ASCO 2021 Recap: Leukemia & Lymphoma

Phase 2 Data for Tisagenlecleucel, Tafasitamab Show Objective Responses in More Than Half of Patients

Drugmakers unveiled positive new phase 2 data for a pair of therapies targeting 2 types of non-Hodgkin lymphomas during the 2021 American Society of Clinical Oncology Annual Meeting, held
June 4 to 8 in a virtual format.

The chimeric antigen receptor (CAR) T-cell therapy tisagenlecleucel (Kymriah) had an overall response rate (ORR) of 86% among patients with relapsed or refractory follicular lymphoma, and the humanized Fc-modified cytolytic CD19-targeting monoclonal antibody tafasitamab (Monjuvi) had an ORR of more than 50% when administered in combination with lenalidomide (Revlimid)
to patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL).

TISANGENLECLEUCEL IN FOLLICULAR LYMPHOMA. Novartis AG released the pivotal phase 2 data from its ELARA trial, showing that tisagenlecleucel led to an ORR of 86% (95% CI, 78%-92%) in
patients with follicular lymphoma, and a 66% complete response (CR) rate (95% CI, 56%-75%).¹ None of the 97 patients evaluated for safety experienced grade 3 or 4 cytokine release syndrome
(CRS), the most common adverse event associated with CAR T-cell therapies, although nearly half (49%) had grade 1 or 2 CRS.

“Our goal as researchers is to continue to explore the potential of CAR-T therapy, and the robust ELARA safety and efficacy findings suggest [that] Kymriah may play an important role in the third-line treatment of relapsed or refractory follicular lymphoma,” said Stephen J. Schuster, MD, of the University of Pennsylvania’s Perelman School of Medicine, in a news release.²

The ELARA trial had a median follow-up of 11 months, by which time the median duration of response (DOR), progression-free survival (PFS), and overall survival (OS) were not reached.

Schuster and colleagues estimated DOR for patients with CR at 6 months to be 94% (95% CI, 82%-98%) and 76% for patients with PFS at 6 months (95% CI, 65%-84%). The median number of prior therapies in the cohort was 4 (range, 2-13).

Nine percent of patients reported grade 1 or 2 neurological events, and 1 patient had a grade 4 neurological event, although all recovered. The most common grade 3 or higher adverse events
in the first 8 weeks following infusion were neutropenia (28%) and anemia (13%). No treatment-related deaths were reported. Novartis said it is committed to expanding the availability of CAR T-cell therapies, and will push forward with regulatory submissions for the indication as soon as possible.

TAFASITAMAB RESULTS. Meanwhile, Incyte Corp. and MorphoSys US Inc. said its phase 2 L-MIND trial showed tafasitamab had an ORR of 57.5% (46 of 80 patients; 95% CI, 45.9-68.5) when given to
patients with relapsed or refractory DLBCL in combination with lenalidomide.³ Forty percent of patients achieved CR, and the median DOR was 43.9 months (95% CI, 26.1 - not reached) The
median OS was 33.5 months (95% CI, 18.3 - not reached) and the median PFS was 11.6 months (95% CI, 6.3-45.7).

“The 3-year follow-up data not only show a durable response and consistent safety profile in patients with relapsed or refractory DLBCL treated with tafasitamab plus lenalidomide, it also suggests the combination could potentially lead to durable remission,” said MorphoSys senior vice president Nuwan Kurukulasuriya, in a press release.⁴ “We are looking forward to sharing these long-term follow-up findings with the scientifi c community.”

Tafasitamab in combination with lenalidomide was approved by the Food and Drug Administration via its accelerated approval pathway last July for the treatment in adult patients with relapsed
or refractory DLBCL not otherwise specified, including those arising from low-grade lymphoma, who are not eligible for autologous stem cell transplantation.

References

1. Schuster SJ, Dickinson MJ, Dreyling MH, et al. Efficacy and safety of tisagenlecleucel (tisa-cel)
in adult patients (pts) with relapsed/refractory follicular lymphoma (r/r FL): primary
analysis of the phase 2 Elara trial.J Clin Oncol. 2021;39(Suppl 15):abstr 7508. doi:10.1200/
JCO.2021.39.15_suppl.7508
2. Novartis’ Kymriah pivotal trial demonstrates strong response rates and remarkable safety
profile in relapsed or refractory follicular lymphoma. News release. Novartis; June 2, 2021.
Accessed June 19, 2021. https://www.novartis.com/news/media-releases/novartis-kymriah-
pivotal-trial-demonstrates-strong-response-rates-and-remarkable-safety-profile-relapsed-
or-refractory-follicular-lymphoma
3. Düll J, Maddocks KL, Gonzalez-Barca E, et al. Long-term analyses from L-MIND, a phase II
study of tafasitamab (MOR208) combined with lenalidomide (LEN) in patients with relapsed
or refractory diffuse large B-cell lymphoma (R/R DLBCL). J Clin Oncol. 2021;39(Suppl
15):abstr 7513. doi:10.1200/JCO.2021.39.15_suppl.7513
4. Incyte and MorphoSys announce three-year results from phase 2 L-MIND study of tafasitamab
in combination with lenalidomide for the treatment of relapsed or refractory DLBCL.
News release. BusinessWire; June 4, 2021. Accessed June 19, 2021.https://www.businesswire.
com/news/home/20210604005569/en/Incyte-and-MorphoSys-Announce-Three-Year-Results-
from-Phase-2-L-MIND-Study-of-Tafasitamab-in-Combination-with-Lenalidomide-forthe-
Treatment-of-Relapsed-or-Refractory-DLBCL

ASCO Clinical Spotlight: Christopher Arendt, PhD, on OPTIC Findings for Dose Optimization of Ponatinib in Patients With CP-CML

CHRISTOPHER ARENDT, PHD, head, Oncology Therapeutic Area Unit, Takeda, speaks on effi cacy
and safety findings of the OPTIC study examining dose optimization of ponatinib in patients with
chronic phase chronic myeloid leukemia (CP-CML) that is resistant to second-generation tyrosine
kinase inhibitor therapy.

