Proposed Pathway & Evidence for Non-Small Cell Lung Cancer UPDATE in PROGRESS

Proposed Pathway & Evidence for Non-Small Cell Lung Cancer– UPDATE IN PROGRESS

Adjuvant (stage II to III)

Stage IA pts: poorly differentiated, vascular invasion, wedge resection, >4 cm tumor, visceral pleural involvement, and incomplete node sampling (Nx) chemo is a 2B recommendation

NCCN:Stage II-III : All are 2A recommendations

Published Chemo Regimens: Cisplatin-Vinorelbine, Cisplatin-Etoposide, Cisplatin-Vinblastine

Other Acceptable Cisplatin based Regimens: Cisplatin-Gemcitabine, Cisplatin-Docetaxel, Cisplatin-Pemetrexed

Regimens for pts with comorbidities : Carbo-paclitaxel

Pathway Preference / Regimen / Evidence / Total Cost
ClinicMargin
Preferred / Cisplatin-vinorelbine
(Cisp 100 mg/m2 on day 1 + vinorelbine 25 mg/m2 on days 1,8,15 and 22 of a 28 day cycle) /

ANITA trial had 840 pts and compared cisplatin + vinorelbine to observation
Overall survival (OS) was statistically significant 65.7 mo vs. 43.7mo (CI 0.76-0.98, p = 0.03)
No benefit of chemo seen with stage I pts
Nausea, vomiting, anorexia, asthenia and hematologic toxicities were more common in the treatment group
Bone mets were 3x lower in chemo group (4%vs 11%, p = 0.0001)

/ $X
$X
Preferred / Cisplatin-vinorelbine
(Cisp 50 mg/m2 on day 1 and 8 + vinorelbine 25mg/m2 on days 1,8,15 and 22 of a 28 day cycle) /

NEJM 2005 study of 482 pts of cis-vinorelbine vs observation
Study started with 30 mg/m2 vinorelbine but was changed to 25 mg/m2 due to hematologic toxicity
Median OS 94 mo vs. 73 mo was statistically significant (CI 0.52- 0.91, p =0.009)

/ $X
$X
Preferred / Cisplatin-etoposide /

LACE trial was pooled data from 5 recent large lung trials showed no difference between cis-etop and cis-vinorel but it wasn’t powered to show a difference and have very small number of study participants.

/ $X
$X
NP / Cisplatin-docetaxel /

TAX 326 study enrolled 1218 pts who were stage IIB -IV
Pts were assigned to Docetaxel + Cisplatin (DC) or Vinorelbine + Cisplatin (VC) or Docetaxel + Carboplatin (DCb)
Overall survival for DC 11.3 mo vs. VC 10.1 mo (CI 0.989-1.416)
Overall survival for DCb 9.4 mo vs. VC 9.9 mo (CI 0.877-1.253)
Grade III/IV anemia, nausea, and vomiting were significantly higher in VC group vs. DC or DCb groups.

/ $X
$X
NP+ / Cisplatin-gemcitabine /

Extrapolated from studies in advanced stage pts
4 arm Japanese study of 602 pts comparing cisp/iri vs. carb/pac vs. cisp/gem vs. cisp/vinor
No difference in OS between arms
QoL and tolerability were similar between arms

/ $X
$X
NP / Cisplatin-pemetrexed
(non-squam) /

Limited studies in the adjuvant setting

/ $X
$X

+NP = non-preferred

LACE trial showed that pts with adjuvant NSCLC with PS 2 should NOT receive chemotherapy as there may actually be a detrimental effect.

No data to support use of chemotherapy in stage IA patients.

Carbo-paclitaxel:

Theoretically for pts with comorbidities or who cannot tolerate cisplatin based therapy
CALGB study compared Carbo/paclitaxel to observation alone
No difference in OS (CI 0.64-1.08, p = 0.125)
Median survival was 95 months vs 78 months.
Subpopulation of pts with tumor size > 4cm showed a statistical significance in OS (CI 0.48-0.99)
Well tolerated
No toxicity related deaths in study
Summary: do not use chemotherapy, observation alone is equivalent

Chemotherapy + Radiation (Stage IIB-III)

NCCN:

Preferred: Cisp-etop and cis-vinblastine

2A: carbo-pem, cisp-pem

2B: carbo-paclitaxel

Pathway Preference / Regimen / Evidence / Total Cost
Clinic Margin
Preferred / Cisplatin-vinblastine /

