Trial Title:
Model to Predict pCR and IrAEs in Early Stage Non-small Cell Lung Cancer
NCT ID:
NCT06250829
Condition:
Non-small Cell Lung Cancer Stage IB (Resectable)
Non-small Cell Lung Cancer Stage II (Resectable)
Non-small Cell Lung Cancer Stage ⅢA (Resectable)
Conditions: Official terms:
Lung Neoplasms
Carcinoma, Non-Small-Cell Lung
Study type:
Observational
Overall status:
Recruiting
Study design:
Time perspective:
Prospective
Intervention:
Intervention type:
Other
Intervention name:
Observational
Description:
Observational study of body composition, cytokine profile, immune status, ctDNA, serial
radiology.
Summary:
Lung cancer is the chief cause of cancer death. The new standard-of-care (SOC) in
operable lung cancer combines chemotherapy and an immune-stimulating drug before the
surgery (neoadjuvant approach). This results in a large increase in complete cancer
clearance rates compared to chemotherapy alone (±30% with combination vs ±4% with
chemotherapy alone), leading to much better long-term survival and probably many more
cures. However, most still don't achieve complete clearance, and a few have increases in,
or spread of, their tumors while on treatment. Therefore, we need to understand why some
patients benefit (responders) and others don't benefit (non-responders) on an
immunotherapy-based treatment. Also, some patients unpredictably develop severe
immune-type side effects related to the immunotherapy drug, although such side effects
may be associated with improved anti-cancer effects. In short, the same treatment can
result in complete cancer clearance in one patient, and in a worst-case scenario may
result in severe toxicity or fail to control spread/growth thus precluding surgery. The
immune system obviously plays a key role in both benefit and harm, yet most of the
research in this field has focused only on the cancer. We plan an in-depth study in 60
patients, focusing on the cancer as well as the patient's immune system, pre-surgery.
This will enable us to identify factors predicting complete cancer clearance, and the
occurrence of immune-type side effects. Using highly sophisticated resources available to
us here in London, we will develop predictive models enabling better patient management
(including possible avoidance of surgery), and identification of key biological
differences between major responders and non-responders, to highlight important new
targets for the development of even newer and better therapies.
Detailed description:
RATIONALE: For patients (pts) with stage I-IIIA NSCLC, surgical resection is the SOC.
Adjuvant chemotherapy (chemo) offers modest survival benefit and there remains equipoise
in the relative value of adjuvant vs neo-adjuvant chemo. Recently, Health Canada approved
neo-adjuvant immunotherapy (nivolumab) with platinum-based chemo (chemo/nivo) in pts with
resectable (IB-IIIA) non-small cell lung cancer (NSCLC), based on a prospective trial
(CM816), showing better event-free (EFS) and overall survival (OS), and pathological
complete responses (pCR), making this approach as the new SoC. pCR rates in CM816 were
24% neoadjuvant nivo/chemo compared to 2.2% neoadjuvant chemo alone. In these trials, OS
benefit was especially seen in pts with tumors expressing programmed death-ligand 1
(PD-L1) and those with pCR.
We propose a prospective single cohort study to analyze the predictors of pCR in a
similar-sized cohort of our pts on the same neo-adjuvant chemo/nivo but employing a range
of parameters that are both broader and, in some cases, more sophisticated. We intend to
make use of parameters that reflect both the tumor itself as well as the integrity of
immune system of the host, obviously a critical determinant of immune-mediated efficacy,
yet strangely neglected in the literature. We will then seek to develop an initial
predictive model for pCR with a good sensitivity/specificity, as a prelude to
refining/testing the model in future work, with a much larger sample.
Noting that immune-related adverse events (IrAE's) are strongly associated with efficacy
with immunotherapy, we will not only be including the emergence of early on-treatment
IrAE's in our pCR modeling, but also develop an additional model as a subsidiary aim to
predict IrAE's themselves. Note the incidence of ≥ grade3 AE's was 33.5% in CM816, and
there is currently no available way to predict their occurrence. This is not to suggest
such a model, if successful, should be used to deny such pts immune checkpoint
inhibitors, but it would allow a more informed consent process, as well as more intensive
pro-active monitoring to avoid the worst outcomes of serious IrAE's (which are
occasionally fatal) by early intervention.
Major Aim: Development of a model predicting pCR after neo-adjuvant chemo/nivo in pts
with resectable NSCLC.
Hypothesis: That an initial model, combining predictive variables from baseline tumor
characteristics, baseline factors likely to be associated with host immunity, as well as
treatment-emergent events, in pts with resectable NSCLC on neoadjuvant chemo/nivo, can
predict a pCR with an area under the Receiver Operator Characteristic (ROC) curve of at
least 0.8.
Objectives: Primary Objectives: (1) To explore the feasibility of acquiring a combination
of baseline and treatment-emergent potentially predictive variables in pts with
early-stage NSCLC subject to neoadjuvant chemo/nivo; (2) To curate these variables and by
uni-and multi-variate analyses, to identify those independently useful in predicting pCR
in these pts; (3) To combine these independently predictive factors into a model with
adequate sensitivity and specificity.
