Tumour-agnostic immunotherapy for rare and uncommon cancers: The patient’s dilemma

Eight Therapeutic Goods Administration (TGA)-approved immune checkpoint inhibitor (ICI) drugs are licensed for cancer immunotherapy, three of which, namely pembrolizumab (Keytruda, Merck), ipilimumab (Yervoy, Bristol-Meyers Squibb) and nivolumab (Opdivo, Bristol-Myers Squibb) are listed on the Pharmaceutical Benefits Scheme (PBS), predominantly for common cancers. Approximately 40% of all cancer deaths (25,000 patients per annum in Australia) are caused by the group of approximately 200 rare and less common cancers (RLCs).^1,2

PBS listing of ICI drugs for RLCs has been confounded by the Pharmaceutical Benefits Advisory Committee (PBAC) requirement of demonstration of efficacy of each new drug for each cancer type in Phase 3 trials, a criterion that cannot be met by the low frequency of individual RLC types.

Drug manufacturers ask high prices for the supply of ICI drugs, which the Federal Government is reluctant to pay. RLC sufferers for whom all conventional therapies have failed are caught in the stalemate between the PBAC and pharmaceutical companies over pricing and evidentiary requirements. These patients can expect to pay A$135,000 for a single course of an ICI drug,³ approximately 1000-fold more than the PBS-subsidised price charged for the same drug to a patient with a common cancer. Homes are remortgaged, businesses are sold, retirement savings are spent and superannuation is cashed in to pay for the ICI drug. The family might never recover.^4–7

Although there is evidence that deaths can be prevented or suffering ameliorated with ICIs, the drug(s) might not work for a given patient because there is response variability not only between cancer types, but also between patients with the same cancer type.⁸

Those with an RLC struggle with guilt over the financial and emotional turmoil their disease brings to their families, with one RLC patient asking ‘How much is my life really worth?’ (Danielle Tindle, neuroendocrine carcinoma, pers. comm., 2015).

PBS listings are too specific in some cases. Thus, the PBS approves ICIs for clear cell renal cell carcinoma (RCC) but not non-clear cell RCC, even though the drug works for all subtypes.⁹ Initiatives to define tumour type not by site of origin or histology but by genetic profile further muddy the waters; even histologically identical tumours arising at the same anatomical site might not be genetically identical.^10,11

History

The cancer immunotherapy revolution took off in 2011 when the US Food and Drug Administration (FDA) licensed ipilimumab, improving the survival of patients with late-stage melanoma refractory to conventional therapies.¹² As later Phase 3 clinical trial data emerged, approval was extended to other common cancer types. Nivolumab, for example, is now approved to treat approximately eight common tumour types alone or in conjunction with ipilimumab.¹³ In Australia, each of these drugs was initially approved by the TGA and PBAC for government subsidy via the PBS for a single common cancer type. Clinicians now use ICIs as single agents or combined with chemotherapies, surgery or tumour-specific vaccines as first- or second-line treatment.¹⁴

By 2021, seven other ICI drugs were licensed.^15,16 These pan-tumour (tumour-agnostic) agents signal an important new paradigm in clinical management in which tumour genomic signature supersedes tumour location and histology in informing treatment decisions.¹⁶

Not all cancer types have responded as well as melanoma or, more recently, non-small cell lung cancer. There is considerable response variability among different tumour types and among patients with the same tumour type. Although transient partial regressions might be achieved, a cure will be realised only for a minority of patients.¹⁶

Knowledge of RLC patient outcomes is incomplete because of inconsistency in data collection.²

Some cancers have evolved mechanisms for avoiding attacks through ICI pathways; some respond less well to ICIs than to standard therapies.^17,18 Only 10–20% of patients treated might obtain clinical benefit. Genome sequencing might identify genetic signatures that are associated with tumour susceptibility to ICIs, allowing future prediction of those patients likely to respond.¹⁹ That, plus multiorgan autoimmune adverse events associated with non-specific immune activation caused by ICI drugs, might indicate high-quality palliative care as a better option in some cases.²⁰

The PBS currently spends A$14.7 billion per annum subsidising drugs for various diseases.²¹ When considering a new immunotherapy drug for subsidy, the PBAC deliberates what it will cost the Federal Government to buy it from the pharmaceutical manufacturer and how effective the drug is compared with existing therapies. With many demands on a limited healthcare budget, cost-effectiveness to the overall population is best served by subsidising the most common cancers individually rather than individual RLCs. For RLCs, the PBAC has been found wanting.

