Maintenance Therapy for Advanced NSCLC: Which Patients, Which Approach? Mark A. Socinski, MD Visiting Professor of Medicine and Thoracic Surgery Director, Lung Cancer Section, Division of Hematology/Oncology Associate Clinical Director, Lung SPORE Co-Director, UPMC Lung Cancer Center of Excellence and Lung and Thoracic Malignancies Program University of Pittsburgh
Defining Maintenance Therapy Treatment beyond initial 4 (maybe 6) cycles of first line chemo doublet-based therapy with goal of maintaining best response with minimal toxicity Continuation maintenance: use of one or more agents given in first-line therapy Switch maintenance: initiation of a different agent that was not given in first-line therapy National Comprehensive Cancer Network website. http://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf. Accessed 3/31/10.
The Dawn of Maintenance Therapy in NSCLC ECOG 4599 First-line Adv. NSCLC nonsquamous cell (N = 878) R A N D Sandler, N Engl J Med. 2006 Carbo/pac 6 cycles Carbo/pac 6 cycles + bevacizumab q3wk RR: 15% (chemo) vs. 35% (chemo/bev) if no PD Observe until PD Maint bev until PD
Switch Maintenance Therapy
Immediate vs. Delayed Docetaxel Primary Endpoint: Overall Survival Adv. NSCLC Chemonaïve PS 0-2 N = 562 First-Line Chemo Gemcitabine/Carbo Every 3 wks x 4 cycles Gemcitabine 1000 mg/m2 IV d1, 8 q21 Carboplatin AUC 5 IV d1 q21 if no progression R A N D N = 307 46% drop off 95% of pts. received chemo Immediate Docetaxel 75mg/m 2 on Day 1, every 21 days until PD or maximum of 6 cycles Delayed Docetaxel Best supportive care, then start therapy at PD 75mg/m 2 on Day 1, every 21 days, until PD or maximum of 6 cycles 63% of pts. received chemo Fidias, J Clin Oncol 2009
Immediate vs. Delayed Second-Line Docetaxel Efficacy Progression-Free Survival Overall Survival Median 2 vs 4 mo p = 0.0001 HR=0.63 Median 9.1 vs 12.5 mo p = 0.08 HR=0.80 Fidias, J Clin Oncol 27:591-598, 2009
Survival for Patients Actually Receiving Docetaxel on Immediate and Delayed Arms (Fidias) 14 12.5 12.5 12 10 8 6 Immediate Delayed 4 2 0 MST (months) N 145 98
JMEN: Maintenance Pemetrexed vs. Placebo after First-Line Chemotherapy Does going on maintenance pemetrexed after four cycles of firstline chemo improve progression-free survival (PFS)? Advanced NSCLC No progression after 4 cycles of first line chemo (not including pemetrexed) N = 663 N = 441 R A N D N = 222 Maintenance pemetrexed IV every 3 weeks B12 and folate supplementation Maintenance placebo IV every 3 weeks B12 and folate supplementation Belani, Proc ASCO 2009
PFS Probability (%) Survival Probability (%) PFS and OS PFS OS (ITT Population) 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 Pemetrexed: 4.04 mos (95% CI: 3.06 4.44) Placebo: 1.97 mos (95% CI: 1.54 2.76) HR = 0.599 (95% CI: 0.49 0.73) p <.00001 1.0 0.9 0.8 0.7 0.6 0.5 0.4 Pemetrexed 13.4 mos Placebo 10.6 mos HR = 0.79 (95% CI: 0.65 0.95) p =.012 0.1 0.3 0.0 0.2 0.1 0 3 6 9 12 15 18 21 24 Time (mos) 24% censored 0.0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 Time (mos) Ciuleanu, Lancet 2011
Survival Probability (%) JMEN: OS by Histology Non-Squamous (n = 481) SCC (n = 182) HR = 0.70 (95% CI: 0.56 0.88) HR = 1.07 (95% CI: 0.49 1.73) p =.002 p =.678 1.0 0.9 0.8 Pemetrexed 15.5 mos Placebo 10.3 mos 1.0 0.9 0.8 Pemetrexed 9.9 mos Placebo 10.8 mos 0.7 0.7 0.6 0.6 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 (mos) Time (mos) Belani et al, 2009.
