Christina Mattina

While the FDA’s approval of the immunotherapy tisagenlecleucel represents a landmark in the oncology field, the treatment is far from being a cure and should be viewed in context of its $475,000 price tag, a group of oncologists wrote in a 

The 3 oncologists from Memorial Sloan Kettering Cancer Center acknowledged the “impressive science” behind the therapy marketed as Kymriah, which involves genetically modifying each patient’s chimeric antigen receptor (CAR) T cells to target and kill tumor cells. Indicated for pediatric and young adult acute lymphoblastic leukemia, Kymriah is the first CAR T-cell therapy approved by the FDA and “heralds a new era of treatment,” they wrote.

However, the therapy does carry the risk of significant side effects, since the modified cells can also damage healthy cells and tissues, and it is known to cause cytokine release syndrome in some patients, which can be dangerous or even fatal. The technique needed to extract, engineer, and re-inject the patient’s T cells is challenging, so the authors emphasized that it will only be available at a handful of capable institutions.

Another factor contributing to their hesitation is the price of Kymriah; its manufacturer, Novartis, has set a price of $475,000 per course. The authors noted that it is difficult to compare the cost effectiveness of this therapy to other cancer treatments because it is both more efficacious but also substantially costlier than the other treatments, which already have high prices.

Furthermore, the authors point out that the final cost of treatment with Kymriah will rise higher than $475,000 after accounting for toxicity management efforts, treatment of events like cytokine release syndrome, and necessary preinfusion and postinfusion procedures. Expanding the therapy’s indication to other cancers and populations would further increase the cost burden on patients and the healthcare system, even though “the health benefits could be substantial.”

Published less than a week after a group of US Representatives wrote a letter to CMS 

 on the outcomes-based payment agreement developed with Novartis for Kymriah, the 

commentary also raised questions about the specifics of this agreement. The authors proposed some alternate endpoints that may be better surrogates for clinical benefit, but acknowledged that “arguably a more important issue that choosing the right end point is starting at the right price in the first place.”

Finally, the commentary authors wrote that another danger to the appropriate use of Kymriah and other CAR T-cell therapies is the popular hype surrounding the treatment. They advised clinicians to clearly explain the potential benefits and risks of these approaches to patients, including a thorough description of the potential side effects.

Above all, the authors warned clinicians, scientists, and members of the media to avoid using the word “cure” in discussions about CAR T-cell therapies, despite the widespread excitement surrounding them.

“The reason is that the term cure will connote to some patients that a single infusion of this scientifically mystifying, genetically driven therapy will first vanquish their disease and then reset their life expectancy to normal,” they wrote. “Perhaps one day data will support such a hope; as of yet the available data are insufficient to claim much more than CAR-T treatments have large promise at an enormous price.”

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While the FDA’s approval of the immunotherapy tisagenlecleucel represents a landmark in the oncology field, the treatment is far from being a cure and should be viewed in context of its $475,000 price tag, a group of oncologists wrote in a commentary published in JAMA.

JAMA Commentary Urges Realistic View of New CAR T-Cell Cancer Therapy

When immune-related adverse events arise from nivolumab, it may indicate that the therapy is having greater efficacy against non—small-cell lung cancer (NSCLC), as a new study demonstrates a link between these events and improved survival outcomes.

Prior studies have found that the development of immune-related adverse events during a course of immunotherapy is associated with survival benefits for patients with melanoma. A group of oncology researchers from Japan hypothesized that these adverse events may be related to the efficacy of nivolumab in NSCLC, as well. Their findings were 

In the retrospective study, the records of 134 patients with NSCLC treated with nivolumab were reviewed for any instances of immune-related adverse events, as well as progression-free survival (PFS) and overall survival (OS) to measure efficacy. The comparison between those experiencing adverse events and those who had not was conducted after adjusting for age, sex, prior treatment lines, smoking status, mutational status, and brain metastases.

Some of the most common immune-related adverse events included skin complaints, like rashes, gastrointestinal symptoms, like diarrhea, and general symptoms, like fatigue. Of the 69 total patients who experienced an immune-related adverse event, the majority (57) had less severe symptoms (grade 1 or 2). Just 12 patients experienced grade 3 or 4 adverse events.