Findings of the OPTIC study, which examined dose optimization of ponatinib in patients with chronic phase chronic myeloid leukemia (CP-CML), indicated that the highest dose of 45 mg achieved optimal results.¹ These were maintained after lowering the dosage, said Christopher
Arendt, PhD, head, Oncology Therapeutic Area Unit, Takeda.

EVIDENCE-BASED ONCOLOGY™ (EBO): What was the general rationale for the phase 2 OPTIC study? Why are patients taking third-generation tyrosine kinase inhibitors (TKIs) at risk for events such as thrombocytopenia?

ARENDT: This study involved ponatinib [Iclusig], an oral TKI that targets a specific genetic fusion. It’s a fusion of BCR and ABL1 that’s associated with some subtypes of CML, and also [with] Philadelphia chromosome–positive acute lymphoblastic leukemia.

[Ponatinib] was developed by computational- and structure-based drug design. What’s interesting is that it’s able to inhibit this lesion, but it’s also uniquely able to inhibit, in addition, a resistance mutation that develops in response to targeted therapies against BCR-ABL1. That mutation, known as T315I, identifies 1 specific amino acid change that renders these tumors ultimately resistant to the initial classes of targeted therapies against BCR-ABL.

So, [ponatinib] is called a third-generation inhibitor. It has this added virtue that it’s able to address that so-called gatekeeper mutation, or resistance mutation. There’s a bit of a misconception
when it comes to CP-CML that this is a “good” cancer to have, but in reality, there are certainly very resistant forms of disease, as well as intolerant forms of disease that develop, and these are associated with extremely poor outcomes.

Balancing [a drug’s] clinical efficacy with a safety profile is all about threading that needle, and threading that needle at the level of the dosing schedule. You want that dosing schedule to be just high enough to address the tumor growth, but not so high that there are unwanted [adverse] effects. And so, [ponatinib] was already an approved medicine in CP-CML, but it was relegated to the last line of therapy, which we felt was not optimal for patients who could benefit earlier.

What OPTIC sought to do was to optimize, essentially, the dose and schedule, so it evaluated [several] different doses. The study found that a starting dose of 45 mg was optimal. The patients were monitored for a clinical response by a blood test, and when that genetic lesion fell to
a nearly undetectable level—less than 1% in blood—the dose schedule was reduced to a third of that dose, 15 mg daily.

With this, the safety and efficacy profile was really optimized within the OPTIC study. The trial met its primary end point, and toward the end of last year, the FDA approved the [supplemental new drug application] for adult patients with CP-CML who had received 2 prior TKIs.²

This allowed [ponatinib] to move up to an earlier stage of treatment, and we believe that’s going to be very beneficial for patients—again, keeping in mind that resistance ultimately is a hallmark of the first- and second-generation TKIs in this particular treatment setting.

Thrombocytopenia [is a] potential [adverse] effect of this [drug] class, [but] the mechanistic basis for this is not fully clear. It’s thought to be potentially due to inhibiting some of the signal transduction pathways that [ponatinib] hits that are important in megakaryosites, which is in the same kind of myeloid lineage that ultimately we’re targeting in this particular disease setting.

EBO: How do the results presented at ASCO contribute to precision medicine in the treatment of CML?

ARENDT: Precision medicine is all about matching the right medicine to a patient who has an identifi able, if you will, kind of biomarker or genetic signature in that disease setting. What’s exciting around the OPTIC study data is that we now have the ability to tailor the treatment with this medicine to patients who can benefit, because they have that driver mutation that can be specifically identified to have become resistant to the other classes in this space. And again, that’s the T315I mutation. That’s a wonderful example of precision medicine being allowed for that very agile treatment with the appropriate medicine, instead of having to wait and test and allow a cancer to progress when it could benefit from having the right tailored therapy from the start.

Also, clearly, the fact that [ponatinib] moves up in the treatment schedule paradigm allows, we hope, to prevent the development of that particular lesion. To be able to still have that precision, genetic connection between the BCR-ABL1 lesion and offering a patient [ponatinib], and then following that patient with the expectation that the T315I mutation is going to be under a very strong selective pressure from this particular medicine. The hope would be that it doesn’t develop, and the hope would be that patients then can benefit for a longer duration of response.

EBO: What subgroup results are noteworthy?

ARENDT: We looked at different therapeutic doses in the OPTIC study, as I said, and it was all about being able to thread that needle in the best possible way for patient benefit: maximizing responses but ultimately minimizing any [potential] adverse events. So, the most interesting subgroup
is the one that received the highest dose that was tested in that study, initially—that was the 45-mg cohort. These patients had the best initial response and then sustained responses. They were dropped down to that 15-mg dose, maintained, and followed over the course of the study.

References

1. Cortes JE, Apperley J, Lomaia E, et al. OPTIC primary analysis: a dose-optimization study of 3 starting doses of ponatinib (PON). J Clin Oncol. 2021;39(Suppl 15):abstr 7000. doi:10.1200/JCO.2021.39.15_suppl.7000
2. U.S. FDA approves supplemental New Drug Application for Takeda’s Iclusig (ponatinib) for adult
patients with resistant or intolerant chronic-phase CML. News release. Takeda; December 18, 2020.
Accessed June 12, 2021. https://bit.ly/3xoBQDM