Tissue Agnostic Treatment - Review

Annual Review of Cancer Biology
Development of
Tissue-Agnostic Treatments for
Patients with Cancer
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Annu. Rev. Cancer Biol. 2022.6:147-165. Downloaded from www.annualreviews.org
Steven Lemery,1 Lola Fashoyin-Aje,1 Leigh Marcus,1

Sandra Casak,1 Julie Schneider,2 Marc Theoret,2
Paul Kluetz,2 Richard Pazdur,2 and Julia A. Beaver2
1
Office of Oncologic Diseases, US Food and Drug Administration, Silver Spring, Maryland,
USA; email: Steven.Lemery@fda.hhs.gov
2
Oncology Center of Excellence, US Food and Drug Administration, Silver Spring, Maryland,
USA
Annu. Rev. Cancer Biol. 2022. 6:147–65 Keywords

The Annual Review of Cancer Biology is online at
tissue-agnostic, microsatellite instability, NTRK fusion, tumor mutation
cancerbio.annualreviews.org
burden
https://doi.org/10.1146/annurev-cancerbio-060921-
021828 Abstract
This is a work of the US Government and is not
In 2017 the FDA (US Food and Drug Administration) approved pem-
subject to copyright protection in the United States
brolizumab, a programmed death 1 (PD-1) inhibitor, for the treatment
of unresectable or metastatic, microsatellite instability–high (MSI-H) or
mismatch repair–deficient (dMMR) solid tumors, regardless of tumor site
or histology. This represented the first approval based on the identification
of a biomarker and independent of tumor site. Although this approach
may intuitively appear rational, tissue-agnostic drug development can be
complicated by tumor-specific resistance mechanisms or other factors
that can alter a drug’s effect. Inherent with the tissue-agnostic approach is
the fact that there may be residual uncertainty concerning a drug’s effect
in unstudied tumor types (e.g., at the time of approval). However, this
approach may be the only available mechanism to support approval and
provide access to a drug that is indicated for the treatment of patients with
certain rare biomarker-positive cancers.
147
INTRODUCTION
Tissue-agnostic approvals represent a recent development in oncology, with the first approval
occurring in 2017. Currently, the FDA (US Food and Drug Administration) has approved tissue-
agnostic indications for four drugs: pembrolizumab, for microsatellite instability–high (MSI-H)
or mismatch repair–deficient (dMMR) tumors and tumors with high tumor mutational burden
(TMB-H); dostarlimab for dMMR tumors; larotrectinib; and entrectinib. Tissue-agnostic ap-
provals have also been granted by regulatory authorities outside of the United States. The tissue-
agnostic indications are described in detail in the following sections of this review, followed by
sections on ongoing or future clinical development and US regulatory considerations.
TREATMENT OF MICROSATELLITE INSTABILITY–HIGH

OR MISMATCH REPAIR–DEFICIENT CANCERS
Biology
Scientists at Johns Hopkins University first identified microsatellite instability (MSI) as a target
for anti-PD-1 (programmed death 1) therapy following the observation of a patient with an excep-
tional response to nivolumab among 33 patients with colorectal cancer (CRC) (no other patients
with CRC responded) (Brahmer et al. 2010, Poh 2017, Topalian et al. 2012). This patient experi-
enced a prolonged complete response (CR); following the response, the investigators evaluated the
patient for the presence of MSI (Lipson et al. 2013, Poh 2017). Subsequently, study KEYNOTE-
16 was initiated to investigate the effects of pembrolizumab in patients with MSI-H or dMMR
solid tumors (Le et al. 2015). Although many non-MSI-H tumors may respond to anti-PD-1 ther-
apy, responses in CRC to date (with few exceptions) have been limited to MSI-H tumors (Eng
et al. 2019, Lipson et al. 2013, O’Neil et al. 2017).
dMMR usually occurs due to a mutation (somatic or germline) in one of four genes (MLH1,
MSH2, MSH6, or PMS2). These four genes code for proteins that repair mismatches or certain
insertion/deletion errors during DNA replication or recombination, or through methylation of
the MLH1 promoter (Flaherty et al. 2017, Li 2008). MSI occurs via the accumulation of errors
in short repetitive sequences in DNA called microsatellites (Flaherty et al. 2017, Marcus et al.
2019). MSI-H/dMMR cancers share common histopathologic characteristics, such as a hypermu-
tated phenotype, lymphocytic and other immune cell infiltration, medullary histology, and poorly
differentiated histology (Alexander et al. 2001, Cancer Genome Atlas Netw. 2012, Dolcetti et al.
1999, Grogg et al. 2003, Kim et al. 2013, Lin et al. 2015, Ruemmele et al. 2009, Shia et al. 2008,
Shia et al. 2003, Timmermann et al. 2010, Zhao et al. 2014). MSI-H cancers are TMB-H, which
has been linked to an increased probability of expressing neoantigens, some of which may serve
as targets for the immune system (Gubin et al. 2014, Howitt et al. 2015, Schumacher & Schreiber
2015). This mutation burden in MSI-H cancers is among the highest of any anatomically or his-
tologically defined cancers, including melanoma or non-small-cell lung cancer (NSCLC), which
have high mutation burden due to UV radiation or smoking and have derived the most benefit
from immune checkpoint inhibitor (ICI) therapy (Alexandrov et al. 2013, Vogelstein et al. 2013,
Yarchoan et al. 2017). Although MSI-H/dMMR tumors may express neoantigens, upregulation of
the PD-1 ligand may occur, inhibiting active T cell–mediated killing of the tumor cells. ICI thera-
pies, such as PD-1 inhibitors, can block the PD-1/PD-LI (programmed death ligand) interaction,
resulting in immune cell killing of tumor cells (Keytruda® 2020, Opdivo® 2017).
The incidence of MSI-H/dMMR varies across tumor types with rates of over 15% in endome-
trial cancer to less than 1% among glioblastomas or soft-tissue cancers (Le et al. 2017). Further-
more, across many cancer types, incidence of MSI-H/dMMR is stage specific, generally (but not
always) with lower rates of MSI in the metastatic setting (Le et al. 2017). In CRC, approximately
148 Lemery et al.

