Who’s driving the CARs in the race?
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I’m currently browsing the abstracts for the ASCO20 Virtual Scientific Program, which — of course — will be over by the time this editorial is published.
I’m sure it will have been a very different experience from normal at many levels but, as usual, there will be new data to generate excitement, skepticism and controversy — or varying proportions of all of the above.
As I previewed some presentations regarding chimeric antigen receptor T-cell therapy, it reminded me of an editorial I wrote for HemOnc Today immediately after the 2017 ASH Annual Meeting and Exposition.
At that time, results of the ZUMA-1 trial of axicabtagene ciloleucel (Yescarta; Kite Pharma, Gilead) — known as axi-cel — in relapsed/refractory aggressive B-cell lymphoma were emerging and were being compared with outcomes described in retrospective series, particularly the SCHOLAR-1 study.
The results looked promising. An 83% overall response rate and 58% complete response rate compared very favorably with historical series. Despite the excitement, I was skeptical of retrospective comparisons and early claims of victory.
Clearly, my skepticism was misplaced. As data have continued to emerge on the use of CD19-directed CARs, it is clear that many responses are ongoing, as 39% of patients remained in response after further follow-up of the ZUMA-1 trial and median OS had not been reached.
A ‘standard’ emerges
CAR T-cell therapies now are FDA-approved for relapsed aggressive B-cell lymphoma and data are beginning to emerge for patients treated as “standard of care.”
Results of a recently reported series of 298 patients, 43% of whom would not have met eligibility criteria for the ZUMA-1 trial, showed overall and complete response rates very similar to those in the phase 1 study (82% and 64%, respectively) and median PFS of 8.3 months, with median OS not yet reached. The toxicity was manageable and comparable to the original ZUMA-1 trial.
The authors appropriately do not label these results as real-world data. A patient population with a median age of 60 years, in which more than 80% have an ECOG performance status of 0 or 1, is still highly selected, but even someone as curmudgeonly as me can’t fail to be excited and impressed by these unprecedented outcomes in a challenging clinical situation.
Of course, the ultimate test of this approach will be through randomized trials. The ongoing ZUMA-7 trial hopefully will clarify the true impact of CAR-T for this patient population.
There has been a major expansion in the use of CAR T cells and the number of available products — as well as new approvals, indications and clinical trials — since that time.
ASCO studies
Although ASCO Annual Meeting is typically quiet from a hematologic malignancies perspective, this year’s conference does include some new information to add to the burgeoning data on this approach.
Not surprisingly, there has been intense interest in the use of CAR-T for indolent B-cell lymphomas and chronic lymphocytic leukemia.
One presentation featured results of the ZUMA-5 trial of axi-cel for patients with relapsed/refractory low-grade follicular lymphoma and marginal zone lymphoma. Patients in this study had received a median three prior lines of therapy, and two-thirds had developed progressive disease within 2 years of anti-CD20 monoclonal antibody-based therapy — a recognized poor prognostic feature.
Researchers reported a 93% ORR and 80% complete response rate, and the median response duration was more than 20 months. Median OS had not been reached and the safety profile was very similar to that reported for aggressive B-cell lymphomas.
Patients with relapsed and refractory multiple myeloma — particularly those with penta-refractory disease — represent a very challenging patient population for which there is intense interest in the use of CAR T cells.
This year, ASCO featured studies of three different CAR T-cell products, all directed against B-cell maturation antigen (BCMA) and all with broadly similar and somewhat promising results — again, in selected patient groups.
ORRs ranged from 70% to 100%, with an apparent association between response and CAR T-cell dose. Toxicities varied slightly between the products and generally were consistent with what is reported in B-cell lymphomas. Overall, the impression is that there are interesting efficacy signals in these studies that will require further follow-up and confirmation.
In the driver’s seat
These results and many others show how quickly CAR T-cell therapy is advancing, both from a trial perspective and as a recognized standard of care for some patients.
As new off-the-shelf CAR-Ts become more widely available and solid tumor indications emerge, this trend likely will accelerate. All of this progress continues against a backdrop of uncertainty over the future direction and sustainability of these and other cellular and immune strategies for cancer treatment.
Although we all would like to believe that the main stimulus for development is therapeutic benefit and improved patient outcomes and experience, there are many other drivers that influence how these treatments are being used.
Coverage decisions are undoubtedly a factor in the move toward outpatient CAR T-cell therapy. Current CMS coverage decisions leave most institutions at significant financial risk using inpatient treatments, and this is likely driving the trend — albeit a favorable one — to outpatient use.
Competition in the “race” to the optimal cellular constructs also is a potential driver of the direction of clinical research in cell therapy.
The three myeloma trials featured at ASCO use three different products, all directed toward BCMA. A brief review of clinicaltrials.gov shows 11 trials of BCMA-directed CAR T cells for relapsed and refractory myeloma that are actively recruiting. A similar number of CD19-directed trials are open for patients with low-grade follicular lymphoma.
Although there are potential differences between these products, this situation seems analogous to that which exists for trials of checkpoint inhibitors — multiple “me too” agents are recruiting small numbers of patients into small trials that may fail to reach accrual targets. There is a risk that the need for academic recognition of investigators and return on investment for industry sponsors overrides the need for structured and systematic evaluation of these amazing new interventions.
As we return from the virtual world of this year’s ASCO to the real world — if we can use that term in the COVID-19 environment — we need to make sure we are in the driver’s seat in leading development.
This is especially true during the current pandemic, where we are beginning to see sponsors pushing for reintroduction of in-person visits — a judgement call that needs to be made by a treating physician who is in the best position to balance the risks and benefits.
This is also true of the longer-term strategy. Evaluating the big-picture benefit of cellular therapies for cancer requires us, as clinicians and clinical investigators, to be mindful of the extent to which these treatments are safe, effective, applicable, affordable and sustainable, and to drive the research and implementation agenda.
References:
Crump M, et al. Blood. 2017;doi:10.1182/blood-2017-03-769620.
Nastoupil LJ, et al. J Clin Oncol. 2020;doi:10.1200/JCO.19.02104.
Neelapu SS, et al. N Engl J Med. 2017;doi:10.1056/NEJMoa1707447.
The following were presented at the ASCO20 Virtual Scientific Program; May 29-31, 2020.
Berdeja JG, et al. Abstract 8505.
Jacobson CA, et al. Abstract 8008.
Mailankody S, et al. Abstract 8504.
Munshi NC, et al. Abstract 8503.
For more information:
John Sweetenham, MD, FRCP, FACP, is HemOnc Today’s Chief Medical Editor for Hematology. He also is associate director for clinical affairs at Harold C. Simmons Comprehensive Cancer Center at UT Southwestern Medical Center. He can be reached at john.sweetenham@utsouthwestern.edu.
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