Annual Meeting Proceedings Part 1 - American Society of Clinical ...

7553 General Poster Session (Board #46C), Sat, 1:15 PM-5:15 PM
Radiographic assessment and therapeutic decisions at RECIST progression
in EGFR-mutant NSCLC treated with EGFR tyrosine kinase inhibitors.
Presenting Author: Mizuki Nishino, Dana-Farber Cancer Institute, Boston,
MA
Background: EGFR mutated advanced NSCLC treated with EGFR TKIs
typically progresses after initial response due to acquired resistance. TKI
therapy is often continued beyond RECIST progression (PD). We investigated
the frequency of this practice and patterns of RECIST PD via imaging
findings, as well as the association between patient characteristics and
discontinuation of TKI among patients (pts) who progressed while on TKI.
Methods: Among a cohort of 101 advanced NSCLC pts with sensitizing
EGFR mutations treated with first-line erlotinib or gefitinib at DFCI, 70 pts
treated between 2002 and 2010 had at least two CT scans for retrospective
radiographic assessments using RECIST1.1; 56 pts had experienced PD by
the data closure date of June 2011. Results: Among 56 pts experiencing
PD, 46 (82%) were female, median age was 63 (range 35-79), 28 (50%)
were never-smokers, 32 (57%) had distant mets, 32(57%) had exon 19
deletion, and 50 (89%) received erlotinib. 49 pts (88%) continued TKI
therapy for at least 2 mos beyond retrospectively assessed PD. 31/32
(97%) pts who progressed by increase of target lesions continued TKI.
13/16 (81%) pts who progressed by new lesion remained on TKI. Two pts
with PD in non-target lesions discontinued therapy at PD. 5/6 (83%) pts
with both increase of target lesions and new lesion at PD continued TKI. In
49 continuing pts, the median time from RECIST PD to termination of TKI
was 10.1 mos (range: 2.2-64.2 mos). 15/49 (31%) pts who continued TKI
received additional chemo compared to 0/7 pts who discontinued (Fisher’s
p�0.17). Pts who discontinued therapy (n�7) were significantly younger
(median 48 yrs) than those who continued TKI at PD (median 64 yrs,
Wilcoxon p�0.003). Median OS beyond RECIST PD among those who
continued TKI was 31.8 mos (95% CI 15.9- not reached) and though
underpowered, this did not appear to be impacted by TTP when adjusted in
a Cox model (p�0.84). Conclusions: 88% of EFGR-mutant NSCLC pts who
progressed on first-line TKI continued therapy beyond RECIST PD, which is
not the single determining factor for terminating TKI in EGFR-mutant
NSCLC pts. Additional progression criteria specific to this population are
needed to better guide therapeutic decision making.
7555 General Poster Session (Board #46E), Sat, 1:15 PM-5:15 PM
N0821: A phase II first-line study of a combination of pemetrexed (P),
carboplatin (C), and bevacizumab (B) in elderly patients with good
performance status (PS < 2). Presenting Author: Grace K. Dy, Roswell Park
Cancer Institute, Buffalo, NY
Background: In a retrospective exploratory analysis of E4599, patients (pts)
� 70 yo had a higher frequency of and more severe toxicities without
apparent survival benefit from the addition of B to C�paclitaxel. We
hypothesized that in this pt population, B will have better safety and
efficacy profile when used in combination with C�P. Methods: Pts �/� 70
yo with previously untreated stage IIIB/IV (TNM 6th ed) nonsquamous
NSCLC, ECOG PS 0-1, measurable disease and adequate organ function
were eligible. C at AUC 6, P at 500 mg/m2 and B at 15 mg/kg were
administered on day 1 of each 21-day cycle for up to 6 cycles followed by
maintenance P�B in patients with CR, PR or SD. The primary endpoint was
6-month progression-free survival (PFS) rate. The treatment would be
considered promising based on a single arm one-stage binomial design if
34 or more successes out of 55 patients were observed. This design had an
exact significance level of 0.05 at 93% power to detect a true success rate
of at least 70%. Polymorphisms in VEGFA, FPGS, GGH, SLC19A1 and
TYMS in germline DNA were correlated with treatment outcome. Results:
58 eligible pts were enrolled; 29 males/29 females. Median age was 75.
Median treatment cycles received was 6. Grade 3 or higher adverse events
(AE) were reported in 49 (85%) pts. There were no treatment-related
deaths. The most common grade 3/4 AEs(regardless of attribution) were
hypertension (10%), fatigue (28%), dehydration (9%), neutropenia (43%)
and thrombocytopenia (21%). There were 3 (5%) grade 3/4 hemorrhagic
events. 8 (14%) had grade 4 neutropenia and 3 (5%) had grade 4
thrombocytopenia. Grade 3/4 ischemic/thromboembolic events occurred in
6 pts (10%). Thirty-four out of the first 54 (63%, 95% CI: 48.7-75.7%)
evaluable pts met the primary endpoint (4 pts were lost to follow-up prior to
6 months). The confirmed ORR was 37.9% (95% CI: 25.5-51.6%).
Median time to treatment failure was 4.8 months (95% CI: 3.9-6.4).
Median PFS was 7.1 months (95% CI: 5.9-11.7), median OS was 13.7
months (95% CI: 9.4-15.7). Results of SNP analysis will be presented.
Conclusions: C�P�B followed by maintenance P�B is an active and
tolerable first-line regimen for elderly patients with good PS.
