Kymriah’s label throws lymphoma potential into doubt

With Kymriah’s US lymphoma approval in the bag as of yesterday the CAR-T market has its first head-to-head battle. The green light – the second for the Novartis therapy – pits it directly against Gilead’s Yescarta, approved for lymphoma last October, and thanks to the US labels doctors now have the basis for a like-for-like comparison.

Unfortunately for Novartis, the numbers make for worrying reading; for one thing, Kymriah’s label shows remission rates to be lower than those for Yescarta. And prescribers have been given a headscratcher by the FDA seeing it fit to exclude 58% of all-comers in its calculation of Kymriah’s efficacy (see tables below).

The problem that many Kymriah patients never get to be infused with CAR-T cells was first highlighted when results of Juliet, Novartis’s pivotal lymphoma trial, were presented last June (ICML – Novartis’s non-infusion mystery centres on Juliet’s design, June 14, 2017).

The product’s updated US label throws this into sharp relief: 160 subjects were enrolled into Juliet, of whom 19 were to have had product manufactured ex-US. Of the remaining 141 subjects relevant to the US label, 49 did not receive CAR-T cells, and a further 24 are excluded largely because it could not be determined whether they actually had diffuse large B-cell lymphoma.

The falloff is also evident in the existing Yescarta label, but is nowhere near as stark.

Parsing the pivotal lymphoma data for commercial CAR-T therapies
Yescarta, Gilead Kymriah, Novartis
Patients in ITT population 111 160
   Manufactured ex-US (0) (19)
   Not infused (manufacturing failure) (1) (11)
   Not infused (subject died) (0) (16)
   Not infused (physician decision) (2) (16)
   Not infused (adverse events) (7) (3)
   Other reason for non-infusion (0) (3)
Patients who received US-manufactured cells 101 92
   No evidence of disease at baseline (0) (8)
   No baseline imaging after bridging chemo (0) (15)
   Disease misclassification (0) (1)
Patient number used for efficacy calculation 101 68
Source: US product labels.

For Novartis two issues will be especially problematic: the fact that there were 11 US manufacturing failures – versus one for Yescarta – and that 32 subjects either died or had consent revoked before infusion (nine Yescarta subjects had adverse events or progressive disease that prevented cell infusion).

Differences in commercial manufacturing have clearly emerged. A relatively long time between apheresis and reinfusion opens up a window in which Kymriah patients risk suffering disease progression.

Novartis attempts to minimise this risk with bridging chemotherapy, though this raises its own problems in terms of ascertaining the reason behind a subsequent benefit. In Juliet 90% of the 92 US subjects who received Kymriah were bridged.

What’s the efficacy?

All this makes it difficult to figure out the precise efficacy of CAR-T therapy, but the US labels for Yescarta and Kymriah, compiled independently by the FDA, make a direct comparison possible for the first time.

A straight reading of the data shows the Novartis therapy as being less effective than Yescarta, with a 50% overall response rate, versus Gilead’s 72%. Median durations of response cannot yet be compared as the Kymriah data are insufficiently mature.

Kymriah head to head vs Yescarta in lymphoma
Yescarta, Gilead Kymriah, Novartis
Best ORR reported at Ash 2017 82% (101) 53% (81)
ORR per US label 72% (101) 50% (68)
Best CR reported at Ash 2017 54% (101) 40% (81)
CR per US label 51% (101) 32% (68)
Note: numbers in brackets refer to total subjects considered in each given cohort; efficacy declines in the label relative to Ash are largely due to the FDA's stricter remission criteria; ORR=overall remission rate; CR=complete remission.

But the FDA’s surprising decision to exclude over half of the Juliet subjects from its efficacy calculation muddies the waters further. A strict reading of the data might have considered all 141 recruited US subjects as the denominator, yielding overall remission of just 23%.

This is not the kind of conclusion Novartis will want prescribers to draw. It told EP Vantage that patients benefited from having different treatment options, and insisted that differing study designs and patient populations made head-to-head comparisons impossible.

Kymriah has barely made a mark in its first approved indication, childhood leukaemia, registering first-quarter sales of $12m. EvaluatePharma’s sellside consensus sees 2024 sales across all uses of $1.2bn. The lymphoma launch has set up an unusual cost dichotomy, with Kymriah reportedly being priced on a par with Yescarta’s $373,000 per patient – versus its $475,000 outcomes-based price tag in leukaemia.

Gilead yesterday said first-quarter Yescarta sales came in at $40m, suggesting the bigger potential of lymphoma, but also showing how much there is still to do: Yescarta 2024 consensus sits at a no less daunting $1.3bn. Attention will soon turn to Celgene’s JCAR017, due to be filed for lymphoma in the second half on the strength of the pivotal cohort of the Transcend study.

And Gilead has problems of its own too. Its stock fell 5% on a disastrous first quarter, in which sales and net profits fell 22% and 43% respectively. The previous explanation that the available pool of hepatitis C patients is dwindling thanks to Gilead’s curative drugs has been dispelled by $850m first-quarter sales of Abbvie’s hep C doublet Mavyret.

Clearly Yescarta alone cannot make up the shortfall, but for now it looks set to benefit from Kymriah’s own goal.

To contact the writer of this story email Jacob Plieth in London at [email protected] or follow @JacobPlieth on Twitter

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