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Casadei et al. J Cancer Metastasis Treat 2022;8:21 https://dx.doi.org/10.20517/2394-4722.2022.05 Page 9 of 19

Moreover, tazemetostat showed a favorable safety profile in clinical trials. This led the FDA to approve the
drug for third-line therapy of patients with EZH2mut FL, as well as for patients with R/R FL with no other
satisfactory treatment choice. A few studies are currently evaluating the role of tazemetostat in combination
with other agents, namely anti-CD20 mAbs (rituximab, ublituximab, and obinutuzumab), lenalidomide,
umbralisib, and atezolizumab, in order to improve the results obtained with its single-agent use. This may
lead tazemetostat to gain a prominent role in the landscape of third-line therapy for FL.

PI3K-inhibitors
The PI3K-AKT-mTOR is crucial for the survival, growth, and proliferation of lymphoma cells. In 2014, the
first-in-class, orally bioavailable inhibitor of the δ subunit of PI3Kδ idelalisib received accelerated FDA
approval for the treatment of FL patients relapsing after ≥ 2 lines of therapy. The pivotal trial by Gopal et al.
showed 57% ORR with 6% CRR in a population of 125 heavily pre-treated patients with indolent
lymphomas, among whom 72 (i.e., 58%) had FL . The median PFS was 11 months and OS at one year was
[72]
80%. Two subsequent subgroup post hoc analysis were performed on FL patients and, specifically, on high-
risk FL patients who experienced early relapse after initial chemo-immunotherapy [73,74] . Both investigations
reported efficacy and safety results that were consistent with those obtained in the entire study population.
In particular, the significant antitumor activity shown by the drug in POD24-positive FL patients warrants
the development of prospective studies, in order to optimize the use of PI3K-inhibitors (PI3Ki) in this
[74]
setting . However, whereas the first studies reported a favorable toxicity profile, several phase III trials of
idelalisib showed relevant safety issues. Idelalisib treatment is mainly associated with immune-mediated
AEs (in particular, diarrhea, transaminitis, and pneumonitis), secondary to organ infiltration by
dysregulated CD8+ T lymphocytes, and opportunistic infections, especially Pneumocystis jirovecii
pneumonia (PJP) and human Cytomegalovirus (CMV) reactivation [75,76] . Therefore, PJP prophylaxis and
CMV viremia monitoring are considered mandatory for patients receiving idelalisib . Since idelalisib
[76]
approval was based on the results of a phase II trial, continued approval for FL [as well as for small
lymphocytic lymphoma (SLL)] depended on the results of confirmatory phase III studies. However, the
therapeutic landscape of FL has widely evolved over the last few years and has incorporated novel promising
agents, many of which are significantly more manageable than PI3Ki. This has made enrolment in
confirmatory studies harder, leading to the company’s decision to withdraw the FDA indications of
idelalisib for FL and SLL. Duvelisib, an oral dual inhibitor of PI3Kδ and -γ, suffered the same fate. The drug
had been approved by the FDA for the treatment of FL after at least two prior lines of therapy. Approval
came after the publication of the DYNAMO phase II study, in which 83 patients with FL obtained an ORR
of 42% with a toxicity profile similar to idelalisib .
[77]

Copanlisib is the only PI3Ki that currently maintains FDA indication for FL from the third line of therapy.
Copanlisib, an intravenous, pan-class PI3Ki targeting mostly the p110α and -δ isoforms of the enzyme, has
been approved by the FDA following a phase II study conducted on 141 NHL patients (104 of them having
[78]
FL) where it showed an ORR of 59% and CRR of 14%; PFS was 11 months . The drug displays a peculiar
safety profile, mainly characterized by hyperglycemia, hypertension, and skin rash but with lower rates of
gastrointestinal toxicities and infections compared to idelalisib . The intermittent dosing and the i.v.
[78]
administration, which reduces the gut concentration of the drug and the first-pass metabolism, may partly
be responsible for this difference; hyperglycemia, however, seems to be an on-target effect secondary to the
p110α inhibition. Umbralisib is a dual inhibitor of both PI3Kδ and casein kinase-1ε; the drug was
investigated in the phase IIb UNITY study, where 117 FL patients obtained a 45% ORR and 5% CRR;
[79]
median PFS was 10.6 months and median time to next treatment was 4.6 months . Neutropenia, diarrhea,
and transaminase elevation were the most common toxicities, while immune-related events such as non-
infectious colitis and pneumonitis were reported very rarely . In April 2022, TG Therapeutics announced
[79]