Should Small Molecules Be Sequenced or Administered in Combination Regimens in CLL?

Jennifer R Brown, MD, PhD

Whether to administer small molecule combinations or sequence the agents for the treatment of chronic lymphocytic leukemia (CLL) was the topic of a debate on September 29 at the 10th Annual Meeting of the Society of Hematologic Oncology (SOHO 2022).¹

Jennifer R Brown, MD, PhD, a medical oncologist, director of the Chronic Lymphocytic Leukemia Center, and institute physician at Dana-Farber Cancer Institute, as well as the Worthington and Margaret Collette Professor of Medicine in the Field of Hematologic Oncology at Harvard Medical School in Boston, Massachusetts, presented in favor of combining small molecules. Making the argument for sequencing small molecules was Anthony Mato, MD, a hematologist/oncologist, and director of the CLL program at Memorial Sloan Kettering Cancer Center in New York, New York. In separate interviews with The SOHO Daily News prior to the conference, the investigators provided highlights of their respective arguments.

Single-Agent and Combination Small Molecules

“What we’re talking about are new chemicals that are given to patients that are targeted to specific pathways much more so than the generalized cytotoxic chemotherapy from the past. What’s happened over the last 20 to 30 years, is that there’s been this tremendous understanding of the pathways that drive normal cells, and the pathways that drive cancer cells. If you understand what enzymes are, what targets are most important to the cancer cell and important to normal cells, you can exploit those differences and develop inhibitors of those pathways to create a disadvantage for a cancer cell to survive,” explained Mato.

Bruton tyrosine kinase (BTK) inhibitors are the small molecules commonly used as targeted therapy for patients with CLL. Findings from multiple phase 2 and 3 trials have demonstrated the efficacy and safety of these drugs in CLL. For treatment-naïve CLL, single-agent ibrutinib (Imbruvica®; Pharmacyclics; Janssen.) prolonged progression-free (PFS) and overall survival (OS) compared with chlorambucil, regardless of patients’ immunoglobulin heavy chain variable region gene mutational status.1 When ibrutinib was combined with CD20 monoclonal antibodies such as rituximab (Rituxan®; Genentech, Biogen) and obinutuzumab (Gazyva®; Genentech) PFS and OS were also improved compared with chlorambucil/ obinutuzumab.²

In the phase 3 trials, ELEVATE TN (NCT02475681) and ASCEND (NCT02970318), which evaluated single-agent acalabrutinib (Calquence®; AstraZeneca) vs various targeted and chemotherapy combinations. In ELEVATE TN, interim results revealed that acalabrutinib plus obinutuzumab and single-therapy acalabrutinib improved PFS vs obinutuzumab and chlorambucil.³

In ASCEND, acalabrutinib significantly improved PFS compared with idelalisib (Zydelig®; Gilead) plus rituximab or bendamustine (Bendeka®; Teva) plus rituximab.⁴

“This is coming to the forefront as a topic because most of the novel agents have been developed as continuous single agents. [With] BTK inhibitors, for example, their first approvals have all been as continuous single agents. That was also true of PI3 kinase inhibitors, even venetoclax [Venclexta®; AbbVie, Genentech], early on was given as a continuous single agent, but subsequent randomized trials with venetoclax changed to time-limited therapy with discontinuation,” Brown told The SOHO Daily News.

Ongoing Questions

When it comes to both sequencing single-agent small molecules and using combinations, drug resistance and toxicity are concerns, according to Brown. Efficacy, on the other hand, is not likely to be affected either way, said Mato.

“The concern about this continuous single agent therapy is that it breeds drug resistance. We do know that there’s a continuous development of resistance to single-agent BTK inhibitors over time on therapy. Once a patient becomes resistant to that class of agent, they can’t receive it again, not the same category of drug,” Brown added.

Combination therapy also raises concern, explained Brown. “We still have limited data on the mechanisms of resistance that do occur with the combination therapies. We have rather few patients who have relapsed as yet, so we don’t have a lot of data on the possibility of retreatment with the same combinations, although we know that the outcome so far had been good,” Brown stated.

When asked to compare combination small molecule therapy vs sequencing, Mato predicted that outcomes may be similar. “I guess that it’s probably a wash. We may get a very similar outcome in terms of long-term survival, whether you give them all together or sequence them. There are probably some people that the combinations overtreat because they didn’t need them in the first place. The rationale for giving a combination would be that giving 1 drug at a time is an inferior approach. But that’s never been proved yet,” Mato said.

Both physicians agree that more research is needed to select one option over the other. As for the future of small molecules in CLL, Brown predicts that the choice of either small molecule combinations or sequencing will be a tailored decision.

“I do think there will be much more widespread use of combinations and time-limited therapy so that patients can be treated for a certain length of time and then their therapy is stopped, and they hopefully have long remissions off therapy. There’s still likely to be a role for some sequential single agents, especially in the older patients who don’t want to be treated with intensive therapy and don’t want to be monitored as much, and especially if they’re older, they might be able to get enough benefit out of the sequential therapy.”

_REFERENCES:

_{1. Munir T, Brown JR, O’Brien S, et al. Final analysis from RESONATE: up to six years of follow‐up on ibrutinib in patients with previously treated chronic lymphocytic leukemia or small lymphocytic lymphoma. Am J Hematol. 2019; 94(12): 1353-1363. doi: 10.1002/ajh.25638}

_{2. Moreno C, Greil R, Demirkan F, et al. Ibrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab in first-line treatment of chronic lymphocytic leukaemia (iLLUMINATE): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2019;20(1):43-56. doi: 10.1016/S1470-2045(18)30788-5}

_{3. Sharman JP, Banerji V, Fogliatto LM, et al. ELEVATE TN: phase 3 study of acalabrutinib combined with obinutuzumab (O) or alone vs O plus chlorambucil (Clb) in patients (Pts) with treatment-naive chronic lymphocytic leukemia (CLL). Blood. 2019;134 (Supplement_1): 31. doi: 10.1182/blood-2019-128404}

_{4. Ghia P, Pluta A, Wach M, et al. ASCEND: phase III, randomized trial of acalabrutinib versus idelalisib plus rituximab or bendamustine plus rituximab in relapsed or refractory chronic lymphocytic leukemia. J Clin Oncol. 2020; 38(25): 2849-2861. doi: 10.1200/JCO.19.03355}