Erlotinib Maintenance Therapy in Advanced NSCLC: SATURN 1 st Line Adv NSCLC N = 1949 Tissue collected Platinum-based doublet chemo x 4 cycles if no prog R A N D N = 889 Erlotinib 150 mg PO daily Until Progresssion Placebo150 mg PO daily Until Progression 54% dropped off Primary Endpoint: PFS (All, and EGFR IHC positive) Capuzzo, ASCO 2009, WCLC 2009; Lancet 2010
PFS probability SATURN Trial Progression-Free Survival (by Intent to Treat) 1.0 0.8 Erlotinib Placebo PFS at 12 wks (%) 53 40 PFS at 24 wks (%) 31 17 0.6 0.4 0.2 HR=0.71 (0.62 0.82) Log-rank p<0.0001 Erlotinib (n=437) Placebo (n=447) 0 0 8 16 24 32 40 48 56 64 72 80 88 96 Time (weeks) *PFS is measured from time of randomization into the maintenance phase; assessments were every 6 weeks; ITT = intent-to-treat population
SATURN Trial Progression-Free Survival in Clinical Subgroups All HR (95% CI) n 0.71 (0.62 0.82) 884 Male Female 0.78 (0.66 0.92) 654 0.56 (0.42 0.76) 230 Caucasian Asian 0.75 (0.64 0.88) 744 0.58 (0.38 0.87) 128 Adenocarcinoma Squamous-cell 0.60 (0.48 0.75) 401 0.76 (0.60 0.95) 359 Never smoker Former smoker Current smoker 0.56 (0.38 0.81) 152 0.66 (0.50 0.88) 242 0.80 (0.67 0.97) 490 0.4 0.6 0.8 1.0 1.2 Favours erlotinib HR Favours placebo
OS probability SATURN Trial Overall Survival (by Intent to Treat) 1.0 0.8 HR=0.81 (0.70 0.95) Log-rank p=0.0088 0.6 0.4 Erlotinib (n=438) Placebo (n=451) 0.2 0 11.0 12.0 0 3 6 9 12 15 18 21 24 27 30 33 36 Time (months) *OS is measured from time of randomisation into the maintenance phase; ITT = intent-to-treat population
SATURN Trial Quality of Life/Symptom Progression HR (95% CI) p Time to deterioration in QoL (FACT-L) 0.96 (0.79 1.16) 0.6530 Time to pain 0.61 (0.42 0.88) 0.0080 Time to cough 0.77 (0.49 1.21) 0.2546 Time to dyspnea 0.75 (0.48 1.17) 0.2054 Time to analgesic use 0.66 (0.46 0.94) 0.0199 FACT-L = Functional Assessment of Cancer Therapy Lung questionnaire; QoL = quality of life
PFS probability PFS according to EGFR mutation status EGFR mutation+ EGFR wild-type 1.0 0.8 HR=0.10 (0.04 0.25) Log-rank p<0.0001 Erlotinib (n=22) Placebo (n=27) 1.0 0.8 HR=0.78 (0.63 0.96) Log-rank p=0.0185 Erlotinib (n=199) Placebo (n=189) 0.6 0.6 0.4 0.4 0.2 0.2 0 0 0 8 16 24 32 40 48 56 64 72 80 88 96 0 8 16 24 32 40 48 56 64 72 80 88 96 Time (weeks) Time (weeks) Interaction p<0.001
OS probability OS according to EGFR mutation status EGFR mutation+ EGFR wild-type 1.0 HR=0.83 (0.34 2.02) Log-rank p=0.6810 1.0 HR=0.77 (0.61 0.97) Log-rank p=0.0243 0.8 0.8 Erlotinib (n=199) Median 11.3 Placebo (n=189) Median 10.2 0.6 0.6 0.4 0.4 0.2 Erlotinib (n=22) Median NR Placebo (n=27)* Median 23.8 0 0 3 6 9 12 15 18 21 24 27 30 33 36 Time (months) 0.2 0 0 3 6 9 12 15 18 21 24 27 30 33 36 Time (months) *Note that 67% of patients with EGFR mutation+ disease in the placebo arm received a second-line EGFR TKI
