Pemmaraju Discusses Data, Approvals, and Challenges for Hematologic Malignancies

Naveen Pemmaraju, MD

Targeted Oncology^TM was joined on Twitter by Naveen Pemmaraju, MD, for a discussion on all things hematology, highlighting new data from clinical trials, unmet needs, and his own research.

During the event, Pemmaraju, associate professor, Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, emphasized some of the important abstracts and data that have recently been uncovered, including findings from the ASAP trial (NCT02461537) for patients with acute myeloid leukemia (AML), and a new discovery regarding the monoclonal antibody, INCA033989.

He then discussed how findings from these trials influenced some of the recent FDA approvals, including pirtobrutinib (Jaypirca) for patients with mantle cell lymphoma (MCL), and zanubrutinib (Brukinsa) for patients with chronic lymphocytic leukemia (CLL) or small lymphocytic leukemia (SLL).

Updates From ASH 2022

To kick off the chat, Pemmaraju discussed some of the practice-changing abstracts which were presented at the 2022 ASH annual meeting.

The first session that Pemmaraju highlighted during the Twitter Spaces event was findings from the phase 3 ASAP trial. The trial enrolled adult patients with relapsed or refractory, high-risk AML following first induction therapy or first untreated relapse who were fit for intensive chemotherapy and allogeneic hematopoietic cell transplant (alloHCT).¹

Those enrolled in the ASAP trial were randomized in a 1:1 fashion to a remission induction strategy (RIST arm) with 3 g/m2 cytarabine (1 g/m² for patients >60 years) twice a day on days 1-3, 10 mg/m² mitoxantrone on days 3 to 5, and subsequent alloHCT or to disease control (DISC arm) prior to sequential conditioning and alloHCT.

“Results were similar in terms of overall leukemia-free survival compared with intensive remission induction chemotherapy, followed by allo transplant. Essentially, 281 patients were enrolled, almost all of whom were available for analysis. These are patients with AML, a median age of 61, and essentially, they had a nice median follow-up of approximately 3 years, so 37 months,” said Pemmaraju.

Findings from the study which were presented at ASH 2022 showed that the primary end point of disease-free survival at day 56 was reached by 84.1% of those in the DISC arm (n = 139) and 81.3% of those in the RIST arm (n = 137; P = .047). However, these results did miss statistical significance against the 1-sided α level of 2.5%.

Additionally, patients with relapsed or refractory AML who received an alloHCT had similar overall survival rates vs those who first received intense salvage chemotherapy to achieve complete response (CR).

“What the investigators concluded is that this was the first phase 3, randomized, control trial which asked the question, what is the benefit of intensive remission induction chemotherapy prior to a transplant for patients with relapsed/refractory AML vs this concept of going straight into the stem cell transplant regardless of the remission status? This was something that was provocative and interesting. The data, as presented by the investigators, supported a sequential conditioning and allo transplant without prior remission induction chemotherapy, if and when a feasible stem cell donor was readily available. This underlines the importance of the question of when to give the stem cell transplant and can it be given earlier upfront,” added Pemmaraju.

The second abstract highlighted in the chat was the discovery of INCA033989, a monoclonal antibody that selectively targets mutant calreticulin (mutCALR)-driven oncogenesis in myeloproliferative neoplasms (MPNs).

“This is a preclinical model system which demonstrates and showcases the discovery of this agent in general. This a monoclonal antibody, it selectively targets mutCALR and subsequent driven oncogenesis. This drug, in their preclinical models, was highly effective in not only targeting what it was supposed to, the mutCALR, but also restoration of hematopoiesis in their preclinical and animal models,” stated Pemmaraju.

An in vivo MPN model was used to assess the role of INCA03398.² Findings showed that treatment for 10 weeks with the antibody prevented the development of thrombocytosis as it selectively decreased mutCALR-positive platelets. The antibody therapy did not impact the overall bone marrow cellularity. However, it did promote a decrease in the percentage of all precursor and progenitor cells from mutCALR origin. Additionally, the antibody suppressed the mutCALR-induced accumulation of megakaryocytes in the bone marrow, a hallmark of essential thrombocythemia.

Targeting mutCALR disease was confirmed in this preclinical model by the lack of disease development upon secondary transplantations. Overall, this highly potent monoclonal antibody binds to mutCALR and inhibits oncogenesis in cells expressing mutCALR.

Looking forward, INCA033989 is currently being investigated for patients with MPNs.

“This highly selective monoclonal antibody, first-in-class, binds to the mutCALR and it blocks oncogenesis in those cells only expressing mutCALR. The discovery of this molecule, INCA033989, not only selectively targets the mutCALR and normalizes TPO-R signaling in these patient-derived hematopoietic stem cells in MPN in vivo models, but that it appears that it may be able to restore normal megakaryopoiesis, normal hematopoiesis. I think that's something we should watch out for as it hits the clinic.”

Recent FDA Approvals

Following the ASH conference, multiple agents in the hematologic malignancies space were granted FDA approvals, including pirtobrutinib and zanubrutinib.

“With the introduction of ibrutinib, it changed the paradigm of CLL, and now in some of the other lymphoid diseases, where we were almost exclusively treating patients with an IV chemotherapy multi-agent regimen…Now, you have gone, in basically the span of about a decade, to an almost exclusively oral regimen, whether it's Bruton’s tyrosine kinase inhibitor [BTKi] alone, BCL2 inhibitor venetoclax [Venclexta] alone, the combination of ibrutinib plus venetoclax, or others. Now, [we] have this newer era again of these newer BTKs,” said Pemmaraju.