15% of patients with stage II CRC have MSI-H disease versus 5% in the metastatic setting; a
similar stage-dependent trend in the incidence of MSI-H is observed in gastric cancer (Cristescu
et al. 2015, Sargent et al. 2010, Venderbosch et al. 2014). Although data are limited in many tu-
mor types, MSI-H/dMMR appears to represent a favorable prognostic marker in early stage CRC
due to the lower rate of recurrence after resection, while MSI-H/dMMR appears to be neutral or
adversely prognostic in patients with metastatic CRC (Goldstein et al. 2014, Guastadisegni et al.
2010, Sargent et al. 2010, Sinicrope et al. 2011, Venderbosch et al. 2014).
Testing
The optimal testing strategy for MSI-H/dMMR may depend upon the clinical scenario, including
frequency of MSI-H/dMMR in a particular cancer population and the availability of tissue. For
example, challenges in obtaining sufficient tissue (e.g., in cholangiocarcinoma) may preclude the
ability to conduct extensive tumor testing. In such scenarios, it may be preferable to use a single
testing platform such as next-generation sequencing (NGS) to identify several potential aberra-
tions at once. Multiple studies have reported high (e.g., >95%) sensitivity, specificity, or concor-
dance using different NGS tests to detect MSI (Kautto et al. 2017, Middha et al. 2017, Salipante
et al. 2014, Trabucco et al. 2019, Zhu et al. 2018). In addition to assessing microsatellites, NGS
panels may also directly sequence the four proteins involved in mismatch repair.
In patients with CRC, mismatch repair status has been assessed for decades using immunohis-
tochemistry (IHC) for the dMMR proteins. Even prior to immunotherapy, testing was conducted
either to assess patients for Lynch syndrome (a cancer predisposition syndrome) or to assist
in treatment decisions following complete resection. In patients with CRC, for example, the
American Society of Clinical Oncology (ASCO) guidelines recommend testing for germline
mutations if there is loss of MLH1/PMS2 and the absence of a BRAF mutation or if MLH1
promotor methylation is not identified (Stoffel et al. 2015). Loss of other proteins (MSH2, MSH6,
or PMS2) would also trigger a recommendation for germline genetic testing (Stoffel et al. 2015).
In addition to IHC- and NGS-based tests, traditionally, MSI was assessed using polymerase
chain reaction (PCR)-based methodology that focused on predefined microsatellites (Boland
et al. 1998). In general, PCR and IHC selected concordant populations with respect to
MSI-H and dMMR status (Bartley et al. 2012); however, differences in test results can occur due
to technical factors (e.g., problems with staining, fixation, or processing for IHC) or for uncom-
mon biological reasons (Bartley et al. 2012). For example, some patients with MSH6 germline
mutations are microsatellite stable when assessed via PCR due to a functional redundancy in the
MMR system. Depending on the PCR assay selected (and selected microsatellites), there have also
been reports of differences in positivity in MSI-H results when comparing CRC with endome-
trial tumors (Wang et al. 2017). There are also reports of patients with missense mutations (e.g.,
in MLH1 or MSH6) that produce nonfunctional proteins which stain positive by IHC; however,
the tumors are MSI-H when assessed by PCR (Hampel et al. 2007, Klarskov et al. 2011, Pino &
Chung 2011, Zhang & Li 2013).
Given the factors described above, and the need for accurate test results across a wide spec-
trum of tumors, approval of pembrolizumab for MSI-H/dMMR tumors included postmarketing
commitments to support the availability of an immunochemistry assay to detect dMMR, as well
as a nucleic acid–based assay to detect MSI.
Clinical Data
The initial results of trial KEYNOTE-16 in 2015 reported an immune-related objective response
rate (ORR) for pembrolizumab of 40% (4 of 10 patients) for dMMR metastatic CRC versus 0%
www.annualreviews.org • Tissue-Agnostic Cancer Treatments 149

(0 of 18 patients) for mismatch repair–proficient CRC. These results compared favorably to the
response rate (e.g., <5%) of approved single-agent therapies for patients with CRC in the third-
line or later-line setting (Grothey et al. 2013, Mayer et al. 2015). Additionally, 5 of 7 patients with
dMMR tumors other than CRC responded to pembrolizumab. Le et al. (2017) published updated
results of KEYNOTE-16 in 86 patients, 40 of whom had CRC. In this group of 86 patients, the
reported response rate was 53% [95% CI (confidence interval): 42–64]. Eleven of the patients had
complete radiographic disappearance of their cancer and discontinued therapy after the prespec-
ified two years of treatment.
After the initial observed results for pembrolizumab in KEYNOTE-16, subsequent studies of
pembrolizumab were initiated in patients with unresectable or metastatic MSI-H/dMMR CRC
(KEYNOTE-164) and in patients with MSI-H/dMMR noncolorectal tumors (KEYNOTE-158)
(Marcus et al. 2019). The latter study also enrolled separate cohorts of rare tumor types. The
tissue-agnostic approval of pembrolizumab for the treatment of advanced and refractory MSI-
H/dMMR solid tumors was based on data from these three studies, as well as on data from
11 retrospectively identified patients with PD-L1-positive (and MSI-H/dMMR) solid tumors
from KEYNOTE-12 and KEYNOTE-28. In total, the approval of pembrolizumab for patients
with MSI-H/dMMR solid tumors was based on data from 149 patients (90 with CRC and 15 total
tumor types), which showed an independently reviewed ORR of 39.6% (95% CI: 31.7–47.9) with
7% of patients experiencing a CR (Marcus et al. 2019). Duration of response was 6 months or
longer in 78% of responding patients (Marcus et al. 2019).
Since the May 2017 approval of pembrolizumab, other results of immune checkpoint inhibition
in patients with MSI-H/dMMR cancers have been published. For pembrolizumab, Le et al. (2020)
reported updated results of KEYNOTE-164 that followed 124 patients with CRC for a median
of 31.3 months. The reported response rate per independent central review was 33% with 6%
experiencing a CR and median duration of response was not reached. Marabelle et al. (2020b)
reported updated results of KEYNOTE-158 that followed 233 patients with 27 tumor types other
than CRC and a median follow-up of 13.4 months. The reported response rate was 34.3% with
9% of patients experiencing a CR. The authors stated that in a Kaplan-Meier analysis, 77.6% of
responding patients had response durations of 24 months or longer (Marabelle et al. 2020b).
A notable finding from the update of the KEYNOTE-158 trial was that 0 of 13 patients with
primary brain cancers responded to pembrolizumab. Glioblastoma may be unique in that MSH6
mutations, and hypermutant phenotype, appear to occur in a subset of glioblastomas during temo-
zolomide therapy (Cancer Genome Atlas Res. Netw. 2008, Maxwell et al. 2008, McCord et al.
2020, Yip et al. 2009). As these mutations are not present pretreatment, and given they may be
heterogeneously distributed in the tumor, patients with these mutations may have a lower proba-
bility of responding compared to patients with de novo dMMR tumors. Durable responses to ICIs
have been reported in pediatric patients with congenital dMMR gliomas, where the hypermutant
phenotype was present prior to temozolomide (AlHarbi et al. 2018, Bouffet et al. 2016). Based on
the emergence of these data, pembrolizumab labeling was updated in June 2020 to recommend
testing for MSI/dMMR in primary tumor specimens obtained prior to initiation of temozolomide
(Keytruda® 2020). Additional data to assess central nervous system tumors are expected.
The benefit of PD-1 inhibition across MSI-H tumors has also been demonstrated in tumor-
specific studies including in a randomized trial in advanced MSI-H/dMMR CRC. KEYNOTE-
177, a randomized controlled trial, demonstrated an improvement in progression-free survival
(hazard ratio: 0.60; 95% CI: 0.45–0.80) when pembrolizumab was compared to standard-of-care
chemotherapy in the first-line treatment of patients with metastatic CRC (Andre et al. 2020).
This led to an FDA approval of pembrolizumab in the first-line metastatic setting for patients
with MSI-H/dMMR CRC in 2020.
150 Lemery et al.

