 2009, #8002 Bevacizumab (15mg/kg)+ erlotinib (150mg) to PD 4 cycles of 1st-line chemotherapy* + bevacizumab Chemo-naïve advanced NSCLC N=1,160 Non-PD n=768 (66%) Post progressiontherapy Unblind at PD 1:1 Bevacizumab+ placeboto PD • 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 • Primary endpoint • PFS in all randomized pts • Secondary endpoints • Overall survival • Safety • Exploratory endpoints • Biomarker analyses (IHC, FISH, EGFR & K-Ras mutation) *Carbo/paclitaxel; cis/vinorelbine; carbo or cis/gemcitabine; carbo or cis/docetaxel. **IIIB with pleural effusion

  23. Progression-Free Survival 1.0 Proportion Without Event Bev + Placebo (n=373) 0.8 Bev + Erlotinib (n=370) 0.6 HR=0.722 (0.592-0.881) Log-rank P=0.0012 0.4 0.2 0.0 0 3 6 9 12 15 18 21 Progression-Free Survival (months) Miller et al, ASCO 2009, #8002

  24. ATLAS: Toxicity The most common adverse events were rash and diarrhea Formal statistical comparison testing between treatment arms was not done. 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!) • Patients 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!!! • As 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 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 SCLC (~15%) Squamous Cell Ca (~25%) Adenocarcinoma (~45%) BAC (~5-10%) 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. R JMDB trial: Cisplatin/pemextexed (CP) vs cisplatin/gemcitabine (CG) in Adv NSCLC Randomization Factors • Stage • PS • Gender • Histo vs cyto dx • Brain mets hx Cisplatin 75 mg/m2 day 1 plus Pemetrexed 500 mg/m2 day 1 Cisplatin 75 mg/m2 day 1 plus Gemcitabine 1250 mg/m2 days 1 & 8 Vitamin B12, folate, and dexamethasone given in both arms 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) CG improves survival over CP 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 In two other phase III trials (docetaxel vs. pemetrexed; maintenance pemetrexed vs. placebo), benefit was confined to patients with non-squamous histology Scagliotti GV, et al. J Clin Oncol. 2008; 26:3543–3551

  32. Take Home Points: Histology-based therapy • NSCLC histologyisnow 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 Conducted in China, Japan, Thailand, Taiwan, Indonesia, Malaysia, Philippines, Hong Kong and Singapore Randomization period: March 2006 – October 2007 End points • 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 Gefitinib(250 mg / day) • 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 1:1 randomization Carboplatin (AUC 5 or 6) / paclitaxel (200 mg / m2) 3 weekly# *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 progressionWHO, World Health Organization; PS, performance status; AUC, area under the curve; EGFR, epidermal growth factor receptor Mok et al 2008

  35. Progression-free survival Gefitinib Carboplatin / paclitaxel Probabilityof PFS 1.0 N Events 609 453 (74.4%) 608 497 (81.7%) 0.8 HR (95% CI) = 0.74 (0.65, 0.85) p<0.0001 5.874%48%7% 0.6 Median PFS (months)4 months progression-free6 months progression-free12 months progression-free 5.761%48%25% 0.4 Gefitinib demonstrated superiority relative to carboplatin/paclitaxel in terms of PFS 0.2 0.0 0 4 8 12 16 20 24 Months Patients at risk : Gefitinib 609 363 76 24 5 0 212 C/P 608 412 118 22 3 1 0 Primary Cox analysis with covariates; HR <1 implies a lower risk of progression on gefitinib; ITT populationPFS, progression-free survival; ITT, intent-to-treat; HR, hazard ratio; CI, confidence interval; C/P, carboplatin/paclitaxel Mok et al 2008

  36. IPASS: EGFR mutation positive status and clinical characteristics Overall EGFR mutation positive rate = 59.7% (261 / 437) % of samples EGFR mutation positive 68.5 63.0 60.7 60.2 56.7 60.0 57.1 57.8 49.0 46.9 Male Female PS 0/1 PS 0/2 Neversmoked Light ex-smoker Locallyadvanced Metastatic Age<65 yrs Age>65 yrs

  37. Progression-free survivalin EGFR mutation positive and negative patients EGFR mutation positive EGFR mutation negative Gefitinib (n=132)Carboplatin/paclitaxel (n=129) Gefitinib (n=91)Carboplatin/paclitaxel (n=85) 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 monthsMedian 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 monthsMedian PFS C/P, 5.5 months 1.0 1.0 0.8 0.8 0.6 0.6 Probability of progression-free survival Probability of progression-free survival 0.4 0.4 0.2 0.2 0.0 0.0 0 4 8 12 16 20 24 0 4 8 12 16 20 24 Months Months Patients at risk : Gefitinib 132 108 31 11 3 0 91 21 2 1 0 0 71 4 C/P 129 103 37 7 2 1 0 85 58 14 1 0 0 0 Treatment by EGFR mutation status interaction test, p<0.0001 Cox analysis with covariates; HR <1 implies a lower risk of progression on gefitinib; ITT population Mok et al 2008

  38. First line gefinitib vs. chemotherapy in EGFR mutated NSCLC • Primary endpoint • PFS • 2ndary endpoints • OS • Response • Side-effects • QOL • NSCLC with sensitive EGFR mutations • Stage IIIb/ IV • No prior chemo. • PS 0-1 • age of 20-75 y.o Gefitinib　 n=160 R balanced : Institution sex stage CBDCA+TXL　n=160 • 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 . North East Japan (NEJ) Gefitinib Study Group

  39. PFS OS Memondo, NEJM 2010

  40. Memondo, NEJM 2010

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

  42. Tumor Responses to Crizotinib for Patients with ALK-positive NSCLC (N=82) 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% * *Partial response patients with 100% change have non-target disease present

  43. 77% of Patients with ALK-positive NSCLC Remain on Crizotinib Treatment • Duration of treatment (median: 5.7 months) 0–3 mo 13 pts >3–6 mo 29 pts >6–9 mo 24 pts >9–12 mo 9 pts >12–18 mo  4 pts >18 mo 3 pts Individual patients • Reasons for discontinuation • Related AEs 1 • Non-related AEs 1 • Unrelated death 2 • Other 2 • Progression 13 0 3 69 12 15 18 21 Treatment duration (months) N=82; red bars represent discontinued patients

  44. 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 * 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

  45. Median PFS has Not been Reached 70% of Patients in Follow-up for PFS 1.00 0.75 0.50 0.25 0.00 PFS probability at 6 months: 72% (95% CI: 61, 83%)  Progression-free survival probability Median follow-up for PFS: 6.4 months (25–75% percentile: 3.5–10 months) 95% Hall–Wellner confidence bands 0 2.5 5.0 7.5 10.0 12.5 15.0 17.5 Progression-free survival (months)

  46. Treatment-related Adverse Events in ALK-positive NSCLC (≥10%) *Changes in light/dark accommodation (no abnormalities on ophthalmologic exam) N=82

  47. 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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