15 th Annual West Coast Colorectal Cancer Symposium Oct. 27, 2017 1 Optimizing Treatment Outcomes in Anal Cancer 15 th Annual West Coast Colorectal Cancer Symposium Lisa Kachnic, MD, FASTRO Professor & Cornelius Vanderbilt Chair Department of Radiation Oncology
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15th Annual West Coast Colorectal Cancer Symposium Oct. 27, 2017
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Optimizing Treatment Outcomes in Anal Cancer
15th Annual West Coast Colorectal Cancer Symposium
Lisa Kachnic, MD, FASTRO
Professor & Cornelius Vanderbilt Chair
Department of Radiation Oncology
15th Annual West Coast Colorectal Cancer Symposium Oct. 27, 2017
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Disclosures
UpToDateTM
EPICTM
INSYS Therapeutics
NCI Funding (NRG Oncology, SWOG)
15th Annual West Coast Colorectal Cancer Symposium Oct. 27, 2017
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Background
1. American Cancer Society. Anal cancer. http://www.cancer.org/cancer/analcancer/detailedguide/anal-cancer-what-is-key-statistics. Accessed 5/4/17.
2. American Cancer Society. Cancer Facts and Figures 2016. http://www.cancer.org/research/cancerfactsstatistics/cancerfactsfigures2016/. Accessed 5/4/17.
3. Glynne-Jones R, et al. Ann Oncol. 2014;25 (suppl 3):iii10-iii20.
Anal cancer is fairly rare – much less common than cancer of
the colon or rectum1
– In 2016, approximately 8,080 individuals (5,160 women and
2,920 men) were diagnosed with anal cancer2
– 1,080 estimated deaths (640 women and 440 men)2
The number of new anal cancer cases has been rising for
many years1
Anal cancer is exclusively an HPV-driven disease3;
however, its low prevalence among other GI cancers (2.5%)
makes specialization in this tumor rare
Anal cancer is an area of relatively limited clinical research
TRAEs Occurring in ≥10% of PatientsFatigue 15 (58) - -
Chills 14 (54) - -
Fever 11 (42) - -
Nausea 10 (39) - -
Headache 9 (35) - -
Hypotension 7 (27) 2 (8) -
Vomiting 6 (23) - -
Cytokine release syndrome 5 (19) 3 (12) -
Myalgia 5 (19) - -
Abdominal pain 4 (15) - -
General pain 4 (15) - -
Flu-like symptoms 3 (11) - -
AST elevation 3 (11) - -
Safety findings among patients enrolled in Stage 2 are similar to those reported in detail for Stage 1.*The observed grade 4 TRAE recorded in 1 patient (lung infection and sepsis from Klebsiella pneumoniae) was considered possibly related to treatment.
13 Presented by Huh W, et al. ASCO 2016. Abstract 5516.
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Overall Survival
CI, confidence interval; NR, not reached.
All Patients
(N = 24)
>3 Doses of
ADXS11-001
(N = 12)
6-month OS 42% (n = 10/24) 67% (n = 8/12)
Median OS (95% CI) 4.8 months (3.8–NR) NR (3.5–NR)
Median PFS (95% CI) 2.6 months (2.0–3.2) –
All PatientsSTAGE 1
3 Doses of ADXS11-001
STAGE 2
14 Presented by Huh W, et al. ASCO 2016. Abstract 5516.
15th Annual West Coast Colorectal Cancer Symposium Oct. 27, 2017
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Phase II FAWCETT Study of AXAL Monotherapy in
Recurrent/Metastatic Anal Cancer
Two-stage Trial Design Persistent/recurrent,
loco-regional
metastatic anal
cancer
Received at least
one line of therapy
for their metastatic
disease or
progressed after
platinum-based
therapy
Stage 1N = 31
AXAL monotherapy
Every 3 weeks for up
to 2 years
Stage 2N=24 additional patients
AXAL monotherapy
Every 3 weeks for up to 2 years
Interim Analysis
If ≥10% ORR or
≥20% 6-month PFS
Endpoints
Primary:
Best overall
response
6-month PFS
Other:
Safety and
tolerability
Duration of
response
Overall survival
PI: Eng
Courtesy of C. Eng
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NCI9673: Phase II Design of Nivolumab in
Metastatic Anal Cancer
patients with metastatic squamous cell carcinoma of the anal canal
- treated with at least one prior therapy for metastatic disease
- no prior immunotherapies received as part of cancer treatment
12 patients treated initially with nivolumab3 mg/kg IV every 2 weeks
patients were followed for best response using RECIST criteria 1.1
0 responses ≥ 1 response
stop trialexpand trial to include 25 additional patients with
metastatic SCCA
Simon Optimal, two-stage
phase II study, Ho: p ≤ 0.05
and an alternative
hypothesis Ha: p ≥ 0.20,
α = 0.10 and a β = 0.10
Diagnostic imaging was
completed every 6 wks
Morris et al: Lancet Oncology 4:446-453, 2017.