Overman et al. (2017) reported on the results of 74 patients with MSI-H/dMMR CRC
who received the anti-PD1 antibody nivolumab. The reported investigator-assessed response
rate was 31%. The FDA granted accelerated approval to nivolumab for MSI-H/dMMR
metastatic CRC in July 2017 based on the independently confirmed response rate of 28%
(95% CI: 17–42) in 53 patients who received prior treatment with fluoropyrimidine, oxali-
platin, and irinotecan (Opdivo® 2017). The National Cancer Institute (NCI)-Molecular Anal-
ysis for Therapy Choice (MATCH) trial reported a similar response rate of 36% among 42
patients with non-CRC tumors treated with nivolumab (Azad et al. 2020). Two percent of
4,902 screened patients had dMMR cancer by IHC in the NCI-MATCH study (Azad et al.
2020). In April 2021, dostarlimab-gxly, an anti-PD-1 antibody, was granted accelerated ap-
proval for the treatment of patients with dMMR recurrent or advanced endometrial can-
cer based on data from 71 patients demonstrating an independently confirmed response rate
of 42% (95% CI: 31–55), with median duration of response not yet reached with a median
follow-up for duration of response of 14.1 months ( Jemperl® 2021, Oaknin et al. 2020). Other
studies have reported response rates of 25% or more in patients with endometrial cancer or
in patients with different tumor types who have received different anti PD-(L)1 inhibitors
( J. Chen et al. 2020, Konstantinopoulos et al. 2019). Finally, in August 2021, dostarlimab-gxly
also received accelerated approval for dMMR recurrent or advanced solid tumors based on data
from 209 patients with 15 different tumor types (ORR 41.6%, 95% CI: 34.9–48.6).
TREATMENT OF NEUROTROPHIC RECEPTOR TYROSINE

KINASE-FUSION-POSITIVE CANCERS
Biology
The FDA approved drugs larotrectinib and entrectinib target gene fusions of one of three neu-
rotrophic receptor tyrosine kinase genes, NTRK1, NTRK2, and NTRK3, that code for tropomycin
receptor kinase (TRK) proteins (Drilon et al. 2018). TRK proteins appear important in neuronal
survival and differentiation and have various functions within the nervous system (Chao 2003,
Huang & Reichardt 2001, Tessarollo et al. 1993). In cancers, however, TRK fusions result in a
chimeric oncoprotein, and multiple reports have indicated that these fusions induce the devel-
opment of cancers (Arevalo et al. 2000). For example, ETV6-NTRK3 was found to constitutively
activate both the Ras-MAPK and phosphatidylinositol 3-kinase-Akt pathways and was associated
with constitutive tyrosine phosphorylation of insulin receptor substrate-1 ( Jin et al. 2007, Lannon
et al. 2004). In nude mice, retroviral transfer of this same fusion into mammary epithelial cells re-
sulted in transformed cells that developed into tumors that produced glands and expressed epithe-
lial antigens (Tognon et al. 2002). A different transgenic murine model that expressed the Trk-T1
fusion protein in the thyroid resulted in papillary carcinomas (Russell et al. 2000). Furthermore,
Cook et al. (2017) found that a chromosomal deletion generating the BCAN-NTRK1 gene fusion
can drive the formation of high grade gliomas in an experimental model.
The overall incidence of NTRK fusions across tumors is difficult to estimate because the
incidence (or prevalence) of NTRK fusions in a given population will depend upon the testing
methodology used as well as the distribution of cancer types within the population tested. One
study identified 87 NTRK1-3 fusions in 38,095 samples from 33,997 patients (Solomon et al.
2020). This study used a DNA-based NGS panel and also assessed 2,180 patients using an
RNA-based assay. The identification of NTRK fusions was less than 1% in most tumors tested
including common tumors such as lung cancer, CRC, and breast cancer (Solomon et al. 2020).
The incidence rate was higher in selected rare tumors such as salivary gland cancers (5.1%),
thyroid cancer (2.3%), and inflammatory myofibroblastic tumors (17%) (Solomon et al. 2020).

