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Page 2 of 9 Rosenzweig et al. J Cancer Metastasis Treat 2022;8:46 https://dx.doi.org/10.20517/2394-4722.2022.58

INTRODUCTION
Pancreatic cancer is notable as one of the deadliest cancers. In 2020, it caused almost as many deaths
[1]
(466,000) as cases (496,000) worldwide. Currently, incidence and mortality rates are increasing in the U.S.
and many other highly developed nations , leading to the projection that pancreatic cancer will overtake
[1,2]
[3]
colorectal cancer to become the second leading cause of cancer deaths in the U.S. by 2030 . The difference
between the two is that among the cancers tracked in the U.S., pancreatic cancer has the lowest five-year
[2]
relative survival rate of 11% .
The reasons for the poor prognosis of patients diagnosed with pancreatic adenocarcinoma are expected and
remain the same: too few patients are diagnosed when the disease is in the early, surgically resectable stage,
and too few treatment options provide durable responses. The biological underpinnings of the challenges in
treating pancreatic cancer include mutant KRAS as the driver gene in > 90% of cases, a pathway that has yet
to be effectively targeted, a dense fibrotic stroma that limits the uptake of nutrients, oxygen and
chemotherapies, an exceptionally immunosuppressive microenvironment, and an ability to metastasize at
[4]
an early stage before symptoms are apparent . In the search for new, better treatment options, the standard
clinical trials process has failed many pancreatic adenocarcinoma patients - historically, trials have been
designed with poor alignment with real-world patient characteristics, and too many trials have progressed
to later stages without sufficient clinical evidence of their potential for success . Oncology drug
[5-7]
development is estimated to take more than seven years overall, costing an average of $37.8 M for each drug
tested in phase I-III trials . Despite the high barriers to clinical trial enrollment, thousands of pancreatic
[8]
cancer patients participated in pivotal phase III trials over the past few years, with only 11% of trials
resulting in clinically meaningful changes, and most patients learning that the investigational treatment did
[5]
not provide a survival advantage over the standard of care . The subsets of patients for whom the therapy
did show benefit are infrequently studied to understand whether conditions apply for which this treatment
may be appropriate to administer.

The lack of progress is not from a lack of trying. Since 2019, more than 125 pancreatic cancer clinical trials
have been opened in the U.S. each year . The trends over time indicate an increasing number of trials for
[9]
previously treated patients, the emergence of trials for post-adjuvant or maintenance therapy, and increases
in the number of research-intensive phase 0 trials and the number of phase III trials despite historical
failures. Additionally, there was a dramatic increase in immunotherapy trials over this time and several
biomarker-specified trials were initiated, indicating an increase in a precision medicine approach to
pancreatic cancer treatment. Also notable was a small increase in the number of seamless phase I/II and
II/III trials, an approach that is viewed as an attempt to improve the efficiency of the trial process.

The U.S. Food and Drug Administration (FDA) has acknowledged that more novel clinical trial designs can
be attractive to overcome some of the challenges identified in pancreatic cancer clinical research
[10]
[Figure 1]. For example, when tumor alterations may be rare within a single tumor type but may occur
across multiple tumors, a basket trial is an excellent avenue that has led to the tumor-agnostic approvals of
Pembrolizumab and other therapies that can be applied to occasional pancreatic cancer patients . Focusing
[11]
on a single cancer type at a time, umbrella trials allow patients to be assigned personalized arms of
[10]
treatment based on their and their tumor’s biological and clinical characteristics . Beyond data on the
efficacy of platinum-based chemotherapies and PARP inhibition in pancreatic cancer patients with germline
and/or somatic DNA damage repair alterations , there are few molecularly matched treatments offered to
[12]
patients as standard practice. Umbrella clinical trials can provide additional data necessary for standardizing
these approaches.