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

504s Lung Cancer—Non-small Cell Metastatic
7599 General Poster Session (Board #52A), Sat, 1:15 PM-5:15 PM
A large retrospective analysis of the activity of pemetrexed (PEM) in
patients (pts) with ALK-positive (ALK�) non-small cell lung cancer
(NSCLC) prior to crizotinib (CRIZ). Presenting Author: Giorgio V. Scagliotti,
University of Turin, Orbassano, Italy
Background: Retrospective small cohort studies suggest ALK� NSCLC may
be particularly sensitive to PEM. Methods: PROFILE 1005 (NCT00932451;
Pfizer) is a large phase 2 multi-center, single-arm study of CRIZ in
previously treated ALK� NSCLC. Eligibility criteria included pts with
progressive disease from the PEM arm of companion trial PROFILE 1007.
We retrospectively assessed objective response rate (ORR) and time to
progression (TTP; 1st dose to objective progression) in pts who received
PEM prior to CRIZ. ORR with CRIZ post-PEM was assessed. Results: Of the
439 ALK� pts enrolled as of June 2011, 369 (84.1%) received prior PEM
(single agent or combination; any line advanced/metastatic) with a cumulative
ORR of 18.7%. In pts who received PEM combinations 1st-line (1L;
n�120) or 2nd-line (2L; n�60), ORR was 24.2% and 16.7%; and median
TTP was 6.9 months (mo; 95% CI: 6.0–7.4) and 6.9 mo (95% CI:
4.8–8.8), respectively. In pts who received 2L single-agent PEM (n�80),
ORR was 12.5% and median TTP was 5.3 mo (95% CI: 3.0–6.6). In pts
treated with PEM 3rd-line (3L) or later (n�138), ORR was 16.7%. By line
of PEM treatment, ORR was lower and TTP shorter than that reported in
small ALK� cohorts evaluating multiple lines of treatment. In 2L, previously
reported ORR and median PFS with single-agent PEM in adenocarcinoma
NSCLC were 12.8% (n�158) and 3.5 mo (n�283), and comparable
to our findings. Pts who received 2L single-agent PEM (n�80) subsequently
achieved higher ORR with CRIZ (54%; 95% CI: 42–65). Similar
analyses in the 1L and 3L groups are ongoing. Conclusions: This retrospective
study in predominantly never-smokers with ALK� NSCLC reports lower
ORR and shorter TTP with PEM than that reported in smaller retrospective
ALK� NSCLC cohorts. This finding may be in part due to the inclusion of
crossover pts from PROFILE 1007. This analysis and previous reports
observed a tendency to a higher response rate and better PFS or TTP with
PEM than in unselected populations in 2L, which may not be specifically
related to ALK status but to a higher sensitivity to cytotoxic agents in
never-smokers. Results from an ongoing phase 3 trial (PROFILE 1007) will
provide additional information.
7601 General Poster Session (Board #52C), Sat, 1:15 PM-5:15 PM
Clinical benefit from pemetrexed before and after crizotinib exposure in
patients with ALK positive non-small cell lung cancer (ALK� NSCLC).
Presenting Author: Eamon Berge, University of Colorado Health Sciences
Center, Aurora, CO
Background: Crizotinib (Criz) produces high response rates and prolonged
progression free survival (PFS) in ALK� NSCLC. Retrospective analyses
suggest enhanced sensitivity to pemetrexed (Pem) in Criz-naïve ALK�
NSCLC. Different biological mechanisms of Criz resistance have recently
been discovered. Clinical cross-resistance between Criz and Pem has not
been previously investigated. Methods: Patients with stage IV ALK� NSCLC
treated in sequence with Pem then Criz (Pem-Criz), or Criz then Pem
(Criz-Pem) were identified. Excluding CNS only progression events when no
new systemic treated was started, PFS was compared using Cox Proportional
Hazards. Correlations between molecular features of ALK positivity
and Pem PFS were analyzed using Spearman correlations. Treatment
sequence effect was explored using Fisher’s exact test. Results: We
identified 19 Pem-Criz and 9 Criz-Pem ALK� patients. Pem was given as
monotherapy in 37% vs. 66%, and as median 2nd vs. 3rd line cytotoxic in
the Pem-Criz and Criz-Pem groups, respectively. For the Pem-Criz group,median
PFS was 8.9 months with Pem (range: 1-21.5 months), and 14.7
months with Criz (range:2.9� -27.5 months). For the Criz-Pem group,
median PFS was 8.4 months with Criz (range: 2-29 months), and 4.4
months with Pem (range: 0.5-10.5� months). Patients were more likely to
progress on Pem given after Criz than before, but confidence intervals were
wide (HR 1.51, 95% CI 0.626-3.66). Neither native or rearranged signal
copy number, nor percent cells ALK� in the tumors correlated with PFS on
Pem. Conclusions: Both Criz and Pem appear to be active drugs in
ALK�NSCLC given in either order. Numerically, benefit from Pem was less
when given post-Criz compared to pre-Criz, however this difference was not
statistically significant. Several potential confounders exist in our small
dataset (notably differences in line of therapy and use in combo vs.
monotherapy). To fully address whether there may be a significant
difference in overlap of induced specific drug resistance mechanisms, the
clinical effect of Criz/Pem sequencing should be explored in a larger series
adjusting for confounding effects.