Secondary Objectives: (1) To assess outcomes in patients with resectable NSCLC treated
with neoadjuvant chemo/immuno; (2) To evaluate exploratory and potential biomarkers for
predicting pCR, major pathological responses (MPR), overall response rate (ORR),
event-free survival (EFS), overall survival (OS) and IrAE's; (3) To assess if a
post-treatment (but pre-surgery) metabolic response by
F18-Fluorodeoxyglucose(FDG)-Positron emission tomography(PET)/CT and a blood-only
molecular residual disease assay (ctDNA clearance) can accurately predict a pCR added to
or instead of a more complex model.
Endpoints: Primary: (1) To determine the predictive power (sensitivity, specificity, ROC
characteristic curves) of a model, combining variables, in predicting pCR; (2) To
determine whether a similar model can be constructed to predict IrAE's
Secondary Endpoints: (1) Assess pCR, MPR, clinical objective response rates (ORR), EFS
and OS; and IrAE's; (2) Exploratory the feasibility of acquiring novel potential
biomarkers - e.g., Lymphocyte-activation gene 3 (LAG3), Lysine-specific histone
demethylase1A (LSD1), Leukemia inhibitory factor (LIF), Interleukin 6 (IL6), Interleukin
7 (IL7).
Study Population: Participants with histologically confirmed Stage IB-IIIA NSCLC who are
considered to have a resectable disease; with available baseline tumor tissue for
immunohistochemistry (IHC) and next-generation sequencing (NGS) except those with known
epidermal growth factor receptor (EGFR) mutations, anaplastic lymphoma kinase (ALK) or
receptor tyrosine kinase (ROS1) translocation; or active, known, or suspected autoimmune
disease.
Study Design: A prospective single cohort (N=60) study.
Treatment Details: Patients with resectable stage Ib-IIIa NSCLC will be treated with new
SoC, 3 cycles of neoadjuvant nivolumab immunotherapy plus platinum doublet chemo.
Sample Size: Our planned accrual of 60 patients will result in approximately 15 pCRs,
assuming an event rate of 25%. This will allow us to explore our potential predictors and
their univariable associations with pCR and/or no-pCR outcomes. The top predictors
identified in univariable analyses could be used as candidate predictors in a
multivariable prediction model. This framework would allow for an exploratory
multivariable model predicting no-pCR with up to 9 of the top candidate predictors
identified in univariable analyses, and/or up to 3- 4 of the top candidates predicting
pCR. This assumes a two-sided type I error rate of 0.0516.
Feasibility: Our centre treats an average 60 patients per year with resectable NSCLC who
are eligible for neoadjuvant therapy. As such, we should be able to meet our enrollment
goal in approximately 12-14 months.
Significance: A model that can predict pCR could help in identifying pts most likely to
benefit from neo-adjuvant chemo/nivo. If subsequently validated such a model would have
several applications including pt selection for neo-adjuvant chemo/immuno; potential
avoidance of surgery in reliably-predicted pCR pts of morbid thoracotomy; identification
of pts needing additional treatments (e.g. CTLA4 inhibitors, or radiotherapy);
acquisition of important insights into the biological underpinnings of resistance; and
most crucially, identification of novel targets or strategies to overcome resistance.
Criteria for eligibility:
Study pop:
Stage iB to IIIA resectable non-small cell lung cancer
Sampling method:
Non-Probability Sample
Criteria:
Inclusion Criteria:
-
1. Participants with histologically confirmed Stage IB (≥ 4 cm), II, IIIA (N2)
NSCLC (as per the 8th American Joint Committee on Cancer (AJCC)) who are
considered to have resectable disease.
2. Measurable disease according to Response Evaluation Criteria in Solid Tumors
version 1.1 (RECIST 1.1).
3. Participants must have tumor tissue available for PD-L1 immunohistochemical
(IHC) testing.
4. Eastern Cooperative Group (ECOG) Performance Status 0-2. 5. Able to give
informed consent.
Exclusion Criteria:
-
1. Presence of locally advanced, unresectable, or metastatic disease. 2.
Participants with known EGFR mutations, ALK or ROS1 translocation. 3. Subjects
with active, known, or suspected autoimmune disease (except subjects with type
I diabetes mellitus, residual hypothyroidism due to autoimmune thyroiditis only
requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or
alopecia) not requiring systemic treatment).
4. Subjects with a condition requiring systemic treatment with either
corticosteroids (10 mg daily prednisone or equivalent) or other
immunosuppressive medications within 14 days of study drug administration.
Inhaled or topical steroids are permitted in the absence of active autoimmune
disease.
5. Subjects with previous malignancies are excluded unless a complete remission
was achieved at least 5 years prior to study entry and no additional therapy is
required or anticipated to be required during the study (non-melanoma skin
cancer and other indolent malignancies not requiring any treatment and that are
unlikely to affect blood-based biomarkers are allowed).
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Locations:
Facility:
Name:
London Regional Cancer Program
Address:
City:
London
Zip:
N6A 5W9
Country:
Canada
Status:
Recruiting
Contact:
Last name:
Morgan Black
Email:
Morgan.Black@lhsc.on.ca
Start date:
October 12, 2023
Completion date:
May 30, 2025
Lead sponsor:
Agency:
Lawson Health Research Institute
Agency class:
Other
Source:
Lawson Health Research Institute
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06250829
