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Putting the CAR Ts before the horse
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“In a fine frenzy rolling...”
– from A Midsummer Night’s Dream
by William Shakespeare
The volume of news emails reaching our inboxes every morning sometimes seems ridiculous.
The daily flood of sponsored and nonsponsored content often reports the same studies, new FDA approvals, latest meetings and so on with such a degree of redundancy that the messages become background noise. The title of an article must be pretty provocative or intriguing to catch my attention and cause me to hesitate before clicking on delete.
It happened to me a couple of days ago — the headline implied that chimeric antigen receptor (CAR) T-cell therapy is much more effective than standard therapy for the treatment of relapsed aggressive lymphoma — I’m not quoting verbatim; the actual headline was more “punchy” than that, but left you with no doubt that the standard of care is about to change. For once, I was hooked and just had to read on.
It turns out this wasn’t really news at all, although you might think so from some of the language used in the article. The basis of the piece was a presentation by Sattva Neelapu, MD, at the European Society for Medical Oncology Congress that compared results of the ZUMA-1 trial of axicabtagene ciloleucel (Yescarta, Kite Pharma/Gilead Sciences; see page 31) with the results of SCHOLAR-1, a recent multicenter analysis of outcomes for patients with relapsed/refractory diffuse large B-cell lymphoma.
I intend no criticism of this study — it is a reasonable attempt, in the absence of a randomized prospective trial, to compare the truly remarkable early results of CAR T-cell therapy with the long and disappointing experience with conventional therapies in this challenging clinical situation.
Misleading representation
There is no doubt that axicabtagene ciloleucel is an exciting and potentially paradigm-changing treatment in this disease, but the language of this article suggests much more.
For example, the article states that patients receiving axicabtagene ciloleucel had “an almost eightfold higher chance of responding, and a 10-fold higher chance of achieving a [complete response] over existing therapies in the SCHOLAR-1 trial, as well as a decreased risk [for] death of 77% compared [with] current standards.”
This is troubling at several levels.
SCHOLAR-1 was not a trial — it was a well-conducted, pooled retrospective analysis from several groups confirming the terrible prognosis in this patient population. Whether intentional or not, describing this as a trial misrepresents it in a way that some might think is favorable to CAR T-cell therapy.
Maybe more disturbing is the observation that the language used regarding the comparisons gives the strong impression of a comparative trial. In reality, the analysis, however carefully conducted, used historical controls — however well matched the populations may be, the selection bias is still a factor. A quick look at the patient characteristics shows that 20% of the SCHOLAR-1 patients had primary refractory disease compared with only 2% in the ZUMA-1 trial. I have previously commented on “spin” in peer-reviewed publications, but this goes beyond that. It may represent overstretching the conclusion of a nice study, careless editing or something else but, whatever the motivation, it has the potential to be misleading to those who do not know this field of study and who do not have the time to look at the original literature.
It’s no surprise that CAR T-cell therapy is generating this kind of attention. The preliminary results in lymphoid malignancy have been extraordinary, and there is no doubt of the potential benefit this may bring. That said, we need to place the current excitement and hype in context — it’s a little early to be claiming victory, when data are so immature and the future feasibility and applicability to the general population with aggressive lymphoma is so unclear.
Joining the stampede
I am just on my way home from the ASH Annual Meeting and Exposition in Atlanta, where CAR T cells remain one of the hot topics.
Samuel M. Silver, MD, PhD, a HemOnc Today Editorial Board Member, chaired a special session at ASH — arranged at quite late notice — to discuss some aspects of CAR T-cell therapy. Although I didn’t make the session, I am told that the attendance was huge — this fact alone demonstrates how much excitement the early data have produced. There are plenty of other examples of that excitement, from patients who now regularly ask me about CAR T cells, to extensive promotional materials, powerful marketing by some centers with CAR T-cell trials, and the increasing pressure other centers are feeling because of the risk for being “left behind” without a CAR T-cell program.
Like many other centers, we are now close to making this therapy available to our patients, adding to the 13 or 14 centers in the United States that have open protocols. Many of our faculty have advocated strongly for us to get started and we will do so, like many others, with an unclear picture of how this will all play out.
In addition to the lack of good comparative data to confirm the effectiveness of this approach, there are open questions around toxicity management, reimbursement, coding of the procedure, regulatory aspects of CAR T-cell processing, financial liability for patients (on or off trial), and durability of responses unless the patients go on to receive a stem cell transplant. None of these concerns should stop the active investigation of CAR T cells, but they should make us think carefully about whether the current “fine frenzy” of activity should give way to a more thoughtful strategy.
Like some of you, I am old enough to remember the rush to autologous stem cell transplantation for breast cancer in the 1990s. I can’t help seeing some parallels — the rapid acceptance of preliminary phase 2 data and the high patient demand, long before definitive trials were done. There was a sense that a breast cancer transplant program was an important metric of credibility for a cancer center — if you didn’t have a program, you had been left behind. Of course, we now know how that story unfolded once well-conducted studies were reported.
I am not suggesting that CAR T-cell therapy will suffer the same fate, and I am truly convinced it will be game changing for some of our patients — although exactly how many is not clear. But, before we all join the stampede to get our CAR T programs going, we might want to learn some lessons from the breast cancer experience.
Handling the hype
This treatment is going to burden our health care system and our patients with enormous costs.
Given the plans of industry for developing new facilities to meet the rising demands for T-cell processing, it’s difficult to see an early prospect of this becoming less expensive. Further, the enormous costs to our patients are not only financial; the toxicities are major and the late effects of this intervention are unknown. We are at risk of losing our judgement — and our shirts — in the rush to establish this unproven treatment. Additionally, the companies in this space seem to have seized the initiative over how and where this therapy is developed — those in the field will need to decide if that’s the best approach.
What is certain is that we need to advocate for a clear research strategy to understand and realize the potential of this therapy; dialogue with regulatory authorities; negotiate with payers to understand the financial implications for health care systems, patients and the country; and complete long-term follow-up and (despite the challenges) prospective trials with relevant survival, economic and patient-reported endpoints.
If that doesn’t happen, there is a risk that programs will be built, careers will be at risk, huge resources will be used up and, in the final analysis, the effects will be less than anticipated and the whole thing will implode.
That seems unlikely given the early promise, but it’s happened before. We need to discourage rather than promote the hype, and make sure we understand what we can achieve with this promising therapy.
References:
Neelapu S, et al. Abstract 1161P. Presented at: ESMO Congress; Sept. 8-12, 2017; Madrid.
Neelapu S, et al. N Engl J Med. 2017;doi:10.1056/NEJMoa1707447.
Crump M, et al. Blood. 2017;doi:10.1182/blood-2017-03-769620.
For more information:
John Sweetenham, MD, FRCP, FACP, is HemOnc Today’s Chief Medical Editor for Hematology. He also is senior director of clinical affairs and executive medical director of Huntsman Cancer Institute at University of Utah. He can be reached at john.sweetenham@hci.utah.edu.
Disclosure: Sweetenham reports no relevant financial disclosures.