Another study evaluated 13,467 samples available from adults using The Cancer Genome Atlas
(TCGA) database (adult tumors) or children using a St. Jude database (Okamura et al. 2018). Fu-
sions were assessed in the study via an integrated analysis of paired-end RNA sequencing and DNA
copy number data from TCGA and RNA sequencing data using the Pediatric Cancer Genome
Project (Okamura et al. 2018). The study identified NTRK fusions in 0.31% of adult tumors and
in 0.34% of pediatric tumors. Cancer types that were identified as having an NTRK fusion at a
relatively higher incidence rate in samples tested include pediatric melanoma (11.1%), pediatric
glioma (3.97%), and adult thyroid cancers (2.34%) (Okamura et al. 2018). Similar incidence rates
(0.27% and 0.44%, respectively) of NTRK fusions were found among 11,502 tumors in another
study that tested samples using a commercial NGS and fusion assay and in a study of 2,031 pedi-
atric (age <21 years) cancers (Gatalica et al. 2019, Pavlick et al. 2017). The pediatric study iden-
tified cases in children with infantile fibrosarcoma, a rare cancer commonly associated with the
ETV6-NTRK3 fusion (Pavlick et al. 2017). Other extremely rare cancers in which the presence of
NTRK fusions is generally considered synonymous with the disease include mammary analog se-
cretory tumors, secretory breast cancer, and congenital mesoblastic nephroma (Cocco et al. 2018).
Testing
NTRK fusions can be detected using different methodologies including fluorescence in situ hy-
bridization (FISH), IHC, reverse transcription PCR, or massive parallel sequencing, including
RNA-based assays (Demetri et al. 2020). Recommendations for testing may depend on the pa-
tient’s underlying tumor type, availability of tissue, or other factors. In general practice, testing
tumors that commonly harbor NTRK fusions such as infantile fibrosarcoma is recommended in
all settings, and a negative test may need to be followed up with testing using a different method-
ology (Demetri et al. 2020).
In pivotal clinical trials of larotrectinib and entrectinib, patients were identified using a central
lab (entrectinib) or local labs (entrectinib and larotrectinib) using FISH or other nucleic acid–
based tests. Due to the rarity of NTRK fusions and unmet need (with identification at local sites
with referral to clinical trial sites), the complexity of developing the companion diagnostic devices
(e.g., due to multiple fusion partners), and clinical results, the FDA approved larotrectinib and en-
trectinib without contemporaneously approving a companion diagnostic device. In each case, post-
marketing commitments were issued to support the future use of a companion diagnostic device.
Clinical Data
Following an early report of a patient with an NTRK-fusion soft-tissue sarcoma with widespread
pulmonary metastases responding to larotrectinib (Doebele et al. 2015) and early reports of
patients with NTRK1-fusion-positive lung or CRC responding to entrectinib (Farago et al. 2015,
Sartore-Bianchi et al. 2016), multiple reports have described antitumor responses in NTRK-fusion
tumors to either larotrectinib or entrectinib (Doebele et al. 2020; Drilon et al. 2017, 2018; DuBois
et al. 2018; Laetsch et al. 2018). Labeling for the initial approval of larotrectinib described efficacy
results among 55 patients analyzed across three clinical trials (LOXO-TRK-14001, SCOUT,
NAVIGATE); however, the FDA review also assessed preliminary efficacy data in additional
patients with NTRK-fusion tumors (CDER 2018, Viktravi® 2018). More than 10 solid tumor
types and 15 different NTRK fusions were represented among the first 55 patients. The most
common tumor types enrolled were salivary gland (22%), soft-tissue sarcoma (20%), infantile
fibrosarcoma (13%), and thyroid cancer (9%) (Viktravi 2018). The ORR among the 55 patients
per a blinded independent review committee was 75% (95% CI: 61–85), with 22% of the 55
experiencing a CR (Viktravi 2018). Response duration was at least 6 months in 73% of patients.
152 Lemery et al.

More recently, updated data across the three trials have been published, reflecting the experience
in 159 patients with NTRK-fusion tumors, with 153 available for response (Hong et al. 2020).
The updated analysis involved patients with all three NTRK genes and 29 upstream fusion
partners. Median age of the population was 43 years with 52 patients younger than 18 years. The
ORR based on investigators’ assessment was 79% (95% CI: 72–85). Responses were observed
across tumor types and fusion partners (all tumor types with at least two patients had at least one
response). Additionally, the median duration of response in this report was 35.2 months.
The approved labeling of entrectinib described results of the first 54 adult patients with
NTRK-fusion tumors who were enrolled in one of three clinical trials (ALKA, STARTRK-1, and
STARTRK-2) representing 20 NTRK gene fusions across 10 anatomically or histologically de-
fined tumor types, with the most common cancers being sarcoma (24%), lung cancer (19%), sali-
vary gland (13%), breast cancer (11%), thyroid cancer (9%), and CRC (7%) (Marcus et al. 2021,
Rozlytrek® 2019). The ORR among the 54 patients per a blinded independent review committee
was 57% (95% CI: 43–71), with 7.4% of the 54 experiencing a CR (Rozlytrek 2019). Response
duration was at least 6 months in 68% of patients (Rozlytrek 2019).
The NTRK-fusion approvals for larotrectinib and entrectinib differ in that entrectinib is ap-
proved for patients age 12 years and older whereas larotrectinib is approved for adult and pedi-
atric patients. This difference was due to the lack of information regarding an appropriate dose in
younger children for entrectinib (Marcus et al. 2021).
Other NTRK-fusion inhibitors are also under development, including drugs designed to treat
patients with acquired resistance to prior NTRK-fusion inhibitors (Lin et al. 2019). In some pa-
tients, this resistance appears to occur via acquired kinase domain mutations, including solvent-
front or gatekeeper mutations (Drilon 2019).
TREATMENT OF TUMOR MUTATION BURDEN–HIGH CANCERS

The FDA approved pembrolizumab in 2020 for the treatment of adult and pediatric patients
who have no satisfactory alternative treatment options for solid tumors that are unresectable or
metastatic TMB-H [defined as 10 or more mutations (mut.) per megabase (Mb) based on the
FoundationOne® Companion Diagnostic (F1CDx) test (Found. Med. 2020)] and that have pro-
gressed following prior treatment.
Biology
TMB represents the overall somatic genomic burden of mutations in a tumor. Multiple reports
have described an association between increasing mutation burden and tumor responses to ICIs,
either within specific tumors such as NSCLC and melanoma or across multiple tumor types (E.X.
Chen et al. 2020, Lu et al. 2020, Rizvi et al. 2015, Rozeman et al. 2021, Samstein et al. 2019, Snyder
et al. 2014, Wang et al. 2019, Yarchoan et al. 2017). A high TMB within a tumor has been linked to
an increased probability of expressing neoantigens, some of which may serve as targets for the im-
mune system (Gubin et al. 2014, Howitt et al. 2015, Schumacher & Schreiber 2015). A threshold of
10 mut./Mb has been identified in literature and in multistakeholder meetings either as a thresh-
old for an increased chance of forming a neoantigen or as a threshold that could be used to study
response to ICIs (Friends Cancer Res. 2020, Schumacher & Schreiber 2015). In the absence of
immunotherapy, it has been reported that TMB does not predict improvements in overall survival
(OS) across tumor types, albeit data were limited for some of the tumor types (Shao et al. 2020).
Clinical Data
The approval of pembrolizumab for the TMB-H indication was based on data from a prospectively
planned retrospective analysis of patients enrolled in a multicohort clinical trial (KEYNOTE-158)
Table 1 Response rates by tumor type in the application supporting the approval of
pembrolizumab: KEYNOTE-158
Tumor type N ORR (95% CI)
TMB ≥ 10 mut./Mb F1CDx
Endometrial 15 47 (21–73)
Neuroendocrine 5 40 (5–85)
Cervical 16 31 (11–59)
Small-cell lung 34 29 (15–47)
Vulvar 12 17 (2–48)
Anal 14 7 (0.2–34)
Salivary 3 PR, SD, PD
Thyroid 2 2 CRs
Mesothelioma 1 PD
TMB < 10 mut./Mb F1CDx