A 6-week landmark analysis demonstrated that patients with immune-related adverse events were more likely to have an overall response to treatment than those without (52.3% vs 27.9%; 

= .02). They also had significantly higher PFS (median, 9.2 vs 4.8 months; 

= .04) and OS (median, not reached vs 11.1 months; 

= .01) than the patients who had not experienced adverse events.

These findings are “suggestive of a robust association between such events and survival,” the study authors wrote. Furthermore, because their analyses were conducted in the early stages of treatment, earlier onset of adverse events “might be predictive of response or durable clinical benefit in patients with NSCLC treated with PD-1 inhibitors” like nivolumab.

Although they could not draw conclusions regarding the underlying drivers of the relationship between immune-related adverse events and treatment outcomes, the findings may have important implications for clinical practice, particularly if they are corroborated in larger studies with longer follow-up duration. Clinicians and patients could make more informed treatment decisions, for instance, if they are aware that their side effects are predictive of better survival.

“Early recognition and proper management of immune-related adverse events are important to maximize the therapeutic benefit of immune-checkpoint inhibitors in patients with NSCLC,” the researchers concluded.

Immune Adverse Events From Nivolumab Predict Better Survival With NSCLC

After CMS and Novartis devised an outcomes-based payment approach for the new chimeric antigen receptor (CAR)-T treatment tisagenlecleucel (Kymriah), a group of representatives are requesting more information on the specifics of the agreement.

“As members strongly concerned with both rising prescription drug prices and the need to protect taxpayer access to therapies developed with public funding, we are watching closely the discussion around pricing for this treatment,” 

 Seema Verma read. It was signed by a group of 9 Democratic members of the House of Representatives.

Novartis had first trumpeted the “groundbreaking collaboration” with CMS in 

 announcing the FDA’s approval of Kymriah. It indicated that pricing would be based on indications and outcomes, and that CMS would only pay for the immunotherapy treatment if the approved patients, pediatric and young adults with acute lymphoblastic leukemia, respond to Kymriah within their first month of therapy.

The representatives acknowledged that Kymriah, the first CAR-T therapy approved in the United States, “is a promising treatment that may benefit cancer patients,” but noted that it will only be effective if patients in need are able to afford it, considering the estimated $475,000 price tag. They also cited concerns about the $200 million in taxpayer funding used to finance the therapy’s development.

The letter included 14 questions for Verma on how CMS developed the outcomes-based payment equation for Kymriah. It asked for an explanation of payment mechanisms, details on data collection, and estimates on the number of patients who would be eligible, as well as how exactly a successful response would be defined. There were also questions about whether any of the CMS political appointees who had developed the agreement had ever worked for Novartis or elsewhere in the pharmaceutical industry.

 by genetically modifying each patient’s T cells to include the CAR gene, then infusing them back into the patient, allowing the cells to target and kill leukemia cells. This customization costs around $20,000 per patient, but that price may decline as production is ramped up, according to Carl June, MD, a CAR-T researcher quoted in the letter. Considering this estimate, the representatives asked Verma how Novartis’ profit margin equates to a fair deal for taxpayers.

“We look forward to the opportunity to learn more about how CMS established this outcomes-based payment agreement and how it will be enacted,” the letter concluded. “We look forward to your reply and your continued engagement as the conversation around outcomes-based pricing moves forward.”

 on the payment arrangement released at the time of Kymriah’s approval indicated its enthusiasm for novel payment models like outcomes-based pricing, particularly for innovative but costly therapies like CAR-T treatment, but did not provide further details on the Novartis agreement.

“Improving payment arrangements is a critical step towards fulfilling President Trump’s promise to lower the cost of drugs,” Verma said in the statement.

Two of the representatives who signed the letter, Peter Welch, D-Vermont, and Elijah Cummings, D-Maryland, 

 to discuss the high cost of prescription drugs. Cummings praised the president for being “aware of the problem” and “enthusiastic” about solutions like allowing Medicare to negotiate prices.

Representatives Probe CMS for Further Detail on New CAR-T Therapy Payment Agreement

Gilead Sciences will acquire Kite Pharma by the end of 2017 in an $11.9 billion transaction that will place Gilead at the forefront of chimeric antigen receptor-T (CAR-T) cell therapy development.

 issued by both Gilead and Kite. In a deal that is expected to close in the fourth quarter of 2017, Gilead will pay $180 in cash per share, which puts Kite’s valuation at $11.9 billion. The acquisition was unanimously approved by both companies’ Boards of Directors.

