Keytruda

[pjoshea13]

A number of men have asked or commented about Keytruda, including Gus, Blair77 & DSim.

New study below.

The target of Merck's Keytruda (Pembrolizumab) is the receptor known as PD-1 (Programmed cell death protein 1), which suppresses T cell activity, thereby dampening the immune response.

The concept behind Keytruda as a viable product is that, while only a minority with a specific cancer type will benefit, the potential market is quite large. Thus, it is a general cancer treatment, that requires pre-screening.

Baas, et al, 2017 [2], looked for PD-1, PD-L1 (its natural ligand), and CD3 (T cell marker) in "tissue samples taken from 25 men with high-grade prostate cancer."

"An overall low expression of PD-1 and PD-L1, and a concurrent high expression of CD3+ T cells was found in high-risk prostate cancer tissue." "Because of this, one might be able to question the role of PD-L1 in local immune suppression in prostate cancer."

From a 2016 paper [3]:

"While programmed cell death 1 (PD-1) inhibitors have shown clear anti-tumor efficacy in several solid tumors, prior results in men with metastatic castration resistant prostate cancer (mCRPC) showed no evidence of activity. Here we report unexpected antitumor activity seen in mCRPC patients treated with the anti-PD-1 antibody pembrolizumab. Patients with evidence of progression on enzalutamide were treated with pembrolizumab 200 mg IV every 3 weeks for 4 doses; pembrolizumab was added to standard dose enzalutamide. Three of the first ten patients enrolled in this ongoing phase II trial experienced rapid prostate specific antigen (PSA) reductions to ≤ 0.2 ng/ml."

A 2015 Canadian paper [4] had found PD-L1 to be highly expressed in Enzalutamide resistant prostate cancer.

It appears that PD-1 activation might be a common resistance response to Xtandi. So Keytruda, in essence, would simply be extending the effectiveness of Xtandi? Or is there added value?

In the new study:

"The genomes of cancers deficient in mismatch repair (MMR) contain exceptionally high numbers of somatic mutations."

We evaluated the "efficacy of PD-1 blockade in patients with advanced MMR-deficient cancers across 12 different tumor types. Objective radiographic responses were observed in 53% of patients and complete responses were achieved in 21% of patients."

From a NY Times article (today) [5]:

"After taking pembrolizumab, 66 patients had their tumors shrink substantially and stabilize, instead of continuing to grow. Among them were 18 patients whose tumors vanished and have not returned."

"The drug, made by Merck, is already on the market for select patients with a few types of advanced lung, melanoma and bladder tumors. It is expensive, costing $156,000 a year.

A test for the mutations targeted by the drug is already available, too, for $300 to $600.

Just 4 percent of cancer patients have the type of genetic aberration susceptible to pembrolizumab."

...

At the same time:

"Merck $MRK has had to hit the brakes on enrolling new patients for two of its late-stage combo studies involving its blockbuster checkpoint Keytruda after the monitoring committee raised a red flag on an imbalance of deaths in the studies involving multiple myeloma." [6]

-Patrick

[1] science.sciencemag.org/cont...

Abstract

The genomes of cancers deficient in mismatch repair (MMR) contain exceptionally high numbers of somatic mutations. In a proof-of-concept study, we previously showed that colorectal cancers with MMR deficiency were sensitive to immune checkpoint blockade with anti-PD-1 antibodies. We have expanded this study to now evaluate efficacy of PD-1 blockade in patients with advanced MMR-deficient cancers across 12 different tumor types. Objective radiographic responses were observed in 53% of patients and complete responses were achieved in 21% of patients. Responses were durable with median progression-free and overall survival still not reached. Functional analysis in a responding patient demonstrated rapid in vivo expansion of neoantigen-specific T cell clones that were reactive to mutant neopeptides found in the tumor. These data support the hypothesis that the large proportion of mutant neoantigens in MMR-deficient cancers make them sensitive to immune checkpoint blockade, regardless of the cancers’ tissue of origin.

[2] ncbi.nlm.nih.gov/pubmed/284...

[3] ncbi.nlm.nih.gov/pmc/articl...

[4] ncbi.nlm.nih.gov/pubmed/254...

[5] nytimes.com/2017/06/08/heal...

[6] endpts.com/merck-halts-enro...

[Dan59]

Thanks for this Patrick

[AlanMeyer]

That's an interesting study. They seem to be implying that cells with defective DNA repair mechanisms and therefore high numbers of DNA mutations will tend to put up strong PD-1 defense against immune responses. To my inexpert mind, that makes sense. Cells that look odd to the immune system are more likely to be attacked by it. Therefore any of those cells that have a strong defense, e.g., lots of PD-1, against immune system attack would be selected and come to dominate the cancer population.

Life is certainly a fascinating process.

Alan

[Hidden in reply to AlanMeyer]

I'm cross posting our story below since this seems to be the main Keytruda thread.

Anyway, to your point: the way the nice Johns Hopkins doc explained it is that highly mutated DNA makes lots of weird proteins. So once the PD-1 defense is out of the way, the immune system can really go at it. My husband also had Provenge a couple years ago, so his immune system was presumably well primed - maybe that partially explains his good response.

One other fascinating thing the JH doc said: my husband's measured PD-1(PD-L1? I forget) was low. We asked if that meant lower possibility of good response. He said, you'd think so, but actually, it's not a good predictor. They're not sure why, but he thought it might be because the assays are unreliable. He said they've seen both low PD-1 responding, and high PD-1 not. So this is an unsolved mystery for now.

Our story: My husband (diagnosed 2014 metastatic G9) has been on Keytruda since July 2017. Biopsy of a growing lymph node metastasis (he was failing Xtandi) showed the MSI-H DNA signature that put him in the category for FDA approved use.

His response has been fantastic so far. The lymph node met in his neck vanished (this was something you could see and touch). PSA dropped to undetectable within 6 weeks and has stayed there. Scans show other lymph node mets have mostly vanished, the one that's left is half the size, and bone mets are stable. Zero side effects (so far) and he is feeling much healthier generally (Lupron side effects are still unpleasant).

Wishing others the same good luck we've had.

[Suziq150 in reply to Hidden]

How did they find the lymph node met

[Hidden in reply to Suziq150]

Not difficult. There was a big lump in his neck, you could see it.

[Daddysdaughter in reply to Hidden]

My father is 78 G9 MCRPC with NEPC - he same he has now failed xtandu, chemo jevtana and carboplatin. Nodes didn’t shrink and during chemo his CT showed metastasis to spine and pelvis. His MO is awaiting results of his biopsy to determine if he will get keytruda. How is your husband doing? How many infusions has he had? Does it seem to be controlling the growth? Wishing him well and your strength to help him through this!

[Hidden in reply to Daddysdaughter]

My husband has received Keytruda since July last year, it’s one infusion every three weeks. So far he’s doing great. His lymph nodes shrank all the way back and while his bone mets may still be there, they haven’t been growing. And no side effects so far. He’s still very tired and achy (Lupron!) but we are very grateful for his excellent response. Good luck with the genetic lottery! Hope your father could benefit from this too.

[Daddysdaughter in reply to Hidden]

My fathers results were MSI- negative so we have to choose a different trial.

[Hidden in reply to Daddysdaughter]

Best of luck. They are learning more every day and I hope you find something that can help.