All year, the availability of the new generation of anti-cancer drugs in New Zealand has been driven by political decisions, as much as by medical ones. Because patients with advanced melanomas made a lot of the initial public fuss, Pharmac and its political masters sought to manage the demand for these expensive treatments by limiting state funding only to those with advanced skin cancer. This week, lung cancer patients have been put in the same position, of needing to mount a public – and highly political – campaign to qualify for similar state funding for what can be life-saving treatments.
Basically…why should people with skin cancer qualify for state funding for these drugs while those with lung cancer currently do not? No good medical reason exists, only a political decision to contain the pharmaceutical costs in the health budget, especially as more and more baby boomers are now entering age brackets where the risk of cancer rises. (Spending on public health is tightly constrained. Big budget Defence items, by contrast, are funded on demand, but that’s another story.)
Pharmac is the meat in this sandwich – caught between rising public demand for sky high expensive drugs on one hand, and Beehive-driven demands for frugality on the other. Given the potential scale of demand, the recent increase in Pharmac funding has been a mere drop in the bucket. It also doesn’t help Pharmac’s ability to make coherent decisions that the overseas test results for these new drugs are still coming in, and changing the landscape on almost a monthly basis.
Initially, Pharmac had followed the trends in the global market by funding Opdivo, the Bristol Myer Squibb (BMS) anti-cancer drug that had been first out of the gate in late 2015 in a testing/marketing race against Keytruda, the similar drug developed by Merck Sharp Dohme (MSD). Both drugs tend to work as ‘second level” treatments – not as the first line of response – and both drugs work by inducing the body’s own immune system to counter the cancerous cells. Not every patient benefits from these drugs; but the most relevant current bio-marker involves a diagnostic test for a protein called PD-L1.
In June, BMS tried – and spectacularly failed – to score a decisive goal for Opdivo in that ongoing marketing battle with Keytruda. Alas though, the test results showed that Opdivo provided no better results than chemotherapy in patients where the rate of PD-L1 expression was in the range of 5% plus, and the company’s share price sank by 23% almost overnight on the news.
Almost simultaneously, MSD released test results for Keytruda that showed glowing outcomes for those patients where the rate if PD-L1 expression was in the range of 50% plus. Keytruda’s marketing profile (and MSD’s share price) rose substantially in the wake.
Clearly though, these two sets of tests were measuring apples and oranges. The Opdivo tests were an ambitious attempt to measure the drug’s “first line of treatment” potential amid a class of patients that included those with early onset (i.e. only 5% plus expression in the tumours) of the disease. The Keytruda tests confirmed the drug’s efficacy later in the disease cycle, after the rate of expression had topped 50%.
Taken together, the tests suggested that the future use of these drugs is unlikely to be as “monotherapies” administered early, in isolation. Instead, their future may well be as “combinant” drugs taken together with other drugs (e.g. Opdivo plus another BMS drug called Yervoy) that will (hopefully) expand the ambit of conditions responsive to these very, very expensive treatments. Here’s how BMS’s CEO Giavanni Caforio summed up the new outlook for Opdivo in the light of its recent testing own-goal (link above):
In the first-line setting we decided to answer two important questions in every patient. The first question we are answering is through this study: What is the role of monotherapy? And the trial tells us that the role of monotherapy is likely to be limited to a very small subset of patients that express PD-L1 at very high levels, which is what we believe we know from a previous study that was reported not a long time ago.
And so the second question, then, becomes: What is, therefore, the role of combination therapy? And there is where we remain very confident that our study 227, which is looking at combination therapy in first line, becomes even more important. And so, to answer your question, we believe that our study clearly answers definitely the question about the use of monotherapy PD-1 in the first-line setting and that is likely to be limited to the 25% of patients that express PD-1 at the very high level.
In other words, combinants may eventually enable these immune system ”biologics” drugs to be deployed far earlier in the disease cycle, and even perhaps as first line treatments. Yet to repeat Caforio’s main point : currently, Opdivo/Keytruda’s use as a first line monotherapy treatment is limited only to the 25 % of patients expressing PD-L1 protein at very high levels. Plainly, these are not miracle cures for everyone.
