As a fan of Ruxandra Teslo’s writing — 25 mentions to date! — it pains me to write that her recent article in “Works in Progress”, for which she shares the byline with Open Evidence chief product officer Amol Punjabi, had me wince about a half-dozen times too many to ignore. Worse yet, I agree with the thrust of the article: that China is eating America’s lunch in cell and gene therapy and will soon come for the rest of biomedicine. Heck, that is one of the main reasons I am soon going back to clinical medicine, seeing too many business flights to Shanghai and Beijing time zone Zoom meetings in my future [Note: In case you were wondering, the correct number of each for me personally is exactly zero. ] had I continued down the industry path.
Alas, Teslo, Punjabi and whichever LLM did their research had cut too many corners on the way to the largely appropriate destination. Let’s count a few of them.
The old, cheap generic chemotherapy drugs still rock. A combination of two or three chemotherapy drugs developed in the 1970s and 80s is still the gold standard for treating testicular cancer. Chemotherapy has tamed what was once a pancreatic cancer-level death sentence into a diagnosis that doesn’t even have a “stage IV”. Speaking of pancreatic cancer: daraxonrasib, the K-Ras inhibitor which Teslo just a few weeks ago deemed a turning point, [Note: That article was, however, still of much higher quality than the one discussed here. Or maybe I don’t know as much about K-Ras and pancreatic cancer as I do about CAR T-cells and myeloma. Could this be a case of reverse Gell-Mann amnesia on my end? ] doesn’t even come close to what bleomycin, etoposide and cisplatin did for testicular. I guess they don’t make turning points like they used to.
The transformation of oncology started long before mid-2010s. The article paints a simplistic picture of oncology’s history. First there was surgery, followed by, in the 1890s and the discovery of X-rays, radiation therapy. Blunt and unsophisticated chemotherapy which relies purely on the cancer cells’ propensity to divide faster than non-cancer cells came in the 1940s and 1950s. Finally, in the mid-2010s, after we learned more about the molecular biology of cancer [Note: I guess that, if you wanted to show off your academic status, you should use a 10-dollar word like “underpinnings” here instead of the plain, grade school level “biology”, much in the same way you should find and replace every “use” with “utilize”. But that would, of course, make you a 10-dollar ass. ] came “immunotherapies” by which the article largely means CAR T-cell therapies in general and one in particular, ciltacabtagene autoleucel, known to friends as cilta-cel (generic name) or Carvykti (brand name and the one used throughout the essay; this is telling).
Look, I am no fan of Siddharta Mukherjee’s but at least his history of cancer, The Emperor of All Maladies got the sequence right. Rituximab, a monoclonal antibody which some still consider the original immunotherapy — after all, it acts mainly by siccing patients’ own immune cells and complement towards the target lymphoma and leukemia cells — was approved in 1997 after a Phase 1 trial that started in 1994. Trastuzumab, another monoclonal, was approved for Her2-positive breast cancer in 1998. Imatinib, a revolutionary wonder-drug which inspired dozens of me-too small molecule competitors, had its first-in-human study in 1998 and was approved just three years later, in 2001. Each needed just 3 years to get from the very first patient being dosed to FDA approval; remember that factoid it may become relevant in a few paragraphs. These were actual cures for lethal, aggressive cancers. But if the narrative is that China has accelerated the development of the first true advancement in cancer cures since the advent of chemotherapy let’s just pretend they don’t exist.
Myeloma treatment is not as brutal as painted. Although, of course, everything is in the eyes of the beholder, or rather the mind of the patient having to suffer through it. I do take issue with all three of the specific side effects that the essay highlights, as well as the time burden of myeloma is described. To wit:
Patients come in and out of the clinic for injections, take pills at home and undergo repeated blood tests, living according to a calendar organized around treatment days and recovery days. They also have to contend with the side effects of the medications. Dexamethasone can produce a sleepless agitation followed by a physical and emotional crash. Bortezomib often damages peripheral nerves, causing tingling and a burning pain in the hands. Daratumumab often leads to immune suppression, leaving patients more vulnerable to infections.
Dexamethasone is given in bursts and, thanks to the decidedly non-industry funded trials led by S. Vincent Rajkumar, at a much lower dose than before, minimizing these sorts of side effects. Similarly, bortezomib is now given less frequently and in different ways (under the skin instead of intravenously) to minimize nerve damage. And if you think immunosuppression is bad with daratumumab, well, try wiping out every antibody-producing cell in your body then waiting until you can get all of them back, and yes that includes needing to receive all your childhood vaccines again.
Separately, repeated blood tests are a sine qua non of multiple myeloma management, or really of any cancer management, even after a “cure”. If we aren’t monitoring for recurrence of the primary disease we are fussing over other cancers which may or may not be the result of the treatment itself, or of a person’s general propensity to have cancer. [Note: In fact, two biggest risk factors for having cancer, other than a genetic mutation/hereditary syndrome, are age and prior personal history of cancer. ] And yes, that goes even for patients whose CAR-T treatment leads to durable complete remissions. Especially with CAR-T treatments which are known to cause cancer.
