The Medical Services Advisory Committee (MSAC) has rejected an application to fund the potentially life saving CAR T-cell therapy, tisagenlecleucel, for patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL).

The ruling is a blow for the costly treatment, which was anticipated to be in more widespread use after it gained Therapeutic Goods Administration (TGA) approval in December 2018 – the first of its kind – for use in paediatric and young adult patients with B-cell precursor acute lymphoblastic leukaemia (ALL) and adult patients with DLBCL who have failed other treatments.

The TGA approval was based on two global clinical trials ELIANA and JULIET that showed an incredible 62% relapse-free survival rate at 24 months in paediatric ALL patients and a 43% probability of overall survival at 18 months in adult DLBCL patients.

Hailed as ‘revolutionary’ the CAR T-cell therapy is currently being jointly funded by the Commonwealth and the States under the National Health Reform Arrangements (NHRA) for use in relapsed and refractory acute lymphoblastic leukaemia in children and young adults aged up to 25 years.

But attempts by drug company Novartis to secure subsidised treatment for DLBCL patients have been shelved while the government questions the pharmaceutical giant about its effectiveness data and patient number estimates in the DLBCL setting.

The government committee considered the application at its August 2019 meeting.

A report from the meeting revealed the Committee was sceptical in its assessment of the size and durability of the widely touted treatment benefits.

Arguing that the evidence for tisagenlecleucel in refractory DLBCL is not as promising as was seen for the paediatric acute lymphoblastic leukemia (pALL) population, MSAC members noted the proportion of patients alive at 12 months post infusion was 40% versus 71% for the pALL patients, according to the submission documents.

It also questioned the huge price tag attached to the treatment – patients will need to pay up to $600,000 for the unsubsidised drug. Noting that the therapy can be ‘very toxic’ the Committee also suggested that adverse effects of the treatment could add to the already exorbitant costs.

And while MSAC accepted that tisagenlecleucel has been shown to be ‘clinically effective in some patients’ and have overall benefit compared with the salvage chemotherapy regimen in the JULIET trial, the committee pointed out that the evidence of benefit comes from a single arm trial in which the overall duration of follow-up remains short and the number of patients small.

Among 165 patients eligible to enrol in the JULIET study, around one-third did not go on to receive treatment with tisagenlecleucel. This included 16 patients who died between enrolment and infusion, and a further 16 who had their treating physician decide against further participation between enrolment and infusion, the Committee said.

In its summary document, MSAC argues that ‘more work’ is needed to identify the patients most likely to benefit from the treatment – especially because it is yet to be formally compared head-to-head with any of the current standards of care.

Professor Miles Prince, Director of Molecular Oncology and Cancer Immunology at Epworth Healthcare, told the limbic that while the MSAC outcome is disappointing it is not surprising.

“There was very little data presented to MSAC on the various expected outcomes of people with refractory diffuse large B-cell lymphoma. Some patients can have high dose therapy with autologous stem cell transplant (AuSCT) and potentially be cured while other patients who are not eligible for AuSCT are virtually incurable,” he said.

Then there are those patients who relapse post AuSCT who are also incurable,  he continued, rounding out three patient subgroups.

“So there is a diverse clinical setting in which patients can present with diffuse large B-cell lymphoma and it doesn’t surprise me that when you’ve got this very broad heterogeneous population it creates a lot of uncertainty in terms of what is the clinical efficacy is, let alone the cost efficacy when it comes to this sort of treatment.”

Another problem with subsiding CAR T-cell therapy for patients with DLBCL was the uncertainty around patient numbers, he said.

“I don’t think it’s very clear to any of us how many patient are going to be eligible for this sort of treatment in Australia. I think its fair to say that the sort of numbers that get thrown around are anywhere between 150 to 400 a year in Australia so when you’ve got a lot of variation that will create uncertainty around reimbursement.”

But Prof Prince remained positive about the therapy finding a place in practice.

“This is an exceptional paradigm-shifting therapy. For those of us who have seen patients with relapsed large B-cell lymphoma experience such dramatic improvements when they would otherwise be considered incurable – we’re all stunned. We know that this therapy is going to find a place but the issue now is in which patients? Not everyone with DLBCL is the same and MSAC are saying: ‘explain to us the difference, what can we expect for each of those group?”

According to Professor Prince the biggest question remaining is – will patients with refractory disease who have failed all other top line treatments do better on CAR T-cell therapy or autologous stem cell transplant?

He said haematologists now wanted to see trials of the different options, “and I think it behoves all of the pharmaceutical companies involved in this to recognise that they need good larger randomised studies to address those uncertainties.”

Still, what is known, he adds, is that of the three groups who could be eligible for biologic therapy it’s the patient who is ineligible for autologous stem cell transplant or who has relapsed post transplant who needs the treatment the most.

“These patients are going to die from their lymphoma – there are no other choices and [tisagenlecleucel] could potentially salvage those patients,” he said. He went on to suggest that this might be the subgroup of patients reimbursement could be targeted towards.

“If drug companies could provide the data and tighten up the uncertainty around patient numbers then we could perhaps see subsidised treatment in those two subgroups at least in the not too distant future.”

MSAC said it would consider a review in 2023 when the final results from JULIET are released.

You can find the full MSAC report here .
Professor Prince has been on advisory boards and received research funding for Celgene, Novartis, Janssen and Juno. He own shares in Cell Therapies Pty Ltd.