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Adjuvant Therapy of NSCLC

Winter Lung Cancer Conference2012

Rogerio Lilenbaum, MD, FACPCleveland Clinic Florida

Weston, FL

Adjuvant Therapy of NSCLC

• Stage IB

• Chemotherapy choices

• PORT

LACE – Benefit by Stage

CT may be detrimental for stage IA, but stage IA patients were generally not given cisplatin+vinorelbine (13% of stage IA patients versus ~43% for other stages)

Test for trend: p = 0.051

CategoryNo. Deaths /No. Entered

Hazard Ratio (Chemotherapy /

Control) [95% CI]Stage IA 102 / 347 1.41 [0.96;2.09]Stage IB 509 / 1371 0.92 [0.78;1.10]Stage II 880 / 1616 0.83 [0.73;0.95]Stage III 865 / 1247 0.83 [0.73;0.95]

Strauss Proc ASCO 2004 abs 7019, 2006 abs 7007, JCO 2008

CALGB 9633 CALGB 9633 Overall Survival by Tumor SizeOverall Survival by Tumor Size

• Chemotherapy (N = 99)• Control (N = 97)

– HR = 0.69 – 90% CI: 0.48 to 0.99

– P = .043

• Chemotherapy (N = 63)• Control (N = 71)

– HR = 1.12 – 90% CI: 0.75 to 1.07 – P = .32

Tumor ≥4 cm Tumor <4 cm

Stage IB AnalysisStage IB Analysis

T < 4 cm T ≥ 4 cm

HR OS p HR OS pCALGB 9633 1.02 .51 0.66 .04

JBR.10 1.73 .07 0.66 .13

No Chemo Benefit Potential Chemo Benefit

Strauss JCO 2008, Vincent ASCO 2009

Stage-Specific Hazard RatiosStage-Specific Hazard RatiosRecent Adjuvant TrialsRecent Adjuvant Trials

TrialTrial IB < 4 cmIB < 4 cm IB IB >> 4 cm 4 cm IIII IIIAIIIA

IALTIALT 0.95 0.95 0.93 0.79

BR-10BR-10 1.73 0.66 0.59 N/A

ANITAANITA 1.10 0.10 0.71 0.69

CALGBCALGB 1.02 0.66 N/A N/A

LACELACE 0.92 0.92 0.83 0.83NegativeNegative PositivePositive

IndeterminateIndeterminate Not studiedNot studied

Adjuvant Therapy of NSCLC

• Stage IB – Tumor size matters – Use 4 cm as a parameter

• Chemotherapy choices

• PORT

Adjuvant Therapy of NSCLC

• Stage IB

• Chemotherapy choices

• PORT

E1505 Chemotherapy RegimensE1505 Chemotherapy Regimens

• Therapy to start 6-12 weeks post-operatively– Investigator Choice of Chemo - 4 cycles (12 wks)

• Cisplatin/Vinorelbine– Cis 75 mg/m2 d1, Vin 25 mg/m2 d1,8 q21 d

• Cisplatin/Docetaxel– Cis 75 mg/m2 d1, Docetaxel 75 mg/m2 d1 q21 d

• Cisplatin/Gemcitabine– Cis 75 mg/m2 d1, Gem 1250 mg/m2 d1,8 q21 d

• Cisplatin/Pemetrexed– Cis 75 mg/m2 d1, Pem 500 mg/m2 d1 q21 d

E1505 – Adjuvant ChemotherapyE1505 – Adjuvant ChemotherapyWakelee et al - ASCO 2011Wakelee et al - ASCO 2011

• Between Aug 2007 and Jan 2010, 557 patients were enrolled:– median age 61– 52% female– 54% adeno, 31% squamous – 23% IB, 43% II, 29% IIIA (N2) , 4% IIIA (T3N1)

• Adjuvant regimens:– 28% C-V– 34% C-D– 26% C-G – 12% C-P (added later)

• Overall Gr 3/4 toxicities are increased in Bev arm; Gr 5 toxicity was 2.5% vs. 3.8% without or with Bev

TREAT Design

Cisplatin / Vinorelbine (CVrb)

Cisplatin / Pemetrexed (CPx)

50 mg/m2 d1+8 / 25 mg/m2 d1, 8, 15, 22 q d 29 x 4

75 mg/m2 d1 / 500 mg/m2 d1 q d 22 x 4

R0Winton et al., N Engl J Med (2005) 352: 258

Inclusion:Inclusion:• NSCLC stages IB, IIA, IIB, T3N1M0• ≤ 42 Tage postoperatively, R0, systematic LN-dissection• ECOG 0, 1 - amenable to cisplatin treatment

