ASCO/JSMO JOINT SYMPOSIUM: TUMOR AGNOSTIC VS TUMOR SPECIFIC
APPROACH TOWARD CLINICAL DEVELOPMENTS
AJS-1 Tumor-agnostic drug development: Ready for Prime Time
Howard Burris
Sarah Cannon
Cancer care and clinical research continue to rapidly move in the direction of
personalized care with precision medicines. The molecular alterations found within
many cancers is often more critical to therapy selection than the site of origin. The
ability to molecularly profile tumors has established that each patient’s cancer is
unique, biology is destiny, and tumor heterogeneity is a reality. The utilization of liquid
biopsies has facilitated the process of assessing for mutations, and this modality is
moving quickly into strategies around monitoring for residual disease and detecting
cancers very early. The clinical decision making on choosing an immunotherapy versus
a targeted small molecule is guided by molecular profiling, revealing whether
actionable genomic alterations exist or indicators such as micro-satellite instability
and tumor mutational burden are present. Cancers need to be profiled for the benefit
of the individual patient, for matching to appropriate clinical trials, and for the benefit
of all as we learn about tumor biology and drug resistance. Twenty years ago, new
cancer drug approvals by regulatory agencies were in the range of 8-10 per year. The
last few years has yielded numbers in excess of 50, achieved with biomarker-driven
single arm trials, tumor agnostic studies, and the concept of seamless drug devel-
opment. Pembrolizumab has been approved by the FDA for all cancers with a tumor
mutational burden (TMB) > 10, regardless of histology. Larotrectinib and entrectinib,
oral TKIs targeting nTRK fusions, have similarly received regulatory approval for all
cancers with that alteration. Improved versions of newer technologies such as anti-
body drug conjugates have been highly successful, limited only by identifying tumor
specific targets. It is becoming reality that there are no “undruggable” targets as
superior chemistry has brought us therapies aimed at KRas and TP53 mutations.
Cellular therapies have moved from monoclonal antibodies and CAR-T cells against
blood cancers to bispecifics, trispecfics, and personalized vaccine approaches tar-
geting solid tumors. Molecular targets such as KRas, RET, FGF, Her2, among others are
ideal to study with basket trials including all tumor types. Cell surface receptors /
biomarkers such NaPi2b, Her2, mesothelin, etc are similarly attractive for tumor
agnostic approaches with antibody drug conjugates. The future for cancer care is
bright, with novel approaches all around, and yet limited mostly by our ability to
design and and enroll to well designed clinical trials that will answer key questions
regarding safety and effectiveness in an efficient manner.
https://doi.org/10.1016/j.annonc.2022.05.359
AJS-3 Organ-specific and tumor-agnostic trials based on SCRUM-
Japan MONSTAR-SCREEN
Yoshiaki Nakamura
Translational Research Support Section / Department of Gastrointestinal Oncology,
National Cancer Center Hospital East
To implement precision oncology for patients with advanced solid tumors, we
launched SCRUM-Japan MONSTAR-SCREEN, a nation-wide cancer genomic alterations
screening project. In this project, patients with advanced solid tumors presenting to
Volume 33 - Issue S6 - 2022
network institutions for clinical care were screened using a comprehensive tissue or
liquid biopsy multi-omics analysis. After standard-of-care therapy, these patients were
enrolled in suitably matched clinical trials.
Presently, umbrella/basket-type investigator-initiated clinical trials are being
actively conducted for patients with advanced solid tumors utilizing the SCRUM-Japan
platform to perform screening of candidates for targeted therapies. Patients with
specific cancer types with genomic alterations are enrolled in organ-specific trials.
TRIUMPH study, a phase 2 trial for HER2-amplified CRC, compared treatment with
pertuzumab plus trastuzumab in the trial and non-HER2-targeted standard-of-care
therapies in the SCRUM-Japan Registry, and demonstrated superior efficacy of the
dual-HER2 blockade. The results will be utilized for regulatory submissions.
Recent tumor-agnostic regulatory approvals of targeted agents based on the
presence of specific biomarkers rather than tumor sites have led to a paradigm shift in
precision oncology. To accelerate these innovations, Tumor-agnostic basket-type trials
are being conducted for rare alterations identified in different types of cancers, such
as bTMB-H, FGFR alterations, HER2 amplification, and mutations in homologous
recombination repair-related genes. BRCA1/2-mutated gastrointestinal cancers and
NFE2L2-mutated squamous cell carcinoma are also targeted in our clinical trial plat-
form. Through these organ-specific and tumor-agnostic trials, we aim to revolutionize
cancer treatment.
https://doi.org/10.1016/j.annonc.2022.05.360
AJS-4 Current status and future perspectives of early clinical trial
design for tumor-agnostic/specific approach
Yuki Katsuya
Department of Experimental Therapeutics, National Cancer Center Hospital
In Japan, pembrolizumab for MSI-H solid tumors, entrectinib and larotrectinib for
NTRK fusion, were approved by PMDA based on pooled analysis of both phase I and
global phase II trials. Rare fractions that have been left out of therapeutic develop-
ment and newly diagnosed genetic mutations by cancer gene testing are now being
approached differently from classical anticancer drug development. Although
entrectinib and larotrectinib were designed to target molecular biomarkers, while
MSI-H was a prospectively identified biomarker, both had strong biologic preclinical,
clinical rationales, and consistent clinical efficacy. Neither has a companion diagnostic
agent. Other potential molecular targets suitable for therapeutic development
include FGFR, RET, and KRAS G12C.
Some basket trials and platform trials have failed to achieve the ideal results due
to treatment-effect heterogeneity. Not all studies are suitable for tumor agonistic
approach. In the absence of a strong biological rationale, a proper statistical design,
and a flexible regulatory framework, a conventional tumor-specific approach should
be utilized.
In recent years, phase I trials not only confirm RP2D and MTD, but also explore the
efficacy in expansion cohorts based on mode of action. A balanced enrolment of
cancer types reflecting epidemiology in spite of limited and imbalanced enrolment,
statistical considerations, and other issues remain to be discussed.
https://doi.org/10.1016/j.annonc.2022.05.361
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