Endometrial 67 6 (2–15)
Neuroendocrine 82 1 (0–7)
Cervical 59 12 (5–23)
Small-cell lung 42 10 (3–23)
Vulvar 59 3 (0–12)
Anal 75 11 (5–20)
Salivary 79 4 (1–11)
Thyroid 78 4 (1–11)
Mesothelioma 84 11 (5–19)
Abbreviations: 95% CI, 95% confidence interval; CR, complete response; F1CDx, FoundationOne companion diagnostic;
Mb, megabase; mut., mutations; ORR, overall response rate; PD, progressive disease; PR, partial response; SD, stable
disease; TMB, tumor mutation burden.
and supportive tumor response data from patients with whole-exome sequencing (WES)-derived
TMB scores across several global studies that assessed different tumor types. KEYNOTE-158
was an open-label, nonrandomized, multicohort trial of pembrolizumab for several types of
unresectable or metastatic cancers that had progressed following prior treatment in patients
who had no satisfactory alternative treatments (Marabelle et al. 2020a). TMB was assessed using
the F1CDx test and the cut-off for TMB-H was determined prior to testing patient tissue
samples from KEYNOTE-158. Among the 102 patients with TMB-H tumors (≥10 mut./Mb)
in KEYNOTE-158, the independently reviewed ORR was 29.4% (95% CI: 20.8–39.3) versus
6.3% (95% CI: 4.6–8.3) in the 688 patients with TMB-low tumors (<10 mut./Mb). Responses
were observed across eight tumor types (Table 1). Based on the data cutoff, median duration
of response had not been reached (Kaplan-Meier estimation) in the TMB-H population (range:
2.2+ to 34.8+ months). In an exploratory analysis using prespecified cutoffs, antitumor responses
appeared to increase with increasing TMB values among patients with TMB-H tumors: The
response rate was 13% (95% CI: 4–29) for TMB ≥ 10 mut./Mb and TMB < 13 mut./Mb patients
(32) and 37% (95% CI: 26–50) for TMB ≥ 13 mut./Mb patients (70).
The biologics licensing application (BLA) also included tumor response data obtained from
12 studies across 24 tumor types that were sequenced using WES (Cristescu et al. 2020). The ap-
plicant determined that 175 mut./exome was approximately equivalent to 10 mut./Mb using the
F1CDx test. A total of 1,772 patients with WES TMB results had received pembrolizumab as a
single agent, with 433 being TMB-H. Among patients who were both TMB-H and microsatellite
154 Lemery et al.

Table 2 Response rates by tumor type in the application supporting the approval of
pembrolizumab: whole-exome sequencing data set
Tumor type N ORR (95% CI)
TMB ≥ 175 mut./exome
Melanoma 43 58 (42–73)
NSCLC 158 30 (23–38)
Bladder/urothelial 61 34 (23–48)
HNSCC 59 24 (14–37)
Gastric 53 34 (22–48)
TNBC 22 18 (5–40)
Ovarian 12 17 (2–48)
Prostate 11 9 (0–41)
Other 14 21 (5–51)
TMB < 175 mut./exome

Melanoma 33 9 (2–24)
NSCLC 165 13 (8–19)
Bladder/urothelial 137 16 (10–23)
HNSCC 176 15 (10–21)
Gastric 261 7 (4–11)
TNBC 115 3 (1–7)
Ovarian 281 7 (5–11)
Prostate 115 6 (2–12)
Other 56 11 (4–22)
Abbreviations: 95% CI, 95% confidence interval; HNSCC, head and neck squamous cell carcinoma; Mb, megabase; mut.,
mutations; NSCLC, non-small-cell lung cancer; ORR, overall response rate; TMB, tumor mutation burden; TNBC, triple-
negative breast cancer; WES, whole-exome sequencing.
stable, ORR per independent review was 30.3%, versus 52.4% among 21 patients with MSI-H
tumors, which were all TMB-H. In specific tumor types, ORR was higher in TMB-H tumors
compared with the TMB-low tumors (Table 2). Additionally, the WES data set included tu-
mors not represented in the KEYNOTE-158 data set, including head and neck squamous cell
cancer (HNSCC), gastric cancer, triple-negative breast cancer, and bladder or urothelial cancer.
Finally, the application also contained supportive exploratory analyses of ORR, progression-free
survival (PFS), and OS when subgrouped by WES TMB in three trials of pembrolizumab versus
chemotherapy (Cristescu et al. 2020).
Following the approval of pembrolizumab for TMB-H tumors, data related to immunotherapy
treatment across TMB-H tumors have been published. One group used a different assay than was
used to support the FDA approval to assess TMB status and concluded that survival was not dif-
ferent between TMB-H and TMB-low tumors among patients with mismatch repair–proficient
CRC treated with various ICIs (Rousseau et al. 2021). They also found that the upper bounds of the
95% CIs for the hazard ratios for death comparing treatment effects in TMB-H versus TMB-low
tumors across multiple tumor types crossed one; these were reported as TMB-insensitive tumors.
Importantly, these were not randomized analyses and there were important potential differences
between TMB-H and TMB-low patients (e.g., differences in tumor sidedness for CRC). Addi-
tionally, there were limitations in the numbers of patients in the analyses (e.g., 13 patients with
TMB-H and microsatellite-stable CRC), and the point estimates for each of the tumor types were
less than one (favoring the TMB-H groups). Another publication reported that TMB-H tumors

