Cancer – reasons for hope in the near future

[Swerd]

And finally, this clinical trial in Ghent, Belgium: Switching From Adalimumab to Infliximab (ADA-IFX)
is still ongoing. It's in patients with Crohn's Disease and will assess the efficacy of switching to Infliximab among patients who failed to respond to or who lost response to Adalimumab.

It has multiple locations in Belgium, so I suspect its a big trial. However, I don't know how common Crohn's disease is, nor do I know how many of those patients experience treatment failure of Adalimumab.

It's quitting time.

 

[Beave]

Perhaps because this isn’t my field I’m easily impressed, but are you a medical or pharmacy professional, Beave?

Nope, but I did stay at a Holiday Inn Express last night ;-)

 

[Beave]

I'll keep looking for that. In the cancer world, the FDA usually asks for a head-to-head clinical trial to directly compare a newly approved drug vs. the previously approved drug.

In the world of these drugs, they aren't compared head to head often, if at all. FDA approval is all about showing clear superiority to placebo over a certain pre-determined length of time.

Since these conditions tend to wax and wane, with spontaneous improvements/remissions, most of the drug trials show a consistent 30-35% improvement in the placebo arm. So these drugs have to beat that.

 

[Beave]

In 1st world countries, Crohn's prevelance is around 1/500 people, and UC is similarly about 1/500, with all forms of IBD (Crohn's, UC, intdeterminate IBD, microscopic IBD) being maybe 1/200 people (those are rough estimates).

 

[Beave]

FWIW, my academic background is EE and math. I worked in audio/video electronics for 15+ years.

I have a good friend with occasional flareups of iritis. I remember taking him to the ER one day in grad school 25 years ago. He gets by with steroid eye drops when it flares up.

My brother has UC and has been on Simponi and now Remicade.

I have an official diagnosis of Crohn's disease and Undifferentiated Connective Tissue Disease (though some docs kinda think I have some strange hybrid of a lupus-like Crohn's or a Crohn's-like lupus or some mix. My neurologist thinks I have a form of vasculitis as well, but others disagree).

I was a case presentation at an annual medical conference about 15 years ago, was invited to attend, and have been attending ever since as a guest of one of the conference organizers.

The conference is an annual review of data & recommendations on using these medications in treatment of IBD. But since these 'autoimmune' diseases often go hand in hand, they've brought in speakers to talk about treating uveitis, AS, rheumatoid arthritis, psoriasis, etc, along with the main talks about IBD treatment.

 

[Swerd]

In the world of these drugs, they aren't compared head to head often, if at all. It's all about showing clear superiority to placebo over a certain pre-determined length of time.

It comes down to statistical analysis and care that the patient populations are as equivalent as possible. In a typical randomized clinical trial with two arms, drug A is compared to a placebo or another existing therapy. If another trial compares drug B to a placebo, the patient population may not have been the same. Therefore any comparison becomes statistically iffy. To keep the statisticians happy, you have to do a two-arm randomized clinical trial where the exact same patient population, a carefully selected group, is randomized into two arms. One arm gets drug A and the other gets drug B. A head-to-head trial.

In cancer clinical trials, placebos are rarely used because it would be unethical to not treat a cancer patient with at least a standard first-line chemotherapy drug. So patients in randomized two-arm trials get whatever is the standard first line chemotherapy in both arms. Arm 1 gets standard chemotherapy plus drug A, and arm 2 gets standard chemotherapy plus placebo. You should see the fist-fights that can break out when one of the bio-statisticians locks horns with someone from bio-ethics. Clinical trial design was always so much fun.

 

[Swerd]

In 1st world countries, Crohn's prevelance is around 1/500 people, and UC is similarly about 1/500, with all forms of IBD (Crohn's, UC, intdeterminate IBD, microscopic IBD) being maybe 1/200 people (those are rough estimates).

That seems like lots of patients. I wonder if they are as willing to volunteer for clinical trials as many cancer patients are.

 

[Swerd]

FWIW, my academic background is EE and math. I worked in audio/video electronics for 15+ years.

I have a good friend with occasional flareups of iritis. I remember taking him to the ER one day in grad school 25 years ago. He gets by with steroid eye drops when it flares up.

My brother has UC and has been on Simponi and now Remicade.

