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described.

Systemic chemotherapy is the mainstay of treatment for patients with advanced PACC. Several groups of
investigators have analyzed retrospective case series to identify the most beneficial regimens for advanced
PACC patients [169,177-179] . Overall, the objective response rate to FOLFIRINOX appears to be higher than for
any other regimen, with 16 of 21 patients receiving this regimen in the first-line setting achieving objective
responses [169,178,180,181] . All studies also agree that gemcitabine monotherapy has poor efficacy in PACC, with
no responses reported in 10 patients described in 2 studies. Similarly, gemcitabine-based regimens overall
are inferior to fluoropyrimidine-based regimens, with significantly lower progression-free survival observed
in multiple studies [169,178] . Intriguingly, objective responses have been noted to single-agent infusional
5-fluorouracil, S-1 and capecitabine; however, addition of irinotecan or platinum agents clearly increases
efficacy. In a study of 58 advanced disease patients, Takahashi et al. reported a 40% response rate to
platinum-containing regimens and a 29% response rate to irinotecan-containing regimens in the first-line
advanced disease setting. In addition, patients who received these regimens had improved overall
survival . One important caveat of these findings is that almost all of these case series are from Asia, and it
[177]
is unclear whether similar benefits to irinotecan and fluoropyrimidine containing regimens will be
reproducible in a majority Western population who metabolize these drugs differently. However, smaller
case series in Western countries suggest the relationship holds true regardless of race/ethnicity.

Targeted therapies have been demonstrated to produce clinical benefits in PACC patients with sensitizing
mutations. Responses to platinum-containing regimens appear particularly strong in PACC patients with
BRCA mutation, and a beneficial treatment effect of olaparib in this setting has also been reported [151,178] . A
complete response to the RAF/MEK inhibitor combination of dabrafenib/trametinib has been reported in 2
patients with tumors bearing BRAF V600E mutation [182,183] . Treatment with alectinib of a metastatic PACC
patient with a somatic KANK4/ALK fusion resulted in a partial response ongoing at 1 year . The use of
[184]
immunotherapy in a PACC patient with high tumor mutational burden and tumor PD-L1 expression
resulted in a partial response that permitted subsequent re-resection with continued absence of disease . It
[185]
is very clear that precision medicine is of significant benefit to PACC patients with actionable tumor
genetics and providers should advocate for sequencing of available tumor material to expand treatment
options.

Immunotherapy has not been extensively evaluated in PACC. MSI-H/dMMR disease is not uncommon in
PACC and would be expected to respond to anti-PD-1 therapies. It is unclear whether patients lacking
microsatellite instability would respond to single-agent immunotherapy treatment. However, combination
of lenvatinib with an anti-PD-1 therapy was reported effective in one case study, resulting in a partial
[186]
response ongoing for 21 months . Combination of anti-PD-(L)1 therapies with anti-angiogenic agents like
lenvatinib has produced exciting results in several tumor types [187,188] . PACC is a highly vascular tumor, like
renal and hepatocellular carcinomas which have been responsive to this combination. Evaluation of this
combination in PACC would be an intriguing prospect.

Research on PACC
We have recently opened a Phase 2 study evaluating olaparib in patients with previously treated PACC
(NCT05286827). To our knowledge, this is the first-ever PACC-specific prospective treatment study
[Table 4]. This study is based upon the observation that over 90% of PACC patients have down-regulation
of ID3, and that PARP inhibitor is active in ID3-deficient tumors [127,136] . Dedicated clinical studies of PACC
are extremely difficult to accrue, given the extreme rarity of the disease.