PFS probability PFS according to KRAS mutation status KRAS mutation+ KRAS wild-type 1.0 0.8 HR=0.77 (0.50 1.19) Log-rank p=0.2246 Erlotinib (n=49) Placebo (n=41) 1.0 0.8 HR=0.70 (0.57 0.87) Log-rank p=0.0009 Erlotinib (n=205) Placebo (n=198) 0.6 0.6 0.4 0.4 0.2 0.2 0 0 0 8 16 24 32 40 48 56 64 72 80 88 96 0 8 16 24 32 40 48 56 64 72 80 88 96 Time (weeks) Time (weeks) Interaction p=0.95
OS probability Prognosis of patients with SD after first-line chemotherapy in SATURN 1.0 0.8 Placebo: SD on 1st-line chemotherapy (n=235) Placebo: CR/PR on 1st-line chemotherapy (n=210) 0.6 0.4 0.2 0 0 3 6 9 12 15 18 21 24 27 30 33 36 Time (months)
OS probability OS according to response to first-line chemotherapy (ITT population) Stable Disease CR/PR 1.0 1.0 0.8 HR=0.72 (0.59 0.89) Log-rank p=0.0019 0.8 HR=0.94 (0.74 1.20) Log-rank p=0.6181 0.6 0.6 Erlotinib (n=252) Erlotinib (n=184) 0.4 Placebo (n=235) 0.4 Placebo (n=210) 0.2 0.2 0 9.6 11.9 0 3 6 9 12 15 18 21 24 27 30 33 36 Time (months) 0 12.0 12.5 0 3 6 9 12 15 18 21 24 27 30 33 36 Time (months) Multivariate HR for OS in SD population 0.71, p=0.0019 Measured from time of randomisation into the maintenance phase
OS probability OS in patients with SD on first-line chemotherapy according to histology 1.0 Squamous 1.0 Non-squamous 0.8 HR=0.67 (0.48 0.92) 0.8 HR=0.76 (0.59 1.00) Log-rank p=0.0116 Log-rank p=0.0457 0.6 Erlotinib (n=97) Placebo (n=93) 0.6 Erlotinib (n=155) Placebo (n=142) 0.4 0.4 0.2 0.2 0 8.3 11.3 0 3 6 9 12 15 18 21 24 27 30 33 36 Time (months) 0 10.6 13.7 0 3 6 9 12 15 18 21 24 27 30 33 36 Time (months) Measured from time of randomisation into the maintenance phase
OS probability OS in EGFR wild-type group with SD on first-line chemotherapy 1.0 0.8 0.6 0.4 Erlotinib (n=114) Placebo (n=103) HR=0.65 (0.48 0.87) Log-rank p=0.0041 0.2 0 8.7 12.4 0 3 6 9 12 15 18 21 24 27 30 33 36 Time (months) Measured from time of randomisation into the maintenance phase
Erlotinib Confers Survival Benefit Even for Patients with Response Rates of Nearly 0% Survival distribution function 1.00 Male Smokers with Squamous-Cell NSCLC 0.75 HR = 0.66 95% CI = 0.47 0.92 p = 0.016 0.50 Erlotinib median = 5.5 months (n=100) Placebo median = 3.4 months (n=57) 0.25 0 0.0 2.5 5.0 7.5 10.0 12.5 15.0 17.5 20.0 Survival time (months) Clark, Clin Lung Ca, 2006
% Patients NOT Receiving Second Line Treatment in Observation Arms Study # Pts. w CR/PR/SD at end of 1 st line HR for OS # Pts. Obs Arm NOT Receiving Same Rx Fidias (JCO 2009) 309.94 37% Ciuleanu (Lancet 2009) 663.70 (non-scca) 80% Cappuzzu (Lancet Oncol 2010) 889.81 79%
Continuation Maintenance Therapy
Gemcitabine Maintenance vs. Best Supportive Care Stage IIIB/IV NSCLC Chemo-naïve PS 0-2 (N=352) First-line chemo Gemcitabine/Cisplatin x3 cycles If no PD Gemcitabine: 1250 mg/m 2 IV d 1, 8, q 21 d R A N D 2:1 Ongoing gem until PD, + BSC (N = 138) BSC (N = 68) Cisplatin: 80 mg/m 2 IV d 1, q 21 d TTP: 6.6 vs 5 mo (3.6 vs 2.0 mo during maintenance) for gemcitabine maintenance therapy vs best supportive care, respectively; P<.001 No difference in OS Brodowicz T, et al, Lung Cancer. 2006;52(2):155-163.