I have an official diagnosis of Crohn's disease and Undifferentiated Connective Tissue Disease (though some docs kinda think I have some strange hybrid of a lupus-like Crohn's or a Crohn's-like lupus or some mix. My neurologist thinks I have a form of vasculitis as well, but others disagree).

I was a case presentation at a annual medical conference about 15 years ago, was invited to attend, and have been attending ever since as a guest of one of the conference organizers.

The conference is an annual review of data & recommendations on using these medications in treatment of IBD. But since these 'autoimmune' diseases often go hand in hand, they've brought in speakers to talk about treating uveitis, AS, rheumatoid arthritis, psoriasis, etc, along with the main talks about IBD treatment.

Thanks for that info. I'm very glad you posted about this. I'm trying to learn what I can.

 

[Beave]

It comes down to statistical analysis and care that the patient populations are as equivalent as possible. In a typical randomized clinical trial with two arms, drug A is compared to a placebo or another existing therapy. If another trial compares drug B to a placebo, the patient population may not have been the same. Therefore any comparison becomes statistically iffy. To keep the statisticians happy, you have to do a two-arm randomized clinical trial where the exact same patient population, a carefully selected group, is randomized into two arms. One arm gets drug A and the other gets drug B. A head-to-head trial.

That's exactly my understanding.

 

[Beave]

Thanks for that info. I'm very glad you posted about this. I'm trying to learn what I can.

You're welcome. Happy to help. And thanks to you for working on cancer immunotherapies. My elderly father has a stage 4 cancer that has been well-controlled with immunotherapy. For him it has been a miracle treatment for what was previously an untreatable cancer.

 

[Beave]

That seems like lots of patients. I wonder if they are as willing to volunteer for clinical trials as many cancer patients are.

Probably not as willing as cancer, but still very willing. The clinical trials for IBD treatments have included thousands and thousands of patients over the years. And rates of IBD keep increasing, unfortunately, meaning there are more and more newly-diagnosed patients each year.

 

[Swerd]

You're welcome. Happy to help. And thanks to you for working on cancer immunotherapies. My elderly father has a stage 4 cancer that has been well-controlled with immunotherapy. For him it has been a miracle treatment for what was previously an untreatable cancer.

I'm certainly glad to hear that. Ten years ago, no one with stage 4 cancer had a well controlled disease. Did your father get Keytruda (Pembrolizumab) or Opdivo (Nivolumab)? Lung cancer, melanoma, or something else? The whole story of antibodies that block signalling via the PD-1/PD-L1 pathway has been nothing less than a revolution in cancer therapy.

 

[Beave]

Stage 4 melanoma. They found it (the original skin lesion) 15 years ago and didn't think it had metastasized based on tests at the time, but a few years later it showed up in his lungs/spine.

He started with Yervoy - it didn't seem to help much. Then he went to Keytruda, got a good response for several months (tumors shrank), then they started growing again. Went to Yervoy and Opdivo together, and got good response for several months. Stopped Yervoy, continued Opdivo for several more months until side effects started bothering him (pneumonitis, mouth sores, etc). Now he's been off all of them for a year or two with no new tumors and no new growth of existing tumors (just had another PET scan that showed no change from last year).

 

[Swerd]

Stage 4 melanoma. They found it (the original skin lesion) 15 years ago and didn't think it had metastasized based on tests at the time, but a few years later it showed up in his lungs/spine.

He started with Yervoy - it didn't seem to help much. Then he went to Keytruda, got a good response for several months (tumors shrank), then they started growing again. Went to Yervoy and Opdivo together, and got good response for several months. Stopped Yervoy, continued Opdivo for several more months until side effects started bothering him (pneumonitis, mouth sores, etc). Now he's been off all of them for a year or two with no new tumors and no new growth of existing tumors (just had another PET scan that showed no change from last year).

Melanoma oncologists have observed for a long time that ~15% of patients had spontaneous remissions. They suspected that immunity against melanoma might be involved but they could never pin down what happened.

The whole story of how immune T cells get switched on & amplified was of great interest in cancer research, but it never provided any useful therapies. Decades later, the much less sexy story of how those switched on & amplified immune T cells get switched off came out. Few cancer people paid attention during the 1990s because it was about T cell anergy and programmed cell death, and not directly about cancer.

By the first decade of the 2000s, this did lead to the all those antibodies, Yervoy (against CTLA-4), and Keytruda and Opdivo (both against PD-1). Bristol-Myers Squib makes both Yervoy and Opdivo, so they tested them together first. Merck makes Keytruda and couldn't get their hands on Yervoy for a good while. But they rapidly caught up. Now these antibodies are out-of-the-park home runs in cancer therapy.