Curran ASCO abstract 2003 – 3 arm randomized trial looked at concurrent vs sequential chemo/XRT (n=610)
Arm1: cisp/vinb sequential XRT, Arm 2: cisp/vinb concurrent XRT, Arm 3: cisp/etop PO concurrent XRT BID
Median survival was 14.6 mo for sequential, 17 mo for concurrent daily and 15.2 months for concurrent BID (p = 0.046 for sequential compared to daily concurrent, p = NS for sequential compared to BID concurrent)

/ $X
$X
Preferred / Cisplatin-etoposide /

SWOG 9019 trial (n=50)only 33 pts completed all planned treatments, 1 treatment related death
Median overall survival = 15 months, 3 year survival was 17% and 5 year survival was 15%
Toxicity: Grade 4 neutropenia 32%, grade 3/4 esophagitis 20%, grade 3/4 resp infection 8%, grade 3/4 anemia 28%

/ $X
$X
Preferred
(for pts that can’t tolerate cisplatin) / Carbo-paclitaxel /

Belani JCO 2005 Phase II trial (n=276) with 3 treatment arms. Arm 1: Carbo/pac sequential XRT, Arm 2: Carbo/pac sequential XRT + chemo, Arm 3: Chemo +XRT sequential carbo/pac.
Median survival: Arm 1 = 13 mo., Arm 2 = 12.7 mo., Arm 3 = 16.3 mo.

/ $X
$X
NP / Carbo-Pemetrexed /

Non-squam only

/ $X
$X
NP / Cis-Pemetrexed /

Non-squam only

/ $X
$X

Metastatic Disease

NCCN for Metastatic Disease:

Category 1: cis-pem

Category 2A: cis-pac, cis-gem, carbo-pac, carbo-pac-bev, doc alone, pem alone, erlotinib alone

Category 2B: cetuximab regimens

No Evidence: carbo-gem, carbo-pem, gem alone, and bev alone

Non-squamous

EGFR and ALK negative or unknown

Metastatic Disease - 1st Line

Pathway Preference / Regimen / Evidence / Total Cost
Clinic Margin
Carboplatin-paclitaxel q21days /

Schiller NEJM 2002 (n=1155): Cis(75)-pac(135) q21d vs cis(100)-gem(1000) d1,d8,d15 q28d vs carbo(AUC6)-pac(225) q21d vs cis-doc was found to be similar in efficacy with respect to median survival, 1 year survival, 2 year survival and response rate, but none of these endpoints reaches statistical significance. Treatment with cis-gem was associated with longer time to progression than cis-pac (3.4 vs 4.2 mo, p=0.001) but caused more grade 3,4 & 5 renal toxicity.
Inference from two studies:
Bonomi JCO 2000: cis-pac vs cis-etop showed cis-pac to be superior
Belani Ann Onc 2005: cis-etop vs carbo(AUC6)-pac showed no significant difference in survival or response rate between the regimens, but QOL after cycle 3 was better in the carbo-pac group
Ohe Eur Soc Med Oncol 2006 (n=300): Carbo(AUC6)-pac(200) q21d vs cis(80)-gem(1000) d1,d8 q21d found that the regimens had similar efficacy with respect to response rate (32.4% vs 30.1%), median survival time (12.3 vs 14 mo) and 1 year survival rates (51% vs 59.6%), but none of the study end-points reached statistical significance.

/ $X
$X
Cisplatin-pemetrexed /

Non-squamous and large-cell carcinoma. Do not use in squamous cell.
Scagliotti JCO 2008 (n=1725): cis-pem vs cis-gem found that in patients with adenocarcinoma and large-cell carcinoma had better efficacy with respect to survival (12.6 vs 10.9 mo and 10.4 vs 6.7 mo respectively). Rates of neutropenia, anemia, thrombocytopenia, febrile neutropenia and alopecia were lower, but grade 3-4 nausea is more common.

/ $X
$X
Carboplatin-paclitaxel weekly /

Limited evidence to use in NSCLC.
Belani JCO 2004 (abstract from ASCO, n=444):carbo(AUC6) with weekly pac (100) d1,8,15 q28d vs carbo(AUC6)-pac(225) q21 d found more significant toxicity in the q21d group, but no data was available evaluating efficacy.