Speaking of which, cilta-cel/Carvykti is not a walk in the park either. Cytokine release syndrome (CRS) and Immune effector cell-associated neurotoxicity syndrome (ICANS) are two particularly nice side effects of all conventional CAR-T therapies, Carvykti included. They are frequent and severe enough that most patients need to be treated in the hospital and be within driving distance for the next four weeks. Many end up being admitted to the critical care unit. CAR-Ts that target BCMA, like Carvykti, also cause profound immunosuppression (vide supra) and require patients to repeat their childhood vaccination series. Carvykti, however, is in a league of its own as on top of all that it can also cause Parkinsonism. This is not to throw shade at CAR-Ts, they truly are revolutionary. But let’s not condemn other myeloma treatments for their toxicity when the alternative is worse in some ways, about the same in others.
BCMA CAR-Ts are, for most patients with multiple myeloma, not a cure. The essay cites 12-month results of the CARTITUDE-1 trial, where 76% of participants who received the cells [Note: But not including those enrolled to the trial who never got them, whether because they couldn’t be made, they were too sick to get them, or just plain died. This is how you play the denominator game. ] had no signs of myeloma at 12 months. Quote:
But what happened afterwards is perhaps even more striking: in the Abecma progression free survival curve, the line falls continuously. By contrast, in Carvykti, the line starts to plateau. Extended follow-up at five years confirmed that 33 percent of Carvykti patients remained disease-free.
This is false: there is no plateau. Figure 2 of the NEJM article describing these results has some numbers at the bottom not included in the Works in Progress essay. These represent the “number at risk” — participants who were still available for follow-up at a given time point; others have either progressed, resulting in an unwanted “drop” in the curve, or have not yet been followed for that long [Note: There are actually more reason for a participant to be marked as a “tick” without dropping the line, i.e. to be “censored”, some more nefarious than others. For a good primer on this “informative censoring” see, for example, this article ] and are marked with a triangle here though more commonly they are merely a tick. The “plateau” is an artifact of too few participants getting to 24 months, only 9. It completely disappears in extended follow-up, with the curve continuing its descent at and past 24 months in Figure 2A, all the way to 60 months where a cluster of vertical tick marks precedes yet another mirage of a plateau, again with only a handful of patients being at risk. Let’s pray it ain’t so but I suspect that, if we were to continue following these participants to 10 years, the curve will continue going down and down and down.
You could make the same story about artefact plateaus about daratumumab as well. It, too, has been pushed up all the way to first-line treatment and even before overt disease; concerns about longer follow-up needed for what is usually a slow-burning disease remain. Compare and contrast to imatinib in CML in this recent essay from Vinay Prasad, who concludes with:
There is progress in both diseases but more in CML. CML is more clearly a success story. There is much room for progress in myeloma. Myeloma is not yet curative, sadly. Presenting survival over time is misleading and masks more complicated narratives.
Carvykti’s approval timeline was not gobsmackingly fast. Most misleading is the side-to-side comparison of the Chinese cilta-cel and its American predecessor, ide-cel development pathway. Ide-cel includes the development of CAR T-cells in general (1989–2012) and the first BCMA targeting proof-of-concept (2013). Cilta-cel emerged from Zeus’s head in 2014, like it didn’t require both CAR-Ts to be developed and BCMA to be validated as a target. The tag line of the figure is that “China’s BCMA CAR-T reached FDA approval just 11 months after the US, despite starting decades later.” Hogwash.
Note the development timelines: ide-cel’s first-in-human study started in 2014. [Note: I should know: I was there! Funnily enough I was the in-house fellow on call on the days when two of the first 3 participants received their cells and had the honor of escorting them to the intensive care unit that very night. Both had both their myeloma and all of bone marrow wiped out in the process. ] It received FDA approval in 2021, for a total of 7 years of clinical trials. Cilta-cel’s first-in-human was in 2016 with a 2022 approval; 6 years. Let’s finish up our mini-mental test: how long did it take for the FDA to approve rituximab, trastuzumab and imatinib, from the first patient dosed?
These are only the highlights, but going much deeper would be nitpicking. I don’t know whether this amount of laxity with the truth was intentional, but the essay is almost as misleading as a Seattle lady’s GPS, taking her straight onto light rail tracks. Once there, you can only go in two directions: forward, towards loosening up regulations to match China’s Wild West, or backwards, tightening up regulator requirements for Chinese assets and trials and punishing companies for doing business there. [Note: See how I ties going “forward” with less regulation and “backward” with more. This can easily be flipped to portray less regulation as going backwards, but I leave doing that in full as a fun exercise for you, dear Reader. ] What happened to going sideways? Diagonally? Up or down? What if it the time to approve revolutionary cancer treatments has doubled because the follow-ups aren’t as revolutionary? And then get drowned out further by the me-toos and the ghost drugs which make much better competitors in the biotech beauty pageant, where whom you know and where you came from is more important than the increasingly pliant, malleable and quicksand-appearing ground truth?
But sure. China.