 

[Swerd]

@Beave – Now that I understand your interest in Crohn's and Ulcerative Colitis, what's your take on this paper?

Vedolizumab versus Adalimumab for Moderate-to-Severe Ulcerative Colitis
N Engl J Med 2019; 381:1215-1226

The authors concluded: In this trial involving 769 patients with moderately to severely active ulcerative colitis, vedolizumab was superior to adalimumab with respect to achievement of clinical remission and endoscopic improvement, but not corticosteroid-free clinical remission.

Vedolizumab (Entyvio) targets a different protein, Integrin α4β7, than the TNFα protein targeted by adalimumab (Humira). It's known to be located in the gut, specifically in structures in the small intestine known as Peyer's patches. Does that seem important to you?

I'm retired now. At work, I could access the entire NIH library online from my desk. Now I can't get the full text of recent papers until they're a year past publication. However you can still buy a copy from them.

 

[Beave]

I can't access the full paper. I do know that several of those authors have been speakers at the conference I attend. The topic of whether or not Entyvio or an anti-TNF should be first line therapy for UC patients was discussed at last year's conference. Of course, ideally, there would be personalized medicine where some kind of test (blood test? biopsy?) would tell the doctor ahead of time which one the patient would respond to best. But that doesn't exist and may not for a long time.

They said that the anti-TNFs tend to work much quicker than anti-integrins (days or weeks compared to weeks-to-months). But over time the anti-integrins catch up, so to speak, and in the long run may be superior. They (the anti-integrins) also have a better safety profile (lower risk of serious side effects), so that weighs in the the dilemma as well.

Of course, they always stress that the real goal isn't just remission but steroid-free remission, so this study appears to muddy the waters as much as anything.

 

[Swerd]

I can't access the full paper. I do know that several of those authors have been speakers at the conference I attend. The topic of whether or not Entyvio or an anti-TNF should be first line therapy for UC patients was discussed at last year's conference. Of course, ideally, there would be personalized medicine where some kind of test (blood test? biopsy?) would tell the doctor ahead of time which one the patient would respond to best. But that doesn't exist and may not for a long time.

If you want to see this paper now, why not email one of those authors? Tell him who you are and why you want to see the whole paper. I'd bet he can easily download a PDF copy and email it to you. Anyone who works in an academic institution in the US should have access to that.

In older days before the internet, whenever you published a paper, you got printed copies from the journal. Interested people would send postcards asking for a copy. It was routine, and it was considered standard courtesy to mail out copies. This was especially true for people who didn't have access to medical libraries or copiers.

They said that the anti-TNFs tend to work much quicker than anti-integrins (days or weeks compared to weeks-to-months). But over time the anti-integrins catch up, so to speak, and in the long run may be superior. They (the anti-integrins) also have a better safety profile (lower risk of serious side effects), so that weighs in the the dilemma as well.

That's what I gathered just from reading the abstract and introduction. Thanks for the background you learned from the conference.

Of course, they always stress that the real goal isn't just remission but steroid-free remission, so this study appears to muddy the waters as much as anything.

As I've been learning – as you've been telling me. I've been on 20th century anti-inflammation medications for some time. And I've wanted to go on Humira or something like it, for the last 3 years. I guess I had unrealistic expectations about it. It's good to be optimistic about one's future with chronic auto-immune diseases like RA or with cancer, but I'm actually not too surprised that the modern monoclonal antibodies still require additional medications, careful monitoring, and fine tuning.

I'd like to stay in touch with you on this subject. Your experience & knowledge is valuable. I'll send you a PM with my email address.

 

[Pogre]

I just wanna say that I've been following and I care. I've been quiet in this thread because I never know what to say in these situations, but I also wanna let you know, well, you know...

I'm wishing for you the best outcome possible @Swerd! I do have faith in our scientific and medical community. I can easily remember when the prognosis for cancer used to always be dire. It's not that way anymore, and they keep getting better at combating it.

 

[Swerd]

@Pogre – Thanks!

 

[Swerd]

Today is Monday April 6th and my surgery had been set for next Monday, April 13. That got canceled due to Coronavirus. I just got off the phone about an hour ago.

Surgery is now scheduled for June 25th. I certainly hope things are somewhat more like normal than they are now .