Gemcitabine Maintenance after First Line Carbo/Gemcitabine Stage IIIB/IV NSCLC Chemo-naïve PS 0-2 (N=519) First-line chemo Gemcitabine/Carbo x4 cycles Gemcitabine: 1000 mg/m 2 IV d 1, 8, q 21 d Carboplatin: AUC 5 IV d 1, q 21 d If no PD R A N D 1:1 N = 255 (51% drop off) Ongoing gem until PD, + BSC BSC Median age 67 64% of patients performance status 2 (56% PS2-3 during maintenance) Belani, ASCO 2010, #7506
Gemcitabine Continuation Maintenance after First Line Carbo/Gemcitabine: Efficacy PFS OS Belani, ASCO 2010, #7506
PARAMOUNT: Phase III Trial of Pemetrexed Maintenance in Nonsquamous NSCLC Eligibility: Stage IIIB/IV NSCLC Nonsquamous No prior therapy Prior radiation allowed (N=900) Pemetrexed 500 mg/m 2 Cisplatin 75 mg/m 2 q21d 4 cycles Primary endpoint: PFS Secondary endpoints: OS, patient reported outcomes, safety, response (OS data not yet mature) CR PR SD R A N D O M I Z E Pemetrexed BSC Placebo BSC PD Paz-Ares. ASCO. 2011 (abstr CRA7510) & ASCO 2012 (A#LBA7507).
Survival Probability PARAMOUNT: PFS from Randomization PFS: Primary Efficacy Endpoint PFS: Reassessed at Time of Final OS Survival Probability 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 Pemetrexed Placebo Unadjusted HR: 0.62 (0.49-0.79) 0.0 0 3 6 9 12 15 Time (Months) Patients at Risk Pem + BSC 359 132 57 21 4 0 Plac+ BSC 180 52 15 5 0 0 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Patients at Risk Pemetrexed Placebo Unadjusted HR: 0.60 (0.50-0.73) 0 3 6 9 12 15 18 21 24 27 30 33 Time (Months) Pem +BSC 359 215 139 97 67 47 32 22 16 10 5 0 Plac + BSC 180 75 33 16 9 7 6 4 2 0 0 0 Paz-Ares. ASCO. 2011 (abstr CRA7510) & ASCO 2012 (A#LBA7507).
PARAMOUNT: OS from Randomization
PARAMOUNT: Subgroup PFS Hazard Ratios PFS results were internally consistent; benefit was seen across all subgroups All Randomized Patients (N=539) Stage IV (n=489) Stage IIIB (n=50) Induction Response CR/PR (n=242) Induction Response SD (n=280) Pre-randomization PS 1 (n=366) Pre-randomization PS 0 (n=170) Non-smoker (n=116) Smoker (n=419) Male (n=313) Female (n=226) Age <70 (n=447) Age 70 (n=92) Age <65 (n=350) Age > 65 (n=189) Other Histologic Diagnosis (n=32) Large Cell Carcinoma (n=36) Adenocarcinoma (n=471) 0.62 0.62 0.55 0.48 0.74 0.67 0.53 0.41 0.70 0.74 0.49 0.69 0.34 0.70 0.50 0.64 0.39 0.62 0.0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0 Treatment Hazard Ratio (95% CI) Paz-Ares et al, 2011. Favors Pemetrexed Favors Placebo
PARAMOUNT: OS by Induction Response
Efficacy of Maintenance Therapy Results of Recent Phase III Studies Reference n Therapy Primary End Point PFS (HR) OS (HR) Fidias et al, 2009 309 Docetaxel OS 0.63 0.80 Ciuleanu et al, 2009 663 Pemetrexed PFS 0.50 0.79 Belani et al, 2010 255 Gemcitabine OS 1.09 0.97 Cappuzzo et al, 2010 889 Erlotinib PFS 0.71 0.81 Miller et al, 2009 768 Pérol et al, 2010 464 Erlotinib + Bevacizumab Erlotinib vs. Gemcitabine PFS 0.72 0.92 PFS 0.82 0.55 0.91 0.86 Takeda et al, 2010 604 Gefitinib OS 0.68 0.86 Paz-Ares et al, 2011 539 Pemetrexed PFS 0.64 0.78 Zhang et al, 2011 296 Gefitinib PFS 0.42 0.83 PFS = progression-free survival; OS = overall survival; HR = hazard ratio; NR = not reported.