/ $X
$X
Preferred for:

for pts <65
PS 0-1
no hemoptysis
no surgery in the last 8 wks

/ Carboplatin-paclitaxel-
Bevacizumab /

Avoid in patients with the following criteria: surgery within the last 6 weeks, untreated brain mets, uncontrolled hypertension, history of thromboembolic events (even if on warfarin or LMWH), and evidence of nephrotic syndrome.
Sandler NEJM 2006 (n=878): carbo-pac vs carbo-pac-bev showed bev regimen to have 2 month improved overall survival (12.3 vs 10.3 mo, p=003), PFS showed 1.7 mo improvement in the bev group (6.2 vs 4.5 mo, p<0.0001), improvement in response rates (35% vs 15%, p<0.0001). In the bev group, there were 15 treatment related deaths including 5 pulmonary hemorrhage vs only 2 treatment related deaths in the carbo-pac group. Significant bleeding was worse in the bev group (4.4% vs 0.7%, p<0.001).
Lima PLoS ONE 2011 (n=~3,000): meta-analysis of adding bev to platinum-based chemotherapy in metastatic NSCLC found that the absolute benefit in overall survival was 26 days, in PFS an absolute benefit of 1.4 months when adding bev to a platinum-based chemo regimen, overall response showed mixed results, favoring the bev group (OR 2.34, p,0.00001) and significant increase in treatment related deaths when adding bev (OR 1.82, p=0.04). The deaths were related to bleeding events, neutropenia complications and thromboembolic events.
Zhu et al performed a retrospective trial based on SEER data of carbo/taxol vs carbo/taxol/bevacizumab in patients > 65yrs. Median OS was 9.7 mo in the chemo+bev arm vs. 8.9 mo (pts treated 2006-2007) or 8 mo (pts treated 2002-2005) in the chemo alone arm. This was not considered statistically significant.

/ $X
$X
Carboplatin-pemetrexed /

No evidence referenced in NCCN

/ $X
$X

Squamous

EGFR and ALK negative

Metastatic Disease - 1st Line

NCCN:

Category 1: Cisp-Gem

Category 2B: Cisp-Vinorelbine

Pathway Preference / Regimen / Evidence / Total Cost
Clinic Margin
Preferred / Cisplatin-gemcitabine /

Do not use in Non-Squamous Cell, as Scagliotti JCO 2008 showed better efficacy with cis-pemetrexed (overall survival: 10.8 vs 9.4 mo).
Sandler JCO 2000 (n=522): cisplatin alone vs cis-gem found that cis-gem had a 1.5 month improvement in overall survival (9.1 vs 7.6mo, p=0.004), 1.9 month difference in time to progression (5.6 vs 3.7mo, p=0013), significant grade 4 neutropenia (35% vs 1%), and significant thrombocytopenia (25% vs 1%).
See study results above for Schiller NEJM 2002 and Smit JCO 2004 in cis-pac row.

/ $X
$X
NP / Cisplatin-Vinorelbine / $X
$X
NP / Carboplatin- gemcitabine / $X
$X

EGFR positive

Metastatic Disease – 1st line

NCCN: All category 1

Pathway Preference / Regimen / Evidence / Total Cost
Clinic Margin
Erlotinib
150 mg PO Daily /

Rosell et al conducted the EURTAC trial which was a phase III open label trial that studied erlotinib vs. chemotherapy for first line treatment of metastatic patient who had EGFR mutations. PFS: 10.4 mo vs. 5.2 mo. Overall survival was a secondary endpoint of the trial which was not powered for OS. OS did not differ between the 2 groups (19.3 mo in the erlotinib group vs. 19.5 mo). Most common adverse reactions were rash, diarrhea, asthenia, cough, dyspnea and anorexia.

/ $X
$X
Afatinib
40 mg PO Daily /

Sequist et al in the LUX-Lung study investigated afatinib vs cis-pem in 345 pts. PFS was 11.1 mo for afatinib vs 6.9 mo for cis-pem (HR = 0.58, CI 0.43-0.78, p = 0.001). Diarrhea, rash, acne, and stomatitis were more common with afatinib. Nausea, fatigue and anorexia were more common with chemotherapy. Overall survival was not studied.

/ $X
$X

ALK or ROS1 positive

Metastatic Disease – 1st line

NCCN:

Pathway Preference / Regimen / Evidence / Total Cost
Clinic Margin
Preferred / Crizotinib
250 mg PO BID /

ALK positive (or ROS1)
Single arm study (n=934) median duration of treatment was 5.5 mo, 8 pts had complete response, 357 partial for an ORR = 48%, median DR = 11 mo.
Single arm study (n=119) median duration of treatment was 32 weeks, ORR = 61% and median DR- 11.1 mo.
Shaw in NEJM 2013 (n=347) : Phase III open label study, pts had received one chemo, randomized to crizotinib or pemetrexed or docetaxel, median PFS = 7.7 mo for crizotinib vs 3 mo for chemo group (HR = 0.49, CI = 0.37-0.64, p <0.001) response rate = 65% for crizotinib vs 20% for chemo (p<0.001) Overall survival = NS, improvement in global QOL with crizotinib over chemo.