The major driver of this substantial valuation is Kite’s work on CAR-T therapy, a form of cancer-fighting immunotherapy. The company had been buoyed by a string of good news regarding its most advanced CAR-T therapy in recent months, from encouraging clinical trial results to its acceptance for priority review by the FDA.

The treatment, axicabtagene ciloleucel, showed 

 from the ZUMA-1 study published in March, where it produced a 41% objective response rate and a 36% complete response rate in 101 trial participants with chemotherapy-resistant aggressive B-cell non-Hodgkin lymphoma (NHL). This was followed up in July by 

 in 7 patients with diffuse large B-cell lymphoma (DLBCL); 5 demonstrated complete remission and 4 of these remissions were durable long term for as long as 56 months, by the time of publication, without relapse.

In between these 2 promising clinical findings, Kite 

 that its application for priority review had been accepted by the FDA, meaning the review process will now take just 6 months rather than 10. The target action date set under the Prescription Drug User Fee Act is November 29, 2017. Observers expect it to be approved, which would make it the first CAR-T therapy on the US market for refractory aggressive NHL, including DLBCL, transformed follicular lymphoma, and primary mediastinal B-cell lymphoma.

Besides this frontrunner, known as axi-cel, Kite also has clinical trials ongoing for several other immuno-oncology drug candidates, including the CAR-T therapy KITE-585 for use in multiple myeloma. Gilead expressed enthusiasm about this strong pipeline and the broader future of CAR-T therapy in its announcement of the purchase.

“The acquisition of Kite establishes Gilead as a leader in cellular therapy and provides a foundation from which to drive continued innovation for people with advanced cancers,” said John F. Milligan, president and CEO of Gilead. “We are greatly impressed with the Kite team and what they have accomplished, and share their belief that cell therapy will be the cornerstone of treating cancer.”

Kite also voiced excitement about the transaction and its implications for developing more innovative immunotherapies.

“CAR-T has the potential to become one of the most powerful anti-cancer agents for hematologic cancers,” said Arie Belldegrun, MD, FACS, chairman, president, and CEO of Kite, in the joint statement. “With Gilead’s expertise and support, we hope to fulfill that potential by rapidly accelerating our robust pipeline and next-generation research and manufacturing technologies for the benefit of patients around the world.”

Gilead Sciences Announces $11.9 Billion Purchase of CAR-T Developer Kite Pharma

A study on long-term remission of diffuse large B-cell lymphoma (DLBCL) shows that Kite Pharma’s anti-CD19 chimeric antigen receptor-T (CAR-T) cell treatment resulted in remission for up to 56 months.

, followed 7 evaluable patients with relapsed DLBCL, a type of non-Hodgkin lymphoma (NHL), who received the anti-CD19 CAR-T cells. Of these patients, 5 demonstrated complete remission (CR), and in 4 these remissions were durable long-term.

At the time of publication, these 4 patients had achieved CRs of 56, 51, 44, and 38 months’ duration, and none had relapsed.

“We are encouraged to see durable CRs ongoing for more than 3 years, which raises a possibility of cure, from a single infusion of anti-CD19 CAR-T cells in patients with chemorefractory DLBCL, a population that previously had no curative treatment options,” said Kite’s chief medical officer, David Chang, MD, PhD, in 

The trial, which was led by researchers from the National Cancer Institute’s Center for Cancer Research, found a low incidence of severe infections due to the CAR-T therapy “despite long periods of B-cell depletion and hypogammaglobulinemia.” Among the 4 patients who achieved long-term CR, only 1 was hospitalized for an infection.

CAR-T therapy works by killing malignant and normal B cells, but the study found that remission continued in 3 of 4 patients with CR even after recovery of non-malignant B cells. This “demonstrated that remissions of DLBCL can continue after disappearance of functionally-effective anti-CD19 CAR T-cell populations,” the researchers wrote.

in 2015, when the researchers were the first to report CRs in chemotherapy-refractory DLBCL with the use of anti-CD19 CAR-T therapy. At the time, the study authors wrote that the findings “should strongly encourage continued development” of such therapies.