PI Eng
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-1 0 0-9 0-8 0-7 0-6 0-5 0-4 0-3 0-2 0-1 0
01 02 03 04 05 06 07 08 09 0
1 0 0
P a tie n t
% t
ar
ge
t le
sio
n r
ed
uc
tio
n
fro
m b
as
eli
ne
by
RE
CIS
T 1
.1 P ro g re s s iv e D is e a s e
S ta b le D is e a s e
P a rt ia l R e s p o n s e
P R
P D
NCI9673: Primary Endpoint of Response Rate
N=37 (ITT)
N=34 (evaluable)
2 CR’s
7 PR’s
ORR 24%
Patients
CR
Morris et al: Lancet Oncology 4:446-453, 2017.
Morris et al: Lancet Oncology, in press
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NCI9673: Progression-free & Overall Survival
Morris et al: Lancet Oncology 4:446-453, 2017.
PFS
OS
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NCI9673: Toxicities of Therapy
Toxicity (N=37) Grade (%)
1 2 3 4
Fatigue 17 (46) 7 (19) 1 (3) -
Anemia 13 (35) 11 (30) 2 (5) -
Rash 8 (22) 2 (5) 1 (3) -
Hypothyroidism 1 (3) 1 (3) 1 (3) -
Constipation 8 (22) 2 (5) - -
Diarrhea 8 (22) - - -
Anorexia 5 (14) 4 (11) - -
Weight loss 5 (14) 1 (3) - -
Arthralgia 3 (8) 3 (8) - -
Hyperglycemia 3 (8) 1 (3) - -
Lymphedema 1 (3) 1 (3) - -
Pneumonitis - 1 (3) - -
Nausea 2 (5) - - -
Morris et al: Lancet Oncology 4:446-453, 2017.
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Morris et al: AACR 2016; Eng et al: ASCO 2016.
Flow Cytometry Confirmation(Courtesy of IMT Platform)
Tumor Correlatives at Baseline by IHC (N=12)
Non-Responder
Responder
CD-8 PD-1 PD-L1
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Keynote-028: Phase Ib of Pembrolizumab for
Recurrent Anal Cancer
Reck et al: NEJM, 2016
IV pembro 10 mg/kg once every 2 wks up to
2 yrs or progression or toxicity
patients with PD-L1+ tumors
of 24 patients with scc anal:
4PR 10SD
ORR = 17%
median PFS 3 months
median OS 9 months
Ott et al: Annals Oncology 28: 1036-1041, 2017.
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Next Steps for Metastatic Disease
Addition of immune therapy to winner of InterAACT trial
– agents/design still in discussion
– may be R phase II of systemic winner vs. systemic/immune
combo followed by maintenance immuno rx
– immuno rx likely to be nivo but could also consider AXAL pending
results of Fawcett trial
– primary endpoint would be PFS until progression
Reck et al: NEJM, 2016
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Current Approaches
Metastatic
Localized
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Treatment Overview Localized Anal Cancer
Anal margin
– ~ skin cancer
– surgical excision or radiation alone
Adenocarcinoma
– ~ rectal cancer
SCCA of the anal canal
– T1 tumors: local excision, radiation alone or chemoradiation
– T2 and above: chemoradiation therapy with curative intent
– APR salvage for local recurrence
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Wayne State/Nigro Regimen
28 pts; single institution study
RT: 30 Gy in 15 fx via AP/PA fields to the pelvis, medial inguinal LN
and anal canal
Chemo: 5FU (1000 mg/m2/day) x 4 days + MMC (single 15 mg/m2
bolus)
APR planned; 5/6 initial pts had no residual tumor at APR; APR was
then reserved as salvage
Overall, 86% (24/28) clinical CR to chemo-RT
Follow-up series OS5 67%; CFS5 59%
Nigro et al: Cancer 51(10):1826-9, 1983;
Leichman et al: Am J Med 78(2):211-5, 1985.
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Role of Chemotherapy
Trial nGrade 4/5
Acute AEsLC CFS OS
UKCCCR1
RT
RT/5FU/MMC
585 39%
61%
58%*
65%*
EORTC2
RT
RT/5FU/MMC
110 39%
58%
40%
72%
65%*
72%*
RTOG 87-043
RT/5FU
RT/5FU/MMC
310 7%
23%
64%**
83%**
58%**
64%**
65%**
67%**
*3-yr; **5-yr; red denotes statistically significant