The testing/marketing pattern outlined above also helps to explain why Pharmac has zigzagged between Opdivo and Keytruda over these past few months. Right now though….it isn’t as if the fierce competition is lowering the price for either drug. Nor is there much hope for Pharmac that there will be a shortening in the patent term before less expensive generic replacements appear on the horizon. (Eight to 12 years is the likely patent term for these drugs, for the foreseeable.)
Lung cancer is the most common form of cancer in New Zealand. State funding for Keytruda as a late stage treatment option for non-small cell lung cancer (NSCLC) would be highly expensive. Pharmac will be looking hopefully overseas for any test evidence that might help it to target which patients would stand to benefit most from these drugs. This is a genuine problem. In the US, the FDA guidelines do not make PD-L1 levels a pre-condition for treatment, perhaps because the process involved is still somewhat mysterious:
….There is still no consensus regarding the value of PD-L1 expression in NSCLC as a predictive marker of response. Across the board, positivity for PD-L1, while predictive of response, does not always guarantee it, and lack of PD-L1 does not exclude response. Obviously, one must conclude that PD-L1 is just one of several (many?) factors that determine the likelihood of response. To compound the PD-L1 problem, there is a lack of defined criteria about what ‘PD-L1-positive tumor’ really means:
The likely emergence of combinants which may increase the effective scope of these treatments and people eliugible for them – not to mention their combined price – is something else for Pharmac to nervously ponder.
Cancer, meanwhile, isn’t standing still. Disturbingly, there is some sign that the segment of cancer patients who may stand to benefit from these treatments will also have to face the potential for relapse, given the capacity of cancer to develop resistance:
A very recent study came up with some unsettling conclusions about why some patients (about 25%) first show a good response to PD-1 blockade, only to relapse later. Full sequencing analysis of tumors before and after treatment was performed in four melanoma patients who first responded to anti-PD-1 drugs and then experienced a relapse. In three out of four patients, relapsing tumors had new mutations in genes that play a critical role in how cells respond to immune attack by activated T cells. The striking observation was that the activated T cells were still present in the tumors that relapsed; it was a powerful indicator that the immune system was still primed and ready to attack the tumor cells, but the latter had evolved to resist the attack. This was a very small study, and it will need to be extended to more patients who stop responding to anti-PD-1 drugs, but the findings are troubling. Development of resistance was thought to be a major problem with targeted drugs, and the discovery of melanoma’s ability to escape immune attack through the acquisition of new mutations is worrisome, to say the least.
What would be helpful is for the Minister of Health to come out of hiding, and show some leadership on this issue. These drugs will cost a lot of money now and in the coming years, and he’s the guy who holds the purse strings. Is he ready to make more money available, or not?
The Tragically Hip, Adieu
Talking of the toll taken by cancer, the final curtain call of the much loved (in Canada) band called The Tragically Hip has been playing out as a national calamity (in Canada). Even Prime Minister Justin Trudeau has responded with emotion to the news that the band’s lead singer Gordon Downie has terminal cancer.
Clad in his ceremonial jean jacket and Tragically Hip concert T, Trudeau praised the prolific rock group for its long, successful career, which saw them earn international recognition while still remaining “anchored in Canada, in so many ways.” Trudeau followed up his appearance with a series of tweets, thanking Downie and the band for more than 30 years of music.
The band’s recent final concert has been a significant event for all concerned. For outsiders, the response has been more like – who are/were these guys, and do you need to have grown up Canadian to get what this is all about? Probably, yes.
Encountering the Tragically Hip for the first time in these circumstances is – as the Fluxblog site recently pointed out – a bit like coming across this band called REM and going hmmm, that “Losing My Religion” track is kind of impressive. So here’s a sample of what we didn’t realize was a really really important thing (for Canadians). Here for instance, is Gord Downie’s final speech on stage a couple of weeks ago – as a nation mourns, and the camera pans to Trudeau in the crowd, blinking back tears:
And here’s maybe the Tragically Hip’s biggest hit…
But this track, “Grace, Too”…is maybe the high point, for a non-Canadian….