Expert Highlights the Complexities of Novel-Novel Drug Combos in Lymphomas

Kieron Dunleavy, MD

Combinations of novel drugs used for treating patients with lymphomas may have the potential to improve responses and overcome resistance to therapy but can be accompanied by unexpected adverse events (AEs) that demand careful monitoring, Kieron Dunleavy, MD, cautioned during the 2018 Pan Pacific Lymphoma Conference.

Along with the increasing complexity of new treatments, additional indications for novel—novel combinations are emerging. This is highlighted by FDA recommendations for the codevelopment of investigational agents, said Dunleavy, a professor of medicine at George Washington University and director of the Lymphoma Program at GW Cancer Center.

FDA guidelines for the choice of drugs for combination treatments call for compelling biological evidence, proof that the agents under consideration cannot be developed as independent drugs, and preclinical data demonstrating that antitumor activity is more potent with the target combination than individually. The FDA has approved 5 combinations of novel agents so far in 2018, another 2 were approved in 2017, and 2 more in 2016, Dunleavy said.

Novel—novel combinations are essential to address the genetic complexity of tumors, and insight developed into the biology of tumors is opening a window into opportunities for exploration of these dual treatments, according to Dunleavy. “I think we need to better understand and incorporate biomarker studies into new trials of agents that are being combined together,” he said.

BTK and PI3K inhibitors, checkpoint inhibitors, chimeric antigen receptor (CAR) T cells, immunomodulatory drugs, and BCL-2 inhibitors are examples of novel agents being considered for novel combination therapies in B-cell lymphomas. They each bring with them toxicities of a different class compared with chemotherapy treatments, such as pneumonitis, transaminitis, and bleeding (TABLE).¹“We have to be very vigilant [not only] when we’re using these as single agents but also when we combine them. Often when we combine agents, we see that we could not have predicted what would happen when we looked at the [adverse] effect profiles of the individual agents,” Dunleavy said.

Lymphomas have many potential molecular targets, for which a host of small molecular inhibitors exist, so it makes sense to combine inhibitors and target more than 1 thing at a time, he said. Another compelling argument involves the paucity of active single agents in the relapsed/refractory (R/R) setting in diffuse large B-cell lymphoma (DLBCL), he said: “This is in contrast to indolent lymphomas, where that’s not the case.”

A study of the BTK inhibitor ibrutinib (Imbruvica) by Wilson et al²targeted the activated B cell—like (ABC) subtype of DLBCL, which has a poor cure rate compared with the other major subtype, germinal center B cell–like (GCB). The phase I/II study involving patients with R/R DLBCL (n = 80) produced complete remissions (CRs) or partial remissions (PRs) in 38% (15 of 39) of the patients with ABC DLBCL, but in only 5% (1 of 20) of patients with GCB DLBCL (P= .0059), Dunleavy said.

However, it’s important to note that the progression- free survival (PFS) is very short for both ABC and GCB, he said. “I think this is the principal reason why you are not seeing a lot of development of dual inhibitors in R/R aggressive lymphomas,” he added. The median PFS was 2.14 months for patients with ABC DLBCL and 1.31 months for those with GCB (P= .0022).

Dunleavy contrasted those findings with outcomes from the phase II CAPTIVATE trial presented at the 2018 ASCO Annual Meeting in June.3 The frontline combination of ibrutinib and venetoclax (Venclexta) demonstrated a 100% objective response rate for patients with chronic lymphocytic leukemia, with 77% of patients testing negative for minimal residual disease (MRD) in the peripheral blood after 6 cycles, according to early findings.

In 11 patients treated with 12 cycles of ibrutinib and venetoclax with available bone marrow data, the CR rate was 36%, and the rate of CR with incomplete hematologic recovery (CRi) was 18%. Remaining responses consisted of nodular PRs (nPR; 9%) and PRs (36%). All patients with a CR/CRi had confirmed undetectable MRD in the bone marrow, and 60% of those with a PR/nPR were MRD negative.

