Small Molecule Inhibitors Prove Effective in Targeting NHL

Andrew D. Zelenetz, MD, PhD

A greater understanding of molecular pathogenesis in non-Hodgkin lymphoma (NHL) has led to the identification of rational targets for novel small molecule inhibitors, according to Andrew D. Zelenetz, MD, PhD.

“Clinical studies have validated these rational targets [and] have also shown that there is differential clinical activity of these agents,” said Zelenetz, medical director of quality informatics, Memorial Sloan Kettering Cancer Center, during a presentation at the National Comprehensive Cancer Network 13th Annual Congress: Hematologic Malignancies in New York, New York.

Combinations of these therapies may also provide greater responses and the potential for therapy discontinuation; however, physicians should be made aware of the unique toxicities associated with these novel agents as monotherapies and in combination regimens.

BTK Inhibition

Ibrutinib (Imbruvica) is a first-in-class covalent inhibitor of Bruton tyrosine kinase (BTK) and continues to be the standard of care for the treatment of relapsed/refractory mantle cell lymphoma (MCL) since its FDA approval in 2013. It was subsequently approved for indications in other hematologic malignancies, and its efficacy remains the focus of numerous phase II/III trials.

In a pooled analysis of 3 studies, patients with relapsed/ refractory MCL (n = 370) treated with ibrutinib had an objective response rate (ORR) of 66%, with a complete response (CR) rate of 20% and a partial response (PR) rate of 46%.¹Of note, patients with 1 prior line of treatment had a longer overall survival compared with those who had previously received more than 1 line of treatment.

According to Zelenetz, prescribers need to be aware of the adverse effects (AEs) associated with ibrutinib therapy. In a phase II study of 111 patients with relapsed/refractory MCL, the most common AEs from ibrutinib treatment were mild or moderate diarrhea (50%), fatigue (41%), and nausea (31%). Grade 3/4 hematologic AEs were uncommon and included neutropenia (16%), thrombocytopenia (11%), and anemia (10%).²

“One of the most difficult adverse effects that I deal with is muscle cramps. That is the most frequent cause of dose modification and discontinuation among my patients. It is a serious problem,” Zelenetz said.

Ibrutinib is also being investigated in combination with rituximab (Rituxan) in the phase II trial (NCT01880567) in patients with relapsed/refractory MCL. At a median follow-up of 16.5 months, patients (n = 50) had an ORR of 88% (95% CI, 75.7%-95.5%), with 44% achieving a CR (95% CI, 30.0%-58.7%) and 44% achieving a PR (95% CI, 30.0%-58.7%).³

According to Zelenetz, more data are warranted for this combination. “In this setting, I wouldn’t routinely add ritux- imab, though it is worth further investigation.”

Acalabrutinib (Calquence) is a second-generation BTK inhibitor, with fewer off-target effects. It is approved for patients with relapsed/refractory MCL based on the single-arm, phase II ACE-LY-004 trial (NCT02213926). At a median follow-up of 15.2 months, the ORR among 124 patients was 81%, with 40% of those having a CR.⁴

“This drug has its own set of toxicities,” noted Zelenetz. “One of the more difficult ones is headache. It has been

Bcl-2 Inhibition

seen in virtually all the acalabrutinib studies.” Headache was seen in 38% of patients, with other common AEs being diarrhea (31%), fatigue (27%), and myalgia (21%).⁴

Venetoclax (Venclexta) is a B-cell lymphoma 2 (Bcl-2) inhibitor with evidence of response in many diseases, said Zelenetz. The first in-human, phase I M12-175 trial enrolled patients (n = 106) with relapsed/refractory NHL, with subtypes including MCL (n = 28), follicular lymphoma (FL; n = 29), and diffuse large B-cell lymphoma (DLBCL; n = 34).⁵

The ORR for all patients was 44% (MCL, 75%; FL, 38%; DLBCL, 18%). Of the 21 patients with relapsed/refractory MCL who achieved a response, 6 had a CR (21%). “It was an active drug,” Zelenetz observed. “If we look at the numbers, MCL did stand out, but we will never prove this without bigger studies.”

The Bcl-2 inhibitor was generally well tolerated. The most common grade 3/4 AEs were anemia (15%), neutropenia (11%), and thrombocytopenia (9%).

Both venetoclax and ibrutinib have proved to be active as monotherapy agents for the treatment of MCL, and preclinical models predict that dual inhibition of BTK and Bcl-2 is synergistic.

In a phase II study, patients with relapsed/refractory MCL (n = 23) or previously untreated MCL (n = 1) were treated with venetoclax and ibrutinib until progression or intolerable toxicity (NCT02471391). At week 16, the combination induced a CR rate of 42% (95% CI, 22%-63%), according to assessments by computed tomography scan.⁶With the inclusion of positron emission tomography assessments, the ORR was 71% (95% CI, 49%-87%), comprising a CR rate of 62% and a PR rate of 8%.

Of note, 16 patients (67%) had absence of minimal residual disease (MRD) in bone marrow, as assessed by flow cytometry; 9 (38%) had evidence of an absence of MRD in the peripheral blood, as assessed by allele-specific oligonucleotide—polymerase chain reaction.

“This is tremendously good sensitivity, and we did not see this with either venetoclax or ibrutinib alone,” concluded Zelenetz. “There is clear evidence of synergy.”