In January 2023, the FDA approved the BTKi zanubrutinib for the treatment of adult patients with CLL or SLL based on findings from 2 phase 3 randomized studies.³

The first study was ALPINE (NCT03734016) which evaluated zanubrutinib vs ibrutinib (Imbruvica) in patients with relapsed/refractory CL. The second study was the SEQUOIA trial (NCT03336333) of zanubrutinib vs bendamustine and rituximab (Rituxan) for the treatment of treatment-naïve patients with CLL. In both studies, zanubrutinib led to durable responses.

The ALPINE study of 415 patients demonstrated an ORR of 80% for those on zanubrutinib (95% CI, 76-85) and 73% (95% CI, 68-78) for those given ibrutinib (HR, 1.10; 95% CI, 1.01-1.20; P = .0264). The median duration of response (DOR) was not reached in either arm, after a median follow-up of 14.1 months.

For SEQUOIA, the median progression-free survival (PFS) was not reached in the zanubrutinib arm vs 33.7 months (95% CI, 28.1-NE) in the bendamustine and rituximab arm (HR, 0.42; 95% CI, 0.28-0.63; P =< .0001). The estimated median follow-up was 25.0 months. Additionally, a separate non-randomized cohort of the study administered zanubrutinib to 110 patients with previously untreated CLL/SLL with a 17p deletion. In this cohort, the overall response rate (ORR) was 88% (95% CI, 81-94), and the median DOR was not reached after a median follow-up of 25.1 months.

Then later in January 2023, the FDA granted approval to pirtobrutinib for the treatment of adult patients with relapsed/refractory MCL who received at least 2 prior lines of systemic therapy, including a BTKi.⁴

Pirtobrutinib, a highly selective kinase inhibitor, is an agent which utilizes a novel binding mechanism. Pirtobrutinib may be able to reestablish BTK inhibition in patients with MCL who have previously been treated with a covalent BTK inhibitor, including ibrutinib, acalabrutinib (Calquence), or zanubrutinib. Moreover, pirtobrutinib may extend the benefit of targeting the BTK pathway.

The approval of pirtobrutinib was based on the findings of the phase 1/2 BRUIN trial which showed that patients who were pre-treated with a covalent BTK inhibitor who had relapsed/refractory MCL achieved an ORR of 50% with pirtobrutinib, and 13% of patients had a CR at time of analysis. This is the first BTK inhibitor of any kind to be approved by the FDA for this patient population.

“It's an exciting time for our patients and caregivers and [we must] make sure we understand the science of these new BTKi’s, how they differ from each other, and how they respond differently in the different diseases, [including] CLL vs MCL vs the other lymphoid diseases,” added Pemmaraju.

Unmet Needs

Lastly, Pemmaraju discussed some of the many unmet needs that still exist for patients with different hematologic malignancies. As a rare disease and rare blood cancer researcher, Pemmaraju believes that the first need is for more understanding of awareness, including stakeholder collaboration, philanthropy, academic researchers, community physicians, caregivers, and more.

“There's so much more work that needs to be done. I think we've had some success now with narrowing down into what I call subsets of subsets of subsets. We've seen our solid tumor colleagues do this in lung cancer. It used to be histology based, and in non–small cell or small cell, everybody got cytotoxic chemotherapy. Then, within non–small cell lung cancer, do you have a particular mutation…We've seen some developments in the hematologic space, but can we do that in the much more rare diseases those that affect only 500-1000 people a year, oftentimes are life threatening, misunderstood, misdiagnosed, and carry low life expectancies.”

To further promote development, using the rare disease as a field of investigation for other disease types may allow for even more discoveries and findings for patients. Pemmaraju notes that it is important to focus on ultra rare diseases, to cure both those diseases as well as to extrapolate backwards to the more common disease types.

There is also a need to focus on hematologic education. It will be important to train the next generation of hematologists and hematology researchers and to support the education of blood cancer doctors, classical and malignant hematologists, and more.

“It's up to all of us to mentor the next generation and younger physicians. I would say, raising awareness, education, and training standards for blood cancer doctors is going to be very important moving on.”

The chat also placed an emphasis on immunotherapy and its potential use across various cancer types. Pemmaraju notes that no matter what field of hematology one may be in or whether one is using immunotherapies in their practice already or not, it is important to learn about them. As research continues to investigate immune-based therapies, Pemmaraju adds that it will be important to further understand chimeric antigen receptor therapies, bispecifics, antibody drug conjugates, combination therapies, and more agents, as they may all be combined with one another in the future.

Want to hear more? Visit the pinned tweet on our Twitter page, @TargetedOnc, to listen to a recorded version of the entire event!

REFERENCES:

1. Stelljes M, Middeke JM, Bug G, et al. In patients with relapsed/refractory AML sequential conditioning and immediate allogeneic stem cell transplantation (allo-HCT) results in similar overall and leukemia-free survival compared to intensive remission induction chemotherapy followed by allo-HCT: results from the randomized phase III ASAP trial. Blood. 2022;140(suppl 1):9-11. doi:10.1182/blood-2022-159962

2. Reis E, Buonpane R, Celik H, et al. Discovery of INCA033989, a monoclonal antibody that selectively antagonizes mutant calreticulin oncogenic function in myeloproliferative neoplasms. Presented at: 2022 ASH Annual Meeting and Exposition; December 10-13, 2022; New Orleans, LA. Abstract 6.

3. FDA approves zanubrutinib for chronic lymphocytic leukemia or small lymphocytic lymphoma. News release. FDA. January 19, 2023. Accessed March 1, 2023. https://bit.ly/3D1iUjq

4. U.S. FDA approves Jaypirca™ (pirtobrutinib), the first and only non-covalent (Reversible) BTK inhibitor, for adult patients with relapsed or refractory mantle cell lymphoma after at least two lines of systemic therapy, including a BTK inhibitor. News release. Loxo@Lilly. January 27, 2023. Accessed March 1, 2023. https://prn.to/3RdCyOT