Drug developers appear to have taken that encouragement to heart, as CAR-T therapies have emerged as a potential game-changer in the immunotherapy landscape. Recently, the FDA’s Oncologic Advisory Committee 

 to give the green light to Novartis’s CAR-T treatment CTL019 for relapsed or refractory B-cell acute lymphoblastic leukemia, paving the way for it to be approved by the FDA as soon as October.

 from the FDA, and it had been designated a Breakthrough Therapy for DLBCL and 2 other lymphomas since December 2015. The results from the recent study, in which DLBCL patients experienced CR for as long as 56 months, add to the evidence supporting the promise of CAR-T therapy.

“This study helps us to understand the long-term potential for this anti-CD19 CAR-T cell therapy (axicabtagene ciloleucel) in the larger aggressive NHL patient population,” said Chang in the statement.

Kite's CAR-T Therapy Produces Durable Remission in DLBCL, Study Finds

ALTHOUGH CHIMERIC ANTIGEN RECEPTOR (CAR)-T CELLS

 as a treatment for B-cell neoplasms have shown some promising results in clinical trials, their clinical use is limited, partially due to the risk of cytokine-release syndrome (CRS) occurring in response to the treatment. A poster presented at the Annual Meeting of the American Society of Hematology demonstrated that mice receiving CAR-T immunotherapy plus ibrutinib demonstrated longer overall survival and reduced cytokine production than the mice not treated with ibrutinib.

“Cytokine-release syndrome is a serious adverse event of anti-CD19 chimeric antigen receptor T-cell (CART19) therapy and could potentially limit its widespread clinical use,” explained lead study author Marco Ruella, MD, clinical instructor at the Perelman School of Medicine Center for Cellular Immunotherapies at the University of Pennsylvania. “In this preclinical study, we demonstrated that the [Bruton’s tyrosine kinase]-inhibitor ibrutinib administered with CART19 can modulate cytokine production by CAR T cells and neoplastic B cells, therefore reducing CRS and increasing survival.”

They created a human xenograft of CRS by infusing CART19 cells into mice that had a high B-cell tumor burden. The mice began to display signs of distress resembling CRS, including reduced mobility and hyperventilation, 2 days after the injection. Compared with the controls, CART19-treated mice showed significantly higher serum concentrations of several human cytokines. The researchers then tested their hypothesis that ibrutinib would reduce CART19-mediated CRS without impairing the anti-tumor efficacy of these cells.

Ibrutinib, an inhibitor of Bruton’s tyrosine kinase, has been approved as a first-line treatment for chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL). It has been shown to modulate T-cell cytokine production, and the researchers recently demonstrated that its combination with CART19 leads to enhanced antitumor responses in preclinical models of MCL, CLL, and B-cell acute lymphoblastic leukemia.

To test their hypothesis, the researchers administered either a combination of CART19 plus ibrutinib or CART19 alone to mice with a high tumor burden of MCL. Mice treated with the ibrutinib combination demonstrated prolonged overall survival (median 17.5 days) compared with the mice that received the CART19 alone (median 5 days). Serum measurements 4 days after treatment showed that the ibrutinib-treated mice had significantly reduced cytokines, including IL-6, IFNγ, TNFα, IL-2, and GM-CSF.

“In vitro studies revealed that ibrutinib reduced cytokine production by CAR-T cells, as well as by MCL cells, leading us to postulate that both CRS and its successful prevention involve cross-talk between immune cells and cancer cells,” the study authors wrote. They suggested that the CART19/ ibrutinib combination “could be a novel strategy” in preventing CRS.&ensp; 

		Ruella M, Kenderian SS, Shestova O, et al. Kinase inhibitor ibrutinib prevents cytokine-release syndrome after anti-CD19 chimeric antigen receptor t cells (CART) for B cell neoplasms. Presented at: 58th American Society of Hematology Annual Meeting & Exposition, December 3, 2016; San Diego, CA. Abstract 2159.

		Ruella M, Kenderian SS, Shestova O, et al. The addition of the BTK inhibitor ibrutinib to anti-CD19 chimeric antigen receptor T cells (CART19) improves responses against mantle cell lymphoma. 

. 2016;22(11):2684-2696. doi: 10.1158/1078-0432.CCR-15-1527.

A study in a mouse model found that mice receiving chimeric antigen receptor (CAR)-T immunotherapy plus ibrutinib demonstrated longer overall survival and reduced cytokine production than the mice not treated with ibrutinib.