Calling the results impressive, Dunleavy noted that using ibrutinib lowered the incidence of tumor lysis syndrome (TLS). “At the onset, 24% of patients were at risk of TLS, and after 3 cycles of ibrutinib, this was reduced down to just 3%,” he said. “There was also a shift in lymph node bulk. Before ibrutinib was given, 29% of patients had a lymph node mass over 10 cm, but after 3 cycles of ibrutinib, it was reduced down to 6% of patients.” This is an example of using 2 novel agents with the goal not specifically to induce antitumor activity but to reduce TLS, he added.

The major challenge in developing combinations of novel agents is toxicity, which is often unexpected, he said. “This is a real potential pitfall when you’re combining novel agents in lymphoma,” particularly when it comes to immune checkpoint inhibitors and PI3K inhibitors, he said.

A phase I study by Cheah et al4 found that toxicities from the combination of lenalidomide (Revlimid), idelalisib (Zydelig), and rituximab (Rituxan) were unacceptable in patients with R/R indolent B-cell lymphoma. Six of 7 patients (86%) enrolled developed alanine aminotransferase elevation, with 57% grade 3 or higher. This led to therapy interruptions, and 2 deaths resulted from fulminant hepatic failure, sepsis, and hemorrhagic colitis, leading to the study’s termination.

Conversely, the ongoing ZUMA-6 phase I/II trial of axicabtagene ciloleucel (Yescarta) and atezolizumab (Tecentriq) for DLBCL is using atezolizumab to lengthen the persistence of infused CAR T cells (NCT02926833).

Interim results from the phase I portion of the study5 presented at the 2017 American Society of Hematology Annual Meeting demonstrated responses in 8 of the 9 patients (89%). Common grade 3/4 treatment-emergent AEs included anemia, encephalopathy, neutropenia, hyponatremia, decreased lymphocyte count, decreased neutrophil count, pyrexia, and thrombocytopenia. Additionally, grade 3 hypophosphatemia, hypoxia, blood bilirubin increase, and lung infection occurred in 2 patients each. No patient deaths were reported.

Many novel—novel combination studies are under way, and the niche so far remains with indolent lymphomas. One audience member commented that perhaps more restraint about investigating novel combinations is advisable, given the toxicities that have led to trial closures and the risks that patients may face.

Dunleavy suggested that preclinical modeling needs improvement: “There are certain classes of drugs where these toxicities are hugely problematic. We just need to focus on what we know clinically and extrapolate from that and intensify preclinical assessments before moving forward with some of these classes of drugs.

References:

1. Rodgers TD, Barr PM. Pitfalls of combining novel agents in lymphoma.Curr Treat Options Oncol.2018;19(7):35. doi: 10.1007/s11864-018-0548-7.
2. Wilson WH, Young RM, Schmitz R, et al. Targeting B cell receptor signaling with ibrutinib in diffuse large B cell lymphoma.Nat Med.2015;21(8):922-926. doi: 10.1038/nm.3884.
3. Wierda WG, Siddiqi T, Flinn I, et al. Phase 2 CAPTIVATE results of ibrutinib (ibr) plus venetoclax (ven) in first-line chronic lymphocytic leukemia (CLL).J Clin Oncol.2018;36(suppl; abstr 7502). meetinglibrary.asco.org/ record/159485/abstract.
4. Cheah CY, Nastoupil LJ, Neelapu SS, Forbes SG, Oki Y, Fowler NH. Lenalidomide, idelalisib, and rituximab are unacceptably toxic in patients with relapsed/refractory indolent lymphoma.Blood.2015;125(21):3357- 3359. doi: 10.1182/blood-2015-03-633156.
5. Locke FL, JR Westin JR, Miklos DB, et al. Phase 1 results from ZUMA6: axicabtagene ciloleucel (axi-cel; KTE-C19) in combination with atezolizumab for the treatment of patients with refractory diffuse large B cell lymphoma.Blood.2017;130:2826. www.bloodjournal.org/content/130/ Suppl_1/2826?sso-checked=true.