Comparing Maintenance Therapy Strategies Continuation vs. Maintenance Single Agents vs. Combinations Chemotherapy vs. Targeted Therapies
IFCT-GFPC 0502 study design Cisplatin gemcitabine x 4 cycles N=834 PD: off Objective response or stable disease 44% dropoff R* N=464 A B Maintenance treatment Observation N=155 Gemcitabine N=154 PD PD Progression: 2 nd line Pemetrexed Pemetrexed NSCLC Stage IIIB wet IV PS 0-1, 18-70 years Asymptomatic brain mets allowed Tumor tissue EGFR IHC EGFR mutation C N=155 Erlotinib Primary endpoint: PFS PD Pemetrexed Induction chemo: cisplatin 80mg/m 2 d1 + gemcitabine 1,250mg/m 2 d1, d8 Arm B: gemcitabine 1,250mg/m 2 d1, d8 /3 wks Arm C: erlotinib 150mg daily Pérol, J Clin Oncol 2012 *Stratification factors: gender histology: adenocarcinoma vs other histology smoking status: non-smokers vs current/former smokers center response vs stabilization to induction chemotherapy EGFR = epidermal growth factor receptor IHC = immunohistochemistry; PD = progressive disease
IFCT Trial: PFS Benefit with Gemcitabine (Continuation Maintenance Therapy) Pérol, J Clin Oncol 2012
IFCT Trial: PFS Benefit with Erlotinib (Switch Maintenance Therapy) Pérol, J Clin Oncol 2012
Overall Survival: Maintenance Therapy with Gemcitabine or Erlotinib vs. Observation Gemcitabine (continuation) Erlotinib (switch) No OS benefit, arguably from equalizing effect of subsequent effective therapy Pérol, J Clin Oncol 2012
2 nd /3 rd Line Therapies in IFCT-GFPC 0502 Maintenance Arm OBS (n=155) Gem (n=154) Erlotinib (n=155) 2 nd line pemetrexed (%) 83.8 74.0 74.3 RR to 2 nd line pemetrexed (%) 9.9 7.9 9.9 2 nd line other (%) 7.1 3.2 5.1 3 rd line Treatment (%) 58.2 60.5 50 Most commonly used 3 rd line agent Erlotinib Erlotinib Docetaxel Perol M et al J Clin Oncol epub Sept 4, 2012
AVAPERL: Continuation Maintenance Therapy with Pemetrexed vs. Pemetrexed/Bevacizumab First-line Adv. NSCLC Non-squamous N = 362 R A N D O M I Z E Cisplatin/Pemetrexed with Bevacizumab 4 cycles Cisplatin/pemetrexed with Bevacizumab 4 cycles If no PD Bev Maint Rx Pem/Bev Maint Rx Median progression-free survival: 6.6 vs. 10.2 months, favoring combination (HR = 0.50; p< 0.001) No new safety issues ESMO 2011
AVAPERL: Efficacy Progression-Free Surv from Maintenance Overall Survival
Erlotinib Maintenance Therapy Trials in Advanced NSCLC: ATLAS 1 st Line Adv NSCLC Bev Eligible N = 1150 Primary Endpoint: PFS Platinum-based doublet chemo + bevacizumab x 4 cycles if no prog R A N D 1:1 N = 743 (35% drop off) Bev 15 mg/m2 IV Q21d + Erlotinib 150 mg PO daily Until Progression Bev 15 mg/m2 IV Q21d + Placebo150 mg PO daily Until Progression Miler, Proc ASCO 2009
Proportion Without Event ATLAS Trial Progression-Free Survival 1.0 0.8 Bev + Placebo (n=373) Bev + Erlotinib (n=370) 0.6 0.4 HR=0.722 (0.592-0.881) Log-rank P=0.0012 0.2 0.0 0 3 6 9 12 15 18 21 No. of patients at risk: Progression-Free Survival (months) Bev+Placebo Bev+Erlotinib 373 142 58 27 15 6 3 0 370 178 81 43 20 6 3 1 Miler, Proc ASCO 2009
Kabbinivar, Proc ASCO 2010 ATLAS Trial Overall Survival
POINT BREAK Trial: ECOG 4599 vs. ABC/ Patel Regimen Primary investigator: Dr. Jyoti Patel, Northwestern First-line Adv. NSCLC Non-squamous N= 939 R A N D O M I Z E Primary endpoint: Overall survival Carboplatin/paclitaxel Bevacizumab 4* cycles Carboplatin/pemetrexed Bevacizumab 4* cycles If no PD Bev Maint Rx Pem/Bev Maint Rx N = 590 (37% drop off)