7600 General Poster Session (Board #52B), Sat, 1:15 PM-5:15 PM
Clinical characteristics of ALK� NSCLC patients (pts) treated with crizotinib
beyond disease progression (PD): Potential implications for management.
Presenting Author: Gregory Alan Otterson, Department of Internal
Medicine, The Ohio State University Comprehensive Cancer Center, Columbus,
OH
Background: Crizotinib is a first-in-class oral ALK inhibitor for the treatment
(tx) of advanced ALK-positive (ALK�) NSCLC. Dramatic and prolonged
responses to crizotinib are common, but pts do experience PD. Methods:
Clinical characteristics of ALK� NSCLC pts enrolled onto two multicenter,
single arm trials of crizotinib (A8081001, PROFILE 1005) with investigatordefined
PD who were allowed to continue crizotinib if, in the investigator’s
opinion, there was reasonable evidence of ongoing clinical benefit were
assessed. A period of �2 wks was chosen as a reasonable minimum
duration of post-PD crizotinib tx. Results: As of 1 June 2011, 146 pts
(A8081001, n�61, PROFILE 1005, n�85) had PD. PD was observed in
new lesions only (1 organ site, n�62; �1 organ site, n�18), target � new
lesions (� 1 organ site, n�55), clinical PD (n�9), and no site assessment
(n�2). Most common new lesions in single organ sites were brain (brain
MRI not mandatory; n�25), liver (n�20), bone (n�4), and kidney (n�1).
Of the 146 pts, 78 (53%) received crizotinib post-PD for at least 2 wks,
91% of whom had ECOG PS 0 or 1 at PD. In these 78 pts, PD was observed
in new lesions only (1 organ site, n�39; �1 organ site, n�4), target � new
lesions (� 1 organ site, n�29), and clinical PD (n�6); the most common
sites for single organ PD were brain (n�20), liver (n�9), and other (n�10).
Best response before PD (% CR/PR, SD, PD) was 62/27/12 in the 78 pts
who received �2 weeks’ tx post-PD and 31/37/32 in the 68 pts who
received �2 weeks’ tx post-PD or discontinued. Median duration of
crizotinib tx post-PD (n�78) was 10 weeks (range 2–84). 20 pts with PD in
brain only (concurrent local tx or radiation permitted) continue to receive
crizotinib (range 3–82 weeks post-PD). Conclusions: Following initial
crizotinib tx, PD most commonly occurred at a single organ site in ALK�
NSCLC pts. The majority of pts receiving crizotinib post-PD had good PS,
and tended to have single-site PD (most often the brain or liver), and a prior
response on crizotinib. Given these observations, pts may be able to
continue with crizotinib for a period of time following clinical or documented
progression.
7602 General Poster Session (Board #52D), Sat, 1:15 PM-5:15 PM
A first-in-human phase I/II study of ALK inhibitor CH5424802 in patients
with ALK-positive NSCLC. Presenting Author: Katsuyuki Kiura, Department
of Respiratory Medicine, Okayama University Hospital, Okayama, Japan
Background: Anaplastic lymphoma kinase (ALK) is a tyrosine kinase
constitutively activated in a subset of non-small cell lung cancer (NSCLC)
following chromosomal gene translocation. CH5424802 was identified as
a potent, selective, and oral ALK inhibitor with a unique chemical scaffold,
showing preferential antitumor activity against NSCLC cells expressing
EML4-ALK fusion in vitro and in vivo (Cancer Cell, 2011). Our results
support the potential of CH5424802 as a new therapeutic opportunity for
patients (pts) with ALK-positive NSCLC. Methods: Pts with ALK-positive
NSCLC received CH5424802 twice daily orally until progressive disease or
toxicity was observed. In the phase I portion, dose was escalated using an
accelerated titration scheme. The primary objectives were to investigate the
safety, tolerability and pharmacokinetic (PK) parameters under fasting
conditions, and to determine the recommended dose (RD) for use in the
phase II portion. The primary objectives of the phase II portion were to
investigate the efficacy and safety at the RD. The phase I portion was
amended to include an investigation under non-fasting conditions in
addition to fasting conditions. Results: 15 pts (M/F: 9/6) were treated with
CH5424802 under fasting conditions in 6 cohorts (20 mg bid to 300 mg
bid) and 9 pts (M/F: 2/7) were treated under non-fasting conditions in 2
cohorts (240 mg bid and 300 mg bid). Median age was 42.5 years. The
highest dose level defined in the protocol (300 mg bid) did not reach the
MTD. Thus, a DLT was not determined. Toxicities were mild to moderate.
The most frequent toxicity was grade 1 myalgia. Grade 3 toxicity (cases)
occurred as follows; hypophosphatemia (2), neutropenia (2), blood CPK
increased (1) and hypermagnesemia (1). PK data from the fasting cohorts
showed dose-dependent increases of Cmax and AUC. All pts at all dose
levels achieved tumor regression. At dose levels 240 mg bid or more under
fasting conditions, all 7 pts with measurable lesions achieved a partial
response. So far, 11 pts have been on study treatment � 6 months.
Conclusions: CH5424802 was well tolerated with promising efficacy in pts
with ALK-positive NSCLC. The phase II portion is ongoing.
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