with higher levels of infiltrating CD8+ T cells responded favorably to ICIs as opposed to TMB-H
tumors with lower levels of infiltrating CD8+ T cells (McGrail et al. 2021). However, response
rates in the CD8+ T–low/TMB-low group were 20% or higher across the different tumor types
(and in many individual tumors), a finding that is characteristically different than observations
across studies of monotherapy ICIs across several solid tumors, wherein the ORRs in TMB-low
tumors are lower. Furthermore, this study used a different methodology to assess TMB status,
and certain TMB-H tumors in the CD8+ T–low category (e.g., HNSCC, triple-negative breast
cancer, gastric cancer) appeared to respond less favorably in this study than in the pembrolizumab
TMB-H BLA or in other reports of ICIs (Wang et al. 2019). Another retrospective study of 1,678
patients that assessed TMB using a different methodology generally found that tumors with higher
TMB (e.g., ≥10 mut./Mb) had higher response rates compared to those with lower TMB (Valero
et al. 2021). Although the authors found that the response rate among tumor types with a suffi-
cient sample size was generally higher among TMB-H tumors, they indicated that the variability
of response rate by tumor types may favor different TMB thresholds for different tumor types.
Ultimately, additional data are necessary to verify and describe the effects of pembrolizumab
as a treatment for patients with TMB-H tumors. The FDA approved pembrolizumab as an ac-
celerated approval for patients with unmet medical need (without satisfactory available therapy)
with a requirement to collect additional prospective data that will allow for an assessment of the
drug’s effects in patients with different tumor types. As with any accelerated approval, the possi-
bility exists for future modification or withdrawal of the indication. For the TMB-H indication,
this could include an assessment of whether a different TMB threshold would be appropriate, or
whether specific tumor information is warranted. Although there may be tumor-specific effects
(e.g., mutations caused by UV light or MSI may have a differential ability to result in a neoanti-
gen), ultimately, for an approval, an effect at a specific cut-point (i.e., 10 mut./Mb) should predict
sufficient benefit across the spectrum of tumors (understanding benefit may be greater for some
tumors than others).
Testing
Concomitant with the approval of pembrolizumab for the TMB-high indication, the FDA
approved F1CDx to select patients for treatment with pembrolizumab. DNA isolated from
formalin-fixed paraffin-embedded tumor tissue is used to conduct testing. The original approval
of the F1CDx as a companion diagnostic occurred on November 30, 2017 for the detection of
genetic mutations for the selection of 1 of 15 FDA-approved therapies for NSCLC, melanoma,
breast cancer, CRC, and ovarian cancer. Several premarket approval supplements have been
approved since the original approval of F1CDx to select for treatment of patients with additional
drugs. To assess TMB, the F1CDx test counts all synonymous and nonsynonymous variants
present at the 5% allele frequency or greater after filtering. For the review of the CDx, the
applicant submitted data from KEYNOTE-158, as well as concordance data using WES and
repeatability/reproducibility studies.
In addition to F1CDx, other in vitro diagnostic tests include an assessment of TMB as part of
their platforms, which can be assessed using different methods including NGS and WES. These
tests are not approved for selection of patients for treatment with pembrolizumab based on TMB.
Importantly, the TMB value and its correlation to treatment response can be influenced by nu-
merous factors, including but not limited to sample type, tumor heterogeneity, input material
quality, capture region, panel size, depth of sequencing, mutation types, whether germline or tu-
mor mutation variants are excluded, cut-offs, and the source of reference transcripts (Stenzinger
et al. 2019). One multistakeholder effort to standardize TMB assessed results of 11 laboratories
using distinct NGS panels. The analysis found variability between the assessments and increased
156 Lemery et al.

variability for some cancers (e.g., CRC) compared to others (e.g., lung or HNSCC) (Merino et al.
2020). Although variability between tests was observed, TMB values were correlated with WES;
therefore, it may be possible to assess for the reasons for variability between tests. A sample with
a TMB score of 10 mut./Mb on one test may not report the same TMB score on a different test.
FUTURE DEVELOPMENT
Trials such as NCI-MATCH and ASCO TAPUR (Targeted Agent and Profiling Utilization Reg-
istry) are investigating the use of multiple drugs across different biomarkers using a single pro-
tocol with multiple single-group subprotocols. These innovative trial designs can facilitate effi-
cient assessment of the effects of drugs across several tumor types, including indications defined
on the basis of a biomarker and agnostic to tumor site or histology (FDA 2018). For example,
published reports from the NCI-MATCH trial to date include results of ado-trastuzumab em-
tansine in patients with HER2-amplified tumors, excluding breast and gastric/gastro-esophageal

junction adenocarcinomas; nivolumab in dMMR noncolorectal cancers; trametinib in solid tu-
mors and lymphomas harboring non-V600 BRAF mutations or fusions; AZD4547 in tumors har-
boring aberrations in the FGFR pathway; dabrafenib and trametinib in tumors with BRAFV600E
mutations; capivasertib in AKT1E17K -mutated tumors; and binimetinib in codon 12/13 and codon
61 NRAS-mutated cancers (Azad et al. 2020, Chae et al. 2020, Cleary et al. 2021, Jhaveri et al.
2019, Johnson et al. 2020, Kalinsky et al. 2021, Salama et al. 2020). In some of the reports, in-
cluding trametinib in tumors harboring non-V600 BRAF mutations, limited antitumor activity
was observed ( Johnson et al. 2020). In other trials, preliminary activity was reported/observed by
authors in some groups but not others, based on either tumor type or specific mutation(s) (Chae
et al. 2020, Cleary et al. 2021, Jhaveri et al. 2019). For example, in the report describing results
for ado-trastuzumab emtansine, the authors described responses in patients with salivary gland
tumors but no responses in patients with other tumors, including gynecological malignancies or
lower gastrointestinal malignancies ( Jhaveri et al. 2019). For antibody-drug conjugates, it appears
important to assess the sensitivity of the tumor to the payload in addition to whether the target is
present. The dabrafenib and trametinib report described a centrally assessed ORR of 38% (95%
CI: 23–55) across tumors without a clear pattern of resistance; however, the trial excluded patients
with CRC, melanoma, thyroid cancer, or lung cancer (Salama et al. 2020). A prior report described
a lower response rate of dabrafenib and trametinib in CRC (Corcoran et al. 2015). Tumor-specific
resistance to BRAF inhibition in CRC has been found to be caused by reactivation of the MAPK
pathway via the EGFR (epidermal growth factor receptor) (Corcoran et al. 2012). Knowledge of
this resistance pathway led to the development of drug combinations to inhibit both BRAF and
EGFR, and encorafenib is approved in combination with cetuximab based on an improvement in
OS in the BEACON CRC trial, which compared the combination of encorafenib and cetuximab
against the investigators’ choice of either cetuximab and irinotecan or cetuximab and FOLFIRI
(folinic acid, fluorouracil, and irinotecan hydrochloride chemotherapy) (Kopetz et al. 2019).
Whereas NCI-MATCH is a trial of both investigational and marketed drugs, ASCO TAPUR is
designed as a signal-seeking trial to assess the effects of FDA-approved drugs when matched with
prespecified genomic targets or aberrations. In TAPUR, the physician can select the treatment or
consult with the trial’s molecular tumor board (Mangat et al. 2018). As of 2018, over 800 patients
had received treatment in the trial (Mangat et al. 2018). Published results to date have indicated no
or limited activity of cetuximab in KRAS-, NRAS-, and BRAF-wild-type breast, lung, and ovarian
cancer; palbociclib in pancreatic or biliary cancers with CDKN2A loss or mutation; and sunitinib
for FLT3-mutated or -amplified CRC (Al Baghdadi et al. 2019, 2020; Fisher et al. 2020). Although
the palbociclib lung cancer cohort was assessed by the authors as having a positive result, only