Rationale:Rationale:• Need: reduction of toxicity, improvement of dose delivery & compliance

• Cisplatin / pemetrexed in thoracic malignancies: high dose intensity, low toxicities

CPx CVb

Feasibility rate (%) Feasibility rate (%) 95.5 95.5

(CI 87.5-99.1)(CI 87.5-99.1)75.4 75.4

(CI 63.1-85.2)(CI 63.1-85.2)Death (%) 1.5 3.1Withdrawal of consent (%) 0 6.2DLT (%) 3.0 15.4

Reasons for DLT (events)* patients (n=2) patients (n=10)G4 neutropenia >7d 0 4G4 thrombocytopenia >7d 0 0G3/4 febrile neutropenia 1 5Thrombocytopenia with bleeding 0 0G3/4 non-hematologic toxicity 2 1

Results Primary endpoint - feasibility

* multiple reasons possible

p = 0.0010p = 0.0010

EOT CPx CVb

Regular EOT (%) 77.6 36.9

Earlier termination of therapy (%) 22.4 63.1

Reasons for earlier termination (events)* patients (n=15) patients (n=41)• Unacceptable toxicity according to protocol** 4 19

• Unacceptable toxicity perceived by patient 6 7

• Relapse of disease 0 2

• Withdrawal of consent 0 4

• Death (therapy related) 1 (0) 2 (0)

• Non-compliance to protocol 0 2

• Medical decision by investigator 4 5

• Major protocol violation 0 1

• Other reasons 0 4

Results End of therapy

*multiple reasons possible**delay >2 weeks due to toxicity or in case of G3/4 non-hem toxicity

TREAT: Time to treatment failureTREAT: Time to treatment failure

Time from surgery to withdrawal due toTime from surgery to withdrawal due to • AEAE• progression / relapse / deathprogression / relapse / death• failure to return to therapyfailure to return to therapy• refusal of treatment / withdrawal of consent refusal of treatment / withdrawal of consent

Time to treatment failure also in favor of cisplatin/pemetrexed, p<0.001

Adjuvant Therapy of NSCLC

• Stage IB

• Chemotherapy choices– Use cisplatin whenever possible– Cis-Vnb is associated with greater toxicity

• PORT

Adjuvant Therapy of NSCLC

• Stage IB

• Chemotherapy choices

• PORT

ANITA - PORT EvaluationANITA - PORT Evaluation• PORT: 33% on obs, 22% on chemoPORT: 33% on obs, 22% on chemo• For all chemo > XRT = chemo/XRT > 0For all chemo > XRT = chemo/XRT > 0• For N2 chemo/XRT > chemo > XRT > 0For N2 chemo/XRT > chemo > XRT > 0

XRT No No Yes YesChemo No Yes No Yes

All pts MST 26mo 93mo 50mo 46mo

N2 MST 13mo 24mo 23mo 47mo

Rosell, IASLC 11, Abs Pr3, 2005

Overall survival for N2 pts stratified by Overall survival for N2 pts stratified by postoperative radiotherapy (PORT) usepostoperative radiotherapy (PORT) use

– – SEER dataSEER data

There is benefit of PORT in stage IIIA-N2 disease, and the role of PORT

in early stages of NSCLC should be clarified in ongoing phase III trials.

““Lung ART”Lung ART”P.I. Dr Cécile Le PechouxP.I. Dr Cécile Le Pechoux

Completely resected N2 NSCLC Completely resected N2 NSCLC

SSUURRGGEERRYY

Conformal RTConformal RT

No post-op RTNo post-op RT

54 Gy/27-30 fxs54 Gy/27-30 fxs

Primary end-point: DFS (sample size: 700 patients)Primary end-point: DFS (sample size: 700 patients)

Pre or post-op chemotherapy allowedPre or post-op chemotherapy allowedConcomitant chemo not allowedConcomitant chemo not allowed

Sponsors: FNCLCC, IFCT, LARS-G, EORTCSponsors: FNCLCC, IFCT, LARS-G, EORTC

Adjuvant Therapy of NSCLC

• Stage IB

• Chemotherapy choices

• PORT– No benefit in N0 and N1 disease– Consider in N2 patients – especially with multi-station

involvement and/or extra-capsular spread– Do it sequentially

Sunday, February 12, 2012Hollywood, Florida

Co-ChairsRogerio C Lilenbaum, MDMark A Socinski, MD

Co-Chair and ModeratorNeil Love, MD

Faculty

Walter J Curran Jr, MDDavid Jablons, MDMark G Kris, MD

Suresh Ramalingam, MDAlan B Sandler, MD