The pharmaceutical companies defend the high purchase prices they propose, citing expenditure on drug development costs, expensive Phase 3 trials and costs incurred complying with TGA and PBAC submission requirements.²² The asking price is also influenced by what profit margin the companies can sustain internationally. Ultimately, registration for RLCs relies on the willingness of pharmaceutical companies to invest in new drugs; they hesitate to spend in the small markets, which individual RLCs provide. Furthermore, they criticise the PBAC for setting the bar too high by insisting that a company demonstrates the efficacy of a new drug for each individual cancer type, this stipulation being a hangover from the National Health Act 1953, in which legislation on drug subsidy is embedded.

In 1983, the US government passed the Orphan Drug Act to give drug companies certain financial benefits for developing orphan (ie rare disease) drugs. This law is meant to help bring more drugs to patients with rare diseases.

Clinical trials and costing

Enrolling in a clinical trial to access an immunotherapeutic for their cancer has not been an option for most patients with an RLC. Although multicountry randomised trial data have secured PBS subsidy for the uncommon cancers, gastrointestinal stromal tumour, chronic myeloid leukaemia and gall bladder cancer,²³ no such trials have been conducted for most of the approximately 200 RLC types. In 2018 there were roughly 10-fold fewer clinical trials for all RLCs than for common or advanced common cancers.²

There is a call for more innovative trials with more flexible inclusion criteria.²⁴

In collaboration with Big Pharma, Australia has proposed to ‘bolt on’ rare cancers to trials of common cancers with similar genetic signatures or to ‘lump’ several RLC types displaying the same genetic signature together.² The Federal Government’s Clinical Trials Activity initiative provides A$750 million over 10 years between 2022–23 and 2031–32 to increase clinical trial activity, particularly addressing rare diseases, including RLCs.²⁵ The initiative includes bringing investigator-led international clinical trials to Australia.²² The International Rare Cancers Initiative functions as the main global platform for achieving new international clinical trials in rare tumours.²⁶

For use in the UK’s National Health Service (NHS), ICI drugs are considered with less mature clinical trial data on their effectiveness than in the past. In addition, there is a recognition that clinical trials, although essential to proving a drug’s safety and efficacy, might not always reflect a drug’s benefit to patients in a clinical setting. Greater emphasis is now placed on real-world treatment outcomes data to agree on a price that better reflects the drug’s true benefit to NHS patients. If a drug is deemed not cost-effective at the price initially proposed by the manufacturer, the Voluntary Pricing and Access Scheme, an agreement between the UK Government’s Department of Health and the pharmaceutical industry, can negotiate a different pricing arrangement with the manufacturer, often a simple percentage discount on the medicine’s price.

Because Australia is responsible for only 2% of the global pharmaceutical spend, it has little negotiating clout with the international pharmaceutical industry over drug pricing.

An urgency to bring new drugs to patients as early as possible while evidentiary data are still incomplete, plus the uncertain costs of manufacturing complex new drugs foment uncertainty about what a government should pay. More flexible ways for price setting are necessary. Various outcome-based payment models link the price the NHS pays for a drug to the outcomes the drug achieves in practice. These models include manufacturer rebates or refunds if the medicine fails to meet pre-agreed outcome targets for individual patients. Conversely, if a drug is subsequently proven to have clinical value, the manufacturer can renegotiate a price increase. In effect, the patient with an RLC has a safety net; if the drug that costs them so much does not work for them, they get their money back, in whole or in part.

Today, in Australia, many RLC patients must pay approximately A$8000 each time they visit the oncology clinic for their ICI injection. There is little chance of recompense; pharmaceutical company ‘compassionate access schemes’ are notoriously unreliable and non-transparent, hospital and hospital foundation funds are overstretched, any financial help from charities is transient and crowd-funding soon dries up (Box 1).