1 of 29 patients was reported as having a partial response, and the authors concluded that modest
activity was demonstrated and additional investigation is necessary to assess efficacy (Ahn et al.
2020, TAPUR 2021). In a TMB-H breast cancer study, the reported ORR for pembrolizumab was
21% (95% CI: 8–41) among 28 patients with a TMB ranging from 9 to 37 mut./Mb (a different
TMB score compared with that in the FDA approval) (Alva et al. 2021). The authors concluded
that the findings supported the approval of pembrolizumab for TMB-H tumors.
In addition to trials by the government or professional societies, industry is also assessing the
effect of various drugs in master protocols or across different tumors. One such ongoing study is
investigating the effects of different drugs targeted to multiple biomarkers, including ROS, NTRK,
ALK, TMB, AKT, HER2, MDM2-a, wild-type TP53, and PIK3CA, in adult and pediatric patients
with different cancer types (Drilon et al. 2021). Targets with tumor-specific approvals but not
tissue-agnostic approvals that are being investigated in tissue-agnostic clinical trials include RET,
ALK, FGFR, DNA repair deficiency, and ROS1 (Seligson et al. 2021). Other targets are expected
to be investigated as our understanding of the biological underpinnings of cancer increases.
REGULATORY CONSIDERATIONS
To provide a scientific rationale supporting a tissue-agnostic approval there should be strong evi-
dence of a molecular aberration–drug match, allowing for extrapolation to diverse tumors, and an
understanding of resistance mechanisms. Also needed is for the effects across multiple histologies
to be homogeneous, without one tumor type driving response. In addition, to allow for the use
of response rate as an endpoint, and if an accelerated approval is pursued, there should be an ad-
vantage compared to alternatives, for example, with a dramatic effect in an indication with unmet
need. Tissue-agnostic approvals to date have been granted under the accelerated approval path-
way with requirements that sponsors enroll additional patients to verify and describe the effects of
these drugs in patients with various biomarker-positive tumor types. It is important to stress that
these accelerated approvals have been granted in settings where patients do not have adequate
available therapy; hence, the approvals address an unmet medical need with the understanding
that uncertainties will be further investigated in the postapproval setting.
The approvals have been based on results in nonrandomized trials that assessed effects on
durable ORRs. Response rates to a drug can be attributed to the drug in a nonrandomized trial
because, in general, tumors do not shrink in the absence of therapy (Lemery et al. 2017). Although
randomized trials have clear strengths in that they provide a comparative assessment of risks and
benefits and are necessary to assess effects on important time-to-event endpoints such as OS and
PFS, randomized trials would be difficult to conduct in the tissue-agnostic setting due to the
heterogeneity of tumor types and resulting rarity in the biomarker-positive populations. As an
example, although both infantile fibrosarcoma and NTRK-fusion adult lung cancers harbor NTRK
fusions that render them susceptible to entrectinib or larotrectinib, these would not be expected to
behave as the same disease with respect to non-TRK-directed treatments or prognosis. For NTRK-
fusion tumors, given the unprecedented durable responses in most patients (including a subset
with CRs), the rarity of the fusions, and the unmet medical need, it was not considered feasible
or ethical to require randomization to either a placebo or ineffective cytotoxic chemotherapy.
Although the response rates in MSI-H or TMB-H tumors were not as high as observed with
NTRK inhibitors, the FDA considered the totality of evidence to support approval including the
known safety profiles of pembrolizumab, broad efficacy across multiple tumor types, complete
responses in a subset of patients, and the long durations of response.
An important concept for the tissue-agnostic approach is an understanding that some hetero-
geneity may still exist between tumors regarding the treatment effects of the drug. For example,
numerically, response rates of pembrolizumab for CRC appeared lower than for non-CRC
158 Lemery et al.
tumors. Such differences, if related to biological factors, could occur due to multiple reasons
including differential upregulation of other immune checkpoints or differential effects of prior
therapies on immune function. What is important for the tissue-agnostic approach is that it is
reasonably likely that the effect in the different tumor types predicts or provides benefit across tu-
mor types considering the observed heterogeneity of effects of the drug, which may be real or due
to chance. If, however, there is clear resistance of one or more tumor types, then either the drug
should not be considered for a tumor-agnostic approach or labeling may need to address the lack
of responses/benefit in a tumor type. This information may be collected after approval, and thus
indications for tissue-agnostic approvals may be subsequently modified as information emerges.
Of the approvals to date, only two (TMB approval and dostarlimb-gxly) were supported by a
concurrently FDA-approved test to identify patients. In the cases where a contemporaneous ap-
proval of a companion diagnostic device was not possible, it was determined that the benefit out-
weighed the risk of approving without a companion diagnostic. Although not FDA approved as a
companion diagnostic, testing of tumor specimens for MSI-H with a PCR-based test or dMMR
with an IHC-based test was used for decades to guide chemotherapy use in patients with re-
sectable CRC. For NTRK, the rarity of the mutation and the challenges with enrolling based on
a central test prevented contemporaneous approval. For all these cases there was agreement with
the companies to develop a test as part of postmarketing commitments. As more biomarkers are
determined to have therapeutic value across tumors, the need for tests (e.g., NGS platforms) that
can accurately assess multiple biomarkers at the same time will be increasingly important. Never-
theless, there may also be value in having accurate IHC tests in some situations (e.g., MSI-H for
CRC), as these are widely available and can produce a result with limited turnaround time.
For all the tissue-agnostic approvals, there have been certain tumor types that are more rep-
resented in the approval data sets. Furthermore, given caps on the number of patients in clinical
trials for certain tumor types, the number of patients enrolled in clinical trials to support a market-
ing application may not mirror the distribution of patients with the biomarker in the real-world
setting. Nevertheless, tissue-agnostic approvals were justified based on scientific and mechanistic
evidence in the context of an effect considered reasonably likely to predict clinical benefit. Uncer-
tainties in less represented tumor types can be balanced against the unmet medical need for the
populations, as well as addressed by the requirement to obtain additional data in more diverse tis-
sue types in the postmarketing requirements. Ultimately the indication may be modified through
emerging data, but with initial broad labeling, more patients with incurable malignancies without
satisfactory treatment options may benefit during the time the data are collected.
DISCLOSURE STATEMENT
The authors are not aware of any affiliations, memberships, funding, or financial holdings that
might be perceived as affecting the objectivity of this review.
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CA06_TOC ARjats.cls February 25, 2022 10:4
Annual Review of
Cancer Biology
Contents Volume 6, 2022
The Metabolic Relationship Between Viral Infection and Cancer

