Bruce D. Cheson, MD, FACP, FAAAS, FASCO
Some monuments are difficult to topple. At least that was the case dating back to 1976, when investigators from the Southwest Oncology Group demonstrated the importance of doxorubicin in the treatment of patients with a group of lymphoid malignancies then referred to as diffuse aggressive lymphomas. Thus, the legend of CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) was born.
For decades, CHOP defended itself from numerous onslaughts, as one chemotherapy acronym was compared with another (and with CHOP), to no advantage, yet with greater expense and toxicity. It wasn’t until
another quarter-century passed, and the outcome of patients with what was now called diffuse large B-cell lymphoma (DLBCL) was finally improved—not by more chemotherapy, but by a chimeric monoclonal antibody, rituximab. R-CHOP was established as the new standard; yet, once again the field remained stagnant for almost 2 decades.
Eventually, interest in chemotherapeutic agents waned and gave way to therapies that targeted the biology and immunology of the lymphoma cells; some directed at the cell surface, others inhibiting internal pathways, and still more affecting the microenvironment. While some of the new approaches were lymphodepleting, others restored and enhanced the patient’s ineffective immune response.
The first of the new wave of targeted agents including obinutuzumab, lenalidomide, enzastaurin, everolimus, ibrutinib, and bortezomib demonstrated only modest activity in relapsed and refractory DLBCL, yet upfront they went. At that point, they failed the “Christmas tree test”: R-CHOP, representing the holiday evergreen, was adorned with each of these new ornaments. However, they all failed to generate even a twinkle.
Second Wave of Therapies
New drugs for DLBCL long lagged behind other histologies. Now all at once, it would seem, we are in the midst of a second and far more promising wave of drugs with a variety of mechanisms of action. The first therapy to receive U.S. Food and Drug Administration (FDA) accelerated approval for relapsed or refractory DLBCL combined the anti-CD79b antibody-drug conjugate polatuzumab vedotin with the aging couplet of bendamustine and rituximab (pola-BR) for patients who had received at least two prior regimens (in the United States, one prior regimen in Europe).1
In a randomized trial with 40 patients per arm, the overall response rate for pola-BR was 45%, with 40% complete remissions, compared with 34% and 17%, respectively, for BR alone. The progression-free survival was 9.5 vs 3.7 months—also superior with pola-BR, yielding a hazard ratio of 0.36 (95% confidence interval [CI] = 0.21–0.63; P < .001). Whether bendamustine actually contributes to this efficacy is unresolved. Pola-BR was associated with greater hematologic toxicity, and a 43% risk of peripheral neuropathy, which was mostly grade 1 or 2 and generally reversible. The results of the completed POLARIX trial in newly diagnosed patients with DLBCL, comparing R-CHOP with R-CHP plus polatuzumab, will hopefully demonstrate an improved outcome with insertion of the immunologic agent.
Another of the antibody-drug conjugates in development is loncastuximab tesirine, which targets CD19. The objective response rate with this agent in a phase II trial was similar to pola-BR at 45%, with 20% complete responses; the toxicity profile is described as manageable. The biologics license application submission to the FDA is anticipated later this year.
Promising data have also been generated with bispecific T-cell engagers (eg, blinatumomab, REGN1979, mosunetuzumab). Monoclonal antibodies targeting checkpoints such as PD-1 and PD-L1 have not yet found their place in the treatment of DLBCL. However, other novel antibodies directed at the innate immune system, including the CD47-SIRPα (“don’t eat me”) signaling pathway, have shown promise in preliminary studies.2
Selinexor
On June 22, 2020, accelerated approval was granted to selinexor for DLBCL that is progressing after at least two prior regimens.3 Selinexor is an oral inhibitor of exportin-1 (XPO1), the major nuclear export protein for a number of tumor-suppressor proteins and proto-oncogenes from the nucleus to the cytoplasm. Inhibition of XPO1 by selinexor reactivates tumor-suppressor proteins and blocks proto-oncogene translation and DNA damage repair.
The single-arm, pivotal SADAL trial of selinexor accrued 134 patients with relapsed or refractory DLBCL that had progressed following a median of two prior regimens. Adverse events using the newer 60-mg twice-weekly dosing schedule were mostly grade 1 or 2 and manageable with appropriate supportive care, including double antiemetics. Whereas the response rate of 29%, with 12% complete responses, was modest, the impressive median duration of response of 9.3 months and 23 months for the complete responders, the novel mechanism of action, and the ease of administration make this drug an excellent candidate for combination strategies.
Tafasitamab Plus Lenalidomide
The next most likely FDA approval in this setting will be in the summer of 2020, for the combination of tafasitamab and lenalidomide, which has already received Breakthrough Therapy designation.4 Tafasitamab is an anti-CD19 monoclonal antibody with enhanced antibody-dependent cellular toxicity (ADCC); antibody-dependent cellular phagocytosis (ADCP); and direct cell kill, which theoretically should benefit from combination with a drug, such as lenalidomide, that activates NK cells.