/ $X
$X

ALK positive

Metastatic Disease – 2nd line

NCCN:

Pathway Preference / Regimen / Evidence / Total Cost
Clinic Margin
Preferred / Ceritinib
750 mg PO Daily /

ALK positive

/ $X
$X

Metastatic Disease – 2nd line

Pathway Preference / Regimen / Evidence / Total Cost
Clinic Margin
Preferred / Docetaxel(75) /

Fossella JCO 2000 (n=373): doc(100) vs doc(75) vs vinorel vs ifos found doc to be superior to vinorelbine and ifosfamide with improved survival and QOL. The doc(75) regimen is preferred, as it had similar survival rates to doc(100) with less toxicity resulting in hospitalization and less use of G-CSF.
For patients without adenocarcinoma and large cell carcinomas, see pemetrexed alone row.

/ $X
$X
Preferred / Pemetrexed /

Only for non-squamous histology
Hanna JCO 2004 (n=571): in patients with adenocarcinoma and large cell carcinoma - pem alone vs doc(75) showed pem to be slightly superior to docetaxel in overall survival (8.3 vs 7.9mo, p=NS), and similar with respect to 1-year survival rates (29.7%) with less toxicity and hospitalization in the pem group.

/ $X
$X
Preferred / Erlotinib /

EGFR (KRAS mutation) Positive
Must have failed a platinum-based regimens
Patients that cannot tolerate cytotoxic chemotherapy (performance status 3-4)
Shepherd NEJM 2005 (n=731): erlotinib vs placebo found improved survival with the erlotinib group by 2 mo (6.7mo vs 4.7mo, p=0.001). Patients that had adenocarcinoma, never smoked and and EGFR expression were associated with better response to Erlotinib. 19% required dose reductions due to toxicity (mostly rash and diarrhea), however toxicity was very similar between the groups.

/ $X
$X
Preferred / Gemcitabine
1200mg/m2 d1, d8 q21days /

NCCN does not reference any single agent gemcitabine studies for advanced NCSLC.
Morere Lung Ca 2010 (n=127): phase II study in PS 2 or 3 compared gefitinib vs gem (1250) d1,8 q21d vs doc (75) q21d. PFS was 1.9 mo, 2.0 mo, and 2.0 mo respectively (gem vs doc HR 0.67, 95% CI 0.43-1.05), and median survival 2.2 mo, 2.4 mo and 3.5 mo respectively (gem vs doc HR 0.69, 95% CI 0.44-1.09). The docetaxel group had more grade 3-4 toxicities than the other two arms (doc 23%, gef 10%, gem 12%).

/ $X
$X
NP / Gemcitabine
1000mg/m2 d1, d8, d15 q28days /

NCCN does not reference any single agent gemcitabine studies for advanced NCSLC.
See above Morere study.

/ $X
$X
NP / Bevacizumab
15 mg/kg q21 days /

No evidence to give this as a single agent in NCSLC
May be appropriate to use as continuationmaintenance therapy but not as switch maintenance therapy

/ $X
$X

Metastatic – 3rdline – if not already given in previous lines of therapy (category 2B)

Pathway Preference / Regimen / Evidence / Total Cost
Clinic Margin
Preferred / Best Supportive Care /

PS 3-4

/ NA
Preferred / Erlotinib /

Statistically superior to BSC for overall survival
PS 0-4

/ $X
$X
Preferred / Docetaxel /

PS 0-2

/ $X
$X
Preferred / Pemetrexed /

Non-squam only
PS 0-2

/ $X
$X
Preferred / Gemcitabine /

Squamous
PS 0-2

/ $X
$X

BSC= best supportive care
NCCN indicates that cytotoxic chemotherapy is not indicated for any patients with metastatic disease and performance score of 3 or 4. These patientsshould receive BSC orconsider Erlotinib(if they are EGFR positive).

References:

1)Rosell et al. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicenter, open-label, randomized phase 3 trial. Lancet Oncol 2012;13:239-46.

2)Sandler et al. Treatment outcomes by tumor histology in Eastern Cooperative Group Study (E4599) of bevacizumab with paclitaxel/carboplatin for advanced non-small cell lung cancer. J Thorac Oncol 2010;5:1416-23.

3)Sequist et al. Phase III Study of Afatinib of Cisplatin Plus Pemetrexed in Patients with Metastatic Lung Adenocarcinoma With EGFR mutations. JCO 2013; 31:27:3327-3337

4)Zhe et al. Carboplatin and Pacltiaxel With vs Without Bevacizumab in Older Patients with Advanced Non-Small Cell Lung Cancer. JAMA 2012;307(15):1593-1601.

5-2014