Peter J. Mullen and Heather R. Christofk p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 1
Targeting Solid Tumors with Bispecific T Cell Engager Immune

Therapy
Tara Arvedson, Julie M. Bailis, Carolyn D. Britten, Matthias Klinger,
Dirk Nagorsen, Angela Coxon, Jackson G. Egen, and Flavius Martin p p p p p p p p p p p p p p p p p p17
Tracing and Targeting the Origins of Childhood Cancer
Tim H.H. Coorens and Sam Behjati p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p35
Targeting KRAS G12C with Covalent Inhibitors
Jonathan M.L. Ostrem and Kevan M. Shokat p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p49
Gut Microbiota in Colorectal Cancer: Associations, Mechanisms, and
Clinical Approaches
Cayetano Pleguezuelos-Manzano, Jens Puschhof, and Hans Clevers p p p p p p p p p p p p p p p p p p p p p p p p65
Central Role of the Antigen-Presentation and Interferon-γ Pathways
in Resistance to Immune Checkpoint Blockade
Annette Paschen, Ignacio Melero, and Antoni Ribas p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p85
CRISPR Screens to Identify Regulators of Tumor Immunity
Martin W. LaFleur and Arlene H. Sharpe p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 103
TGFβ: Signaling Blockade for Cancer Immunotherapy
Szu-Ying Chen, Ons Mamai, and Rosemary J. Akhurst p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 123
Development of Tissue-Agnostic Treatments for Patients with Cancer
Steven Lemery, Lola Fashoyin-Aje, Leigh Marcus, Sandra Casak, Julie Schneider,
Marc Theoret, Paul Kluetz, Richard Pazdur, and Julia A. Beaver p p p p p p p p p p p p p p p p p p p p p 147
Single-Cell Epigenomics Reveals Mechanisms of Cancer Progression
Lindsay M. LaFave, Rachel E. Savage, and Jason D. Buenrostro p p p p p p p p p p p p p p p p p p p p p p p p p 167
Clonal Hematopoiesis: Confluence of Malignant and Nonmalignant
Diseases
Amy E. Lin, Philipp J. Rauch, Siddhartha Jaiswal, and Benjamin L. Ebert p p p p p p p p p p p p p 187
RB1, Cancer Lineage Plasticity, and Therapeutic Resistance
Letian Zhang and David W. Goodrich p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 201
CA06_TOC ARjats.cls February 25, 2022 10:4
Caught in a Web: Emerging Roles of Neutrophil Extracellular Traps

in Cancer
Xue-Yan He, David Ng, and Mikala Egeblad p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 223
Cancer Genomic Rearrangements and Copy Number Alterations from
Errors in Cell Division
Cheng-Zhong Zhang and David Pellman p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 245
Novel Mouse Models for Cancer Immunology
Kelli A. Connolly, Brittany Fitzgerald, Martina Damo, and Nikhil S. Joshi p p p p p p p p p p p p 269
Oncohistones: Hijacking the Histone Code
Varun Sahu and Chao Lu p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 293

Targeting BET Bromodomains in Cancer

Patrick Trojer p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 313
Errata
An online log of corrections to Annual Review of Cancer Biology articles may be found at
http://www.annualreviews.org/errata/cancerbio

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Annual Review of Cancer Biology

Steven Lemery,1 Lola Fashoyin-Aje,1 Leigh Marcus,1

Annu. Rev. Cancer Biol. 2022. 6:147–65 Keywords

TREATMENT OF MICROSATELLITE INSTABILITY–HIGH

148 Lemery et al.

www.annualreviews.org • Tissue-Agnostic Cancer Treatments 149

150 Lemery et al.

TREATMENT OF NEUROTROPHIC RECEPTOR TYROSINE

www.annualreviews.org • Tissue-Agnostic Cancer Treatments 151

152 Lemery et al.

TREATMENT OF TUMOR MUTATION BURDEN–HIGH CANCERS

TMB < 10 mut./Mb F1CDx

154 Lemery et al.

TMB < 175 mut./exome

www.annualreviews.org • Tissue-Agnostic Cancer Treatments 155

156 Lemery et al.

tansine in patients with HER2-amplified tumors, excluding breast and gastric/gastro-esophageal

www.annualreviews.org • Tissue-Agnostic Cancer Treatments 157

to be investigated as our understanding of the biological underpinnings of cancer increases.

www.annualreviews.org • Tissue-Agnostic Cancer Treatments 159

160 Lemery et al.

Network. Ann. Oncol. 31:1506–17

www.annualreviews.org • Tissue-Agnostic Cancer Treatments 161

targets tumour-specific mutant antigens. Nature 515:577–81

162 Lemery et al.

www.annualreviews.org • Tissue-Agnostic Cancer Treatments 163

164 Lemery et al.

Alexandria, VA. https://www.tapur.org/news

www.annualreviews.org • Tissue-Agnostic Cancer Treatments 165

Contents Volume 6, 2022

The Metabolic Relationship Between Viral Infection and Cancer

Targeting Solid Tumors with Bispecific T Cell Engager Immune

Caught in a Web: Emerging Roles of Neutrophil Extracellular Traps

Varun Sahu and Chao Lu p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 293

Targeting BET Bromodomains in Cancer

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