“Now all at once, it would seem, we are in the midst of a second and far more promising wave of drugs with a variety of mechanisms of action.”— Bruce D. Cheson, MD, FACP, FAAAS, FASCO
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And that possibility appears to hold true in the clinic. In the phase II L-MIND trial, the combination of tafasitamab and lenalidomide achieved a response rate of 60%, with 43% complete responses, which appear superior to results achieved with either tafasitamab or lenalidomide alone. The median number of prior therapies was two, although 49% of the patients had received only a single prior regimen, and those with primary refractory disease were excluded from the study. Nonetheless, patients were considered to be at high risk and not suitable candidates for autologous stem cell transplant, mostly because of age and comorbidities. The progression-free survival of 16.7 months, median duration of response of 21.7 months, and a median overall survival not yet reached can only be viewed as impressive. The phase III front-line FIRST-MIND study in development (tentatively tafasitamab/lenalidomide/R-CHOP vs R-CHOP) will hopefully provide another incremental improvement in survival.
CAR T-Cell Therapy
Chimeric antigen receptor (CAR) T-cell therapy has captured the spotlight and stimulated the imagination of hematologists/oncologists and patients alike. Axicabtagene ciloleucel and tisagenlecleucel achieve high response rates and durable complete remissions in relapsed or refractory DLBCL, providing the foundation for a new era of research and therapy.5 However, at present, CAR T-cell therapy is FDA-approved only for third-line therapy of this disease and beyond, and its use is limited by the restricted, albeit increasing, availability, eligibility criteria, toxicities, and expense. Management of the adverse effects is improving, and different platforms may be associated with fewer adverse effects (eg, lisocabtagene maraleucel).
Recent data, including those presented at the ASCO20 Virtual Scientific Program, suggest that approaches such as allogeneic CAR T cells may allow for more widespread availability. Studies such as ZUMA-7, in which autologous stem cell transplantation is being compared head to head with axicabtagene ciloleucel in the second-line treatment of DLBCL, will hopefully determine their relative positions in the paradigm of second-line therapy for patients with relapsed or refractory DLBCL.
Looking Ahead
Given that the vast majority of patients with relapsed or refractory DLBCL are either not suitable candidates for, do not have access to, or have disease progression following cellular therapy, the continued development of targeted options is critical. In the near term, attention will be appropriately focused on the relative virtues and challenges of new agents; identifying which patients are most likely to benefit from their use, and in what order to sequence them. Bringing promising combinations to the front line will be necessary to achieve an increased number of complete remissions, which is required, but not necessarily sufficient, for increasing the rate of cure. Hopefully, merely tacking them onto CHOP will not condemn us to repeat history; to prevent this possibility, clinical trial designs deviating from the norm should be considered.
Important progress has been made in our understanding of the biology and immunology of the group of diseases now included within DLBCL, and now there is an expanding list of active, targeted options. Unfortunately, the development of future therapeutic strategies will remain empiric until such time as biomarkers are identified with which to direct therapeutic decisions. The integration of molecular, genetic, and metabolic imaging studies is essential for clinical trials involving the rational assembly of drugs with various mechanisms of action and immunologic properties. Nonetheless, in the foreseeable future, chemotherapy may become merely a crumbling relic in the rear-view mirror, as lymphoma continues its inexorable journey down the road to a chemotherapy-free world.
DISCLOSURE: Dr. Cheson has had a consultant or advisory role with AbbVie, Morphosys, Karyopharm, Kite, Epizyme, Roche-Genentech, Janssen, Pharmacyclics, Astra Zeneca, Beigene, and Bristol Myers Squibb; and has received research funding from AbbVie, Roche-Genentech, Trillium, TG Therapeutics, Pharmacyclics, AstraZeneca, and Epizyme.
REFERENCES
1. Sehn LH, Herrera AF, Flowers CR, et al: Polatuzumab vedotin in relapsed or refractory diffuse large b-cell lymphoma. J Clin Oncol 38:155-165, 2020.
2. Advani R, Flinn I, Popplewell L, et al: CD47 blockade by Hu5F9-G4 and rituximab in non-Hodgkin’s lymphoma. N Engl J Med 379:1711-1721, 2018.
3. Kalakonda N, Maerevoet M, Cavallo F, et al: Selinexor in patients with relapsed or refractory diffuse large B-cell lymphoma (SADAL): A single-arm, multinational, multicentre, open-label, phase 2 trial. Lancet Haematol 7:e511-e522, 2020.
4. Salles G, Duell J, González Barca E, et al: Tafasitamab plus lenalidomide in relapsed or refractory diffuse large B-cell lymphoma (L-MIND): A multicentre, prospective, single-arm, phase 2 study. Lancet Oncol 21:978-988, 2020.
5. Locke FL, Ghobadi A, Jacobson CA, et al: Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): A single-arm, multicentre, phase 1-2 trial. Lancet Oncol 20:31-42, 2019.
Dr. Cheson is Scientific Advisor for the Lymphoma Research Foundation.
Disclaimer: This commentary represents the views of the author and may not necessarily reflect the views of ASCO or The ASCO Post.