PointBreak: Overall Results From First Line Progression-Free Survival Overall Survival More neuropathy, alopecia w/paclitaxel; more heme toxicity w/pem Patel, Chicago Multidisciplinary Symposium in Thoracic Onc
PointBreak: Results From Maintenance (63%) Progression-Free Survival Overall Survival Pem/Bev combination appears more effective in maintenance setting Patel, Chicago Multidisciplinary Symposium in Thoracic Onc
ECOG 5508 Trial of Maintenance Therapy Options in Advanced NSCLC Principal Investigator: Suresh Ramalingam Advanced NSCLC bev eligible PS 0-1 Carbo AUC 6 Paclitaxel 200 mg/m2 Bevacizumab 15 mg/kg IV day 1 q 21days x 4 cycles if no PD R A N D O M I Z E Bevacizumab 15 mg/kg q21days to PD Pem 500 mg/m2 q21days to PD Pem 500 mg/m2 Bevacizumab 15 mg/kg q21days to PD PD = progressive disease
Rates of Crossover and Administration of Any 2 nd Line Agent in The Major Maintenance Trials Edelman et al. J Thorac Oncol 7:1331, 2012 2012International Association for the Study of Lung Cancer. Published by Lippincott Williams & Wilkins, Inc. 2
Considerations in Evaluating the Role of Maintenance Therapy in Advanced NSCLC Exposure to effective agents and 2 nd line therapy was compromised on control arms of many trials Patients on control arms had to wait for RECIST defined PD before therapy could be instituted These two factors may have predisposed the control arms on many trials to have poorer survival When 2 nd line therapy defined in the trial design (Perol), survival is equivalent It is probably exposure not timing that benefits patients Do we improve QoL without undue toxicity?
QoL in Maintenance Therapy Author Year Instrument Overall Specific Findings Fidias 2008 LCSS Ciuleanu 2009 LCSS Cappuzzo 2009 FACT-L Better (not sign 0.76) No difference TTD No difference TTD - Delayed in worsening of 2/6 symptoms (pain, hemoptysis) Delayed time to pain & analgesic use (HR 0.96) No diff in time to cough and dyspnea Miller 2009 - - - Perol 2012 - nr nr Paz Ares 2011 EQ5D No difference - Zhang 2011 FACT-L Better Delayed median time to worsening in lung cancer symptoms TTD time to deterioration in QoL
Toxicity in Switch Maintenance Trials EJC Zhang et al. Chest 140 July, 2011
Conclusions - Management after 4-6 Cycles of Therapy Continuation or switch maintenance appear comparable Maximize benefit from each agent before discontinuing it (favor continuation over switch in patients doing well) In bev-eligible patients, PFS but not OS appears better with combinations than bev alone Duration of maintenance unclear (pay attention to gr 1-2 toxicities which adversely effect QoL) Survival benefit with erlotinib is NOT limited to EGFR mutants and is only maintenance agent studied with bev A treatment break is still reasonable and can be therapeutic IF patients get treated later Maintenance an option.but not a mandate
So What Do I Do In My Practice In non-squames after 4 cycles If I use bev, I generally continue it until PD If I use pem with bev, I think I may do more bev alone If I do not use bev, I generally use Pem-based therapy and give the option of continuation Pem or OBS but reassess q4 cycles In squames after 4 cycles I generally offer a treatment break but if SD PD I recommend maintenance with erlotinib or doectaxel