Lung Cancer—Non-small Cell Metastatic
493s
7554 General Poster Session (Board #46D), Sat, 1:15 PM-5:15 PM
Phase II study of pemetrexed (Pem) and cisplatin (Cis) plus cetuximab
(Cet) followed by Pem and Cet maintenance therapy in patients (Pts) with
advanced nonsquamous non-small cell lung cancer (NSCLC). Presenting
Author: Gerald Schmid-Bindert, University Medical Center, Mannheim,
Germany
Background: A prospective, nonrandomized, multicenter study was conducted
to assess the effect of adding cet to pem and cis in pts with
advanced nonsquamous NSCLC. Methods: 113 Caucasian performance
status 0-1 pts received 1st line pem (500 mg/m2 ) and cis (75 mg/m2 )on
day 1 (21d cycle) for 4-6 cycles and cet (400 mg/m2 loading dose followed
by 250 mg/m2 ) weekly. Non-progressive pts received pem 500 mg/m2 on
day 1 (21d cycle) plus cet (250mg/m2 weekly) until progression. Pts
received vitamin B12/folic acid and dexamethasone. Primary endpoint was
objective response rate (ORR) (RECIST 1.0). Secondary endpoints were
progression free survival (PFS), 1 year survival rate, translational research
(TR) and safety. Results: Pts’ characteristics: median age 59.7 years, 64%
male, 50% PS 0, 92% stage IV, and 78% adenocarcinoma. All pts
completed � 1 cycle of induction therapy and 45% and 43% completed �
1 cycle of maintenance with pem and cet, respectively. ORR (n�109) was
38.5% (80% CI 32.2-45.1), all partial responses. Disease control rate
(response/stable disease) was 59.6% (80% CI: 53.1-65.9). Median PFS
was 5.82 months (80% CI: 4.40-6.70). One year survival rate was 0.45
(80% CI: 0.39-0.51). Significant associations were seen between high
EGFR by IHC and increased PFS (cytoplasm: HR�0.46, p�0.035;
membrane: HR�0.41, p�0.008), and between high nuclear TTF-1 and
increased ORR (OR�7.73, p�0.021) / PFS (HR�0.21, p�0.001) / OS
(HR�0.25, p�0.035). Of 113 pts evaluated for safety, 73 (64.6%) pts
had drug related CTC Grade 3/4 adverse events (AE): most frequent were
neutropenia (14.2%), rash (15%), and vomiting (8.8%). Drug related
serious AEs were reported in 27.4% pts: most frequent were anemia
(5.3%), neutropenia (5.3%), vomiting (3.5%), and rash, renal failure,
diarrhea and fatigue (1.8% each). There were 2 potential on-study drug
related deaths (sudden death and large intestinal perforation). Conclusions:
Pem, cis and cet appeared efficacious and tolerable. These results support
further evaluation in a randomized trial. The TR outcomes are hypothesis
generating given the study’s size and nonrandomized nature.
7556 General Poster Session (Board #46F), Sat, 1:15 PM-5:15 PM
Targeting EGFR and ERBB3 in lung cancer patients: Clinical outcomes in a
phase I trial of MM-121 in combination with erlotinib. Presenting Author:
Lecia V. Sequist, Massachusetts General Hospital Cancer Center, Boston,
MA
Background: Erlotinib is effective in NSCLCs with wild-type EGFR and
shows enhanced benefit in EGFR mutation-positive cancers. However,
resistance invariably develops, often involving persistent ErbB3 signaling
and activation of the PI3K/AKT survival pathway. We present the full results
of the Phase 1 study evaluating the safety and tolerability of erlotinib plus
MM-121 a fully human IgG2 monoclonal antibody (mAb) to ErbB3.
Methods: Eligible patients had advanced stage NSCLC, and ECOG 0-2.
Seven cohorts were enrolled, evaluating varying levels of the MM-121 and
erlotinib, as well as alternate MM-121 infusion schedules. Tumor response
was assessed every 8 weeks. Dose levels were determined by safety and
pharmacokinetic (PK) data, and immunogenicity, efficacy endpoints and
exploratory biomarker evaluations were performed. Results: From February
2010 – July 2011 32pts entered the study (median age 63y; 45% male;
18% ECOG 0, 82% ECOG 1. 56% had adenocarcinoma and 30% pts
received 3 or more lines of prior therapies (range 0-7) with 91% having had
prior platinum. 65% had wild-type EGFR status and were never treated or
never responded to EGFR-TKIs (EGFRwt) and 28% had acquired resistance
to erlotinib treatment (EGFRresist). The most common toxicities (any
grade) observed were diarrhea (82%), rash (64%), and fatigue (64%).
DLTs observed in different cohorts were diarrhea, mucositis, rash and
failure to thrive. Clinical activity was observed including 1 PR (an EGFR TKI
naïve EGFR mutant) and 14 SD. Average duration of disease stabilization
was 21.6 wks (range 7.1 -89.3 wks). Median PFS is 8.1 weeks and the 16
week PFS rate was 41% in the overall population. For EGFRwt and
EGFRresist pts the median PFS were 7.7 weeks and 15.1 weeks, and the
16 week PFS rates were 32% and 44%, respectively. 7/20 EGFRwt pts and
5/9 EGFRresist pts achieved SD. Conclusions: This study suggests that the
combination of erlotinib and MM-121 has an acceptable safety profile in
heavily pre-treated NSCLC patients with and without EGFR mutations.
Early signals of patient benefit were seen and a large randomized phase II
study is ongoing.
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