EZH2Inhibition

Enhancer of zeste homolog 2 (EZH2) is an epigenetic regulator of gene expression and plays a critical role in multiple forms of cancer, according to Zelenetz. Tazemetostat, the first-in-class EZH2 inhibitor, has shown monotherapy activity in phase I and II studies for patients with EZH2-mutant and wild-type relapsed/refractory NHL.

In an open-label, phase II study, patients (n = 82) with relapsed/refractory FL were assessed in cohorts according to EZH2 mutational status.⁷As of May 2018, interim data had demonstrated an ORR of 71% for patients with EZH2-mutated FL (n = 28), with 11% achieving a CR. In the EZH2 wild-type cohort (n = 54), the ORR was 33%, with 6% of patients achieving a CR.

PI3K Inhibition

“If you are mutated, even though the response rate was only 71%, almost everyone had disease shrinkage,” said Zelenetz. “Whereas, with wild-type disease, that is not the case. When EZH2 wild-type was present, there were patients who had primary progression.”

Idelalisib (Zydelig) is a first-in-class PI3Kδ inhibitor currently approved for use in patients with relapsed/refractory FL who have received ≥2 prior lines of therapy, as well as for use in other hematologic malignancies.

In a single-arm, phase II study, patients with relapsed/refractory FL treated with idelalisib monotherapy (n = 72) achieved an ORR of 55.6% (95% CI, 43.4%-67.3%; P <.001), with 10 patients (13.9%) achieving a CR and 30 (41.7%) achieving a PR.⁸

The most common AEs for this population were diarrhea (51.4%), cough (31.9%), and pyrexia (29.2%). Diarrhea, pneumonia, and pyrexia were the most frequently reported grade &ge;3 AEs, occurring in 13.9%, 6.9%, and 4.2% of patients, respectively.

Copanlisib (Aliqopa), another PI3K inhibitor tar- geting the &alpha; and &delta; isoforms, was approved in 2017 for patients with relapsed FL who have received &ge;2 prior lines of therapy. This approval was based on the phase II CHRONOS-1 trial, which included a cohort of 104 patients with relapsed/refractory FL (NCT01660451, part B). At the time of primary analysis, the ORR was 58.7%, comprising 15 patients (14.4%) with CR and 46 (44.2%) with PR.9 The AEs were similar to those of idelalisib, with diarrhea, reduced neutrophil count, and fatigue (34%, 30%, and 30%, respectively) being the most common all-grade AEs observed.

Most recently, the PI3K inhibitor duvelisib (Copiktra), which targets the &delta; and &gamma; isoforms, was approved for patients with relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) or relapsed/refractory FL based on the phase III DUO trial (NCT02004522) and the phase II DYNAMO study (NCT01882803), respectively. Both indications are for patients who received at least 2 prior therapies.

&ldquo;This entire class of drug also has a significant infection risk,&rdquo; warned Zelenetz. &ldquo;We worry about the reactivation of cytomegalovirus, [among others].&rdquo;

IMiDs

Several novel PI3K inhibitors have also demonstrated promising efficacy in clinical trials. For example, in a phase Ib trial evaluating ME-401, a highly selective inhibitor of &delta; isoforms, the ORR in patients with relapsed/refractory FL and CLL/ SLL was 83%.¹⁰

Lenalidomide (Revlimid) is an immunomodulatory drug (IMiD) approved for the treatment of patients with relapsed/refractory MCL, with additional indications in multiple myeloma, CLL, and myelodysplastic syndromes.

In the randomized, phase II SPRINT (MCL- 002) trial, lenalidomide was compared with an investigator&rsquo;s choice of single-agent therapy (NCT00875667). With a median follow-up of 15.9 months, patients in the lenalidomide arm (n = 170) achieved an ORR of 40% (95% CI, 33%- 48%; P <.001), with a CR rate of 5% and a PR rate of 35%. Among those in the investigator&rsquo;s choice group (n = 84), 11% achieved an ORR (95% CI, 5%-19%; P <.001), with all patients achieving a PR as their best response.¹¹&ldquo;The ORR was clearly in favor of lenalidomide,&rdquo; he confirmed.

The most common grade 3/4 AEs were typical of those seen with other IMiDs, including neutropenia (44% vs 34%), thrombocytopenia (18% vs 28%), and anemia (8% vs 7%) in the lenalidomide and investigator&rsquo;s choice arms, respectively.

In a phase I/II study, lenalidomide was investigated in combination with rituximab for patients with relapsed/refractory MCL (NCT00294632). With a median follow-up of 23.1 months, the ORR among 44 patients receiving rituximab plus the maximum tolerated dose of lenalidomide was 57%, with 36% of patients achieving a CR and 20% achieving a PR.¹²The response rate, Zelenetz noted, dramatically increased compared with that of lenalidomide monotherapy.

Ibrutinib was added to this combination in the phase II PHILEMON (MCL6) trial for patients(n = 50) with relapsed/refractory MCL (NCT02460276). With a median follow-up of 17.8 months, 76% of patients overall had a response (95% CI, 63%-86%), including 56% of patients achieving a CR and 20% of patients with a PR.¹³

According to Zelenetz, there were more toxicities associated with the combination of ibrutinib, rituximab, and lenalidomide than with all the agents as monotherapies. The most common grade 3/4 AEs were neutropenia (38%), infections (22%), and cutaneous toxicity (14%). There were 3 treatment-related deaths, 2 due to sepsis, and 1 due to embolic stroke.