CAR-T Combos: Potentially the Next Big Thing in Solid Tumors, Yet Pricing ‘Sticker Shock’ is not the Only Hurdle to be Overcome

After years of anticipation, CAR-Ts (chimeric antigen receptor–T-cells) finally made the transition from being promising future therapies, to breakthrough marketed products in 2017. Novartis’s KYMRIAH™ got the FDA nod in late August for pediatric B-ALL (B-cell acute lymphoblastic leukemia), followed by Kite’s YESCARTA™ in October for NHL (Non-Hodgkin lymphoma) (Figure 1). Both events spilled out of the biopharmaceutical industry’s innovation engine and were covered as front-page news. Since then, there has been no sign of waning in interest and this class of therapies is likely to continue dominating the bio-news coverage in 2018 and beyond.


So, what is a CAR-T?

CAR-Ts are perhaps more akin to a transplant than a drug. A patient’s T-cells are removed, sent off to a lab and engineered to attack tumor cells. The cells are then shipped back to the patient and reinfused to fight off cancerous cells. In addition to their initial effectiveness, the CAR-T cells are expected to circulate through the body long-term, continuing to remove any leftover cells that might cause a relapse.

High expectations have been set by the recent success of CAR-T in hematology, but it remains to be seen if clinical potential can also translate to solid tumors overcoming the hostile microenvironment.

Amongst all the buzz, it is important to remember that success with CAR-Ts so far has been limited to hematological malignancies. Outcomes in solid tumors have been less than stellar, creating concern that the technology might remain limited to blood cancers, never providing the same level of clinical benefit in solid cancers, where the unmet need is higher and the commercial opportunity potentially bigger.

One of the leading hypotheses on the challenges of CAR-Ts in solid tumors puts the blame on the hostile tumor microenvironment. One potential way tumor masses can evade immune attacks is by displaying “do not attack me” signals on their surface, which might be stopping the engineered CAR-T cells from doing their job even when they correctly home to the site of the tumor.

Hope is on the horizon as the clinical effectiveness of CAR-Ts may be further boosted by combining with immune checkpoint inhibitors to make the solid tumor cells vulnerable, and the CAR-Ts can then more effectively attack them

Work is ongoing to modify the CAR-T cells to circumvent these inhibitory signals, but there is also the option of using agents designed just for this purpose: Immune checkpoint inhibitors, such as YERVOY™, OPDIVO™, and KEYTRUDA™. These agents can be co-infused with CAR-Ts to uncloak the tumors, which would make them vulnerable to treatment. Feasibility of this approach is currently being tested by Kite and Juno under co-development deals with Roche and Astra Zeneca, respectively. While these early studies target NHL indications, expansion to other therapeutic areas is highly likely if benefit/risk ratio is favorable.

However, while the innovative science is exciting, and the clinical promise for patients is clear, the price of such combination therapies is potentially eye watering to payers

Once a reliable combination of CAR-Ts and checkpoint inhibitors is developed, the next challenge for the manufacturers will be to decide how to price it. Assuming a scenario where one dose of CAR-T is infused at a list price of $300,000-400,000 and the checkpoint inhibitor is maintained for a year for $150,000, the total cost of a CAR-T/PD-1 combo will easily top $500,000. A price tag almost certain to bring about strong payer objections, especially in a solid tumor with a large patient population.

How can manufacturers help ensure access to such innovative combination therapies?

Manufacturers have a number of strategic options to help overcome the sticker shock and potential payer pushback to the price of a CAR-T and checkpoint inhibitor combination treatment:

1) Sacrificing net price of one component (is easier said than done and assumes the manufacturer has both assets in their portfolio):

In order to make the combination net price more acceptable, net price of one component can be heavily discounted, potentially in a non-transparent deal with payers (Figure 2). While this could be a straightforward decision for manufacturers that own both agents, it would pose challenges in a co-development scenario due to potential loss of revenue from the monotherapy. Additional complexity has to be considered in the context of CAR-Ts and checkpoint inhibitors used across multiple indications. Multi-indication asset specific pricing is perhaps the most elegant solution yet, but it is neither routine nor practical in terms of implementation in most major markets.


2) Reduce budget impact by defining a niche target population where value proposition is stronger and / or unmet is need higher:

By targeting combination treatments to patients with highest need and likelihood of response, manufacturers can limit the budget impact and alleviate payer concern of paying for an expensive treatment that may or may not work equally well for all patients. However, while such an approach naturally addresses payer affordability concerns, there remain challenges defining the clinical profile of patients who should receive such potentially life changing therapies. The flip side of the story is a cohort of patients may be denied access to an effective treatment.

3) Reduce budget impact uncertainty and payer concerns by defining treatment duration of checkpoint inhibitors:

Current immuno-oncology agents are generally used until progression or unacceptable toxicity, resulting in high uncertainty in estimating their overall budget impact. Manufacturers can design trials to understand whether use of checkpoint inhibitors can be decreased or stopped entirely after a certain period for all patients, except for those with high-risk of relapse.

4) Value-based, innovative annuity or outcomes-based payment pathways:

CAR-T/PD-1 combinations might create value above the sum of the two components due to the synergy between the agents. However, manufacturers might fail to extract the full value in this case, since payers are unlikely to accept a price above the total price of the two components. On the other hand, if the value provided by the combination is only incremental, manufacturers might face payer pressure to discount one or both agents accordingly (Figure 2).

Innovative payment models where manufacturers only get paid for outcomes in responders and / or where ‘annuity’ payments are distributed over a longer period are already being discussed for current CAR-T monotherapies (Figure 3). Spreading the cost of “one and done” CAR-Ts over time, to better fit within annual payer budgets is logical and makes such annuity payments an attractive proposition. Hurdles with implementation of such payment schemes may well have been overcome by the time combinations are ready to for the market. Nevertheless, while payments for solid tumor CAR-T combinations can be modeled, it will be necessary to re-define “success in treatment” in the context of the specific tumor being targeted.


5) Modify the CAR-T itself to behave like a combo and remove the need for checkpoint inhibitors:

Unlike small molecules or currently available biologics, the CAR-T technology provides an entire cellular platform that can be modified to ignore or circumvent the inhibitory signals from the tumor mass. Manufacturers in the USA and elsewhere are currently tinkering with the cells and if all goes according to the plan, they can provide the effect of the combo in a single package. However, this might also create a safety concern, since physicians will no longer have the flexibility to adjust dosage of each component separately.

Many hurdles will need to be overcome to develop the optimal commercial launch strategy, and just as the science of CAR-Ts has demonstrated, the optimal approach is likely to involve a combination of solutions.

The tumor microenvironment is complex and pairing CAR-Ts with checkpoint inhibitors will definitely not be the end of the story. Eliminating all these roadblocks and bringing the first CAR-Ts to market in a solid tumor indication will surely be an amazing R&D accomplishment. However, a well-thought, robust pricing and reimbursement portfolio strategy is also essential to ensure maximum number of patients can benefit from this cutting-edge technology, without overburdening already stretched global healthcare systems.