As I expected, there was not a great deal of NEW news for melanoma patients coming out of ASCO this year. However, there were a few new things in the works as well as supporting and dismissive data - (this last often being under reported, but certainly important!!!) - for some existing ideas/treatment strategies. Over the next few days I will be posting some of the hits and misses (from my perspective) with my take (in red). Here we go....
#1: I first reported on NKTR in 2013. Click here for that report as well as abstracts and analysis from 2018. After examining the Phase 1 and Phase 2 reports of the PIVOT trial I wrote:
"...back to NKTR-214 combined with nivo. Like many drugs/trials in cancer/melanoma world, the Phase 1 trials were super promising. Phase II results were a little less so. Responses as noted in the article were "(ORR) of 50% in treatment-naïve patients with melanoma, including an ORR of 42% in PD-L1–negative patients". We have already determined that treatment naive patients tend to have the best responses. But even so, 50% beats 40%. Additionally, we also know that PD-L1 status has not been particularly definitive in attaining responses to anti-PD-1 drugs, but it is still good to note a 42% ORR in PD-L1 negative patients and that side effects were really no worse in this combo than when anti-PD-1 is taken alone. So....
I still hold out hope ~ for vaccines, for IDO-inhibitors, and the current responses to NKTR-214 combined with nivo to hold. BUT! Unlike Melanoma Big Dogs in their ivory towers....we canaries in the coalmines...the ratties...you and me...can't afford to pontificate on the hypothetical. We have to deal with the real live results that are happening for real. Today. To us."
That's how I look at melanoma research!!!! ALWAYS! Now....this:
So, this is an open and recruiting trial. It is randomized. Some folks will be getting the NKTR-214 drug with nivo, some will get nivo only. Prior ORR of 53% is better than the usual of about 40% to anti-PD-1 products given alone, but about equal to the ipi/nivo combo. If the side effects of this combo is less than those caused by ipi/nivo, that could be a good thing. Lots of the usual melanoma peeps are excluded. But, there you go.
#2: In 2017, I posted: IMO-2125, a TLR agonist combined with Yervoy (ipi) for folks with melanoma refractory to anti-PD-1 - writing:
"Hmmm..... Well, it is certainly a fact that we have folks who fail to gain effective control of their melanoma with anti-PD-1 and its 40% response rate, leaving them in desperate need of an effective therapy! It is also true that I encourage and fully support looking at any and all possible treatments to help them. Yet, I remain a little puzzled here. This statement sounds strong, but is substantially lacking in, hmmm....what's the word?????? "...data from multiple parameters of immune markers from tumor biopsies have been very informative in establishing proof-of-mechanism and supporting the dose selection for the Phase 2 portion of the trial.” Oh! I know what it is....DATA!!!!!!!!!!!!!!! This report tells us NOTHING about how the folks in the phase 1 trial are doing!!!
An interesting aside: The name TLR, toll-like receptor, came from the appearance the fruit fly larvae developed when used as subjects by researchers to isolate the molecule's function. The larvae in whom the receptor was changed, looked very peculiar, or "droll", according to the German researchers who won a Nobel prize in medicine for this work. And the German word for "droll" (i.e. funny) is "toll"! The more you know....
While I hope IMO-2125 will absolutely be the cure for ever so many cancers, including melanoma, we need to remember that current intratumoral/intralesional therapies that are being combined with immunotherapy daily, to good effect, are available for melanoma patients in need and come WITH data supporting their efficacy! Here's a post reviewing a wide variety of them and the DATA required for them to sally forth:
ASCO 2017: All things intralesional/intratumoral
If TLR agonists become the next great thing....will we all be cured of our melanoma AND have a great sense of humor...or just look a little funny????? Hang tough ratties! The road is long with lots of tolls! And I mean LOTS!!! - c"
Now, there's this:
So....another recruiting option for those who have progressed on anti-PD-1 and have an injectable lesions. Stage III or IV melanoma ratties will be randomized to get either injections of tilsotolimod (IMO-2125) directly into their lesion along with ipi or ipi alone. You cannot have already taken a TLR agonist, ipi (unless it was only as adjuvant more than 12 weeks before progression) and can have no CNS disease other than stable brain mets.
The Future for Melanoma Treatment = Combo's! Dr. Weber breaks it down - This interview/report is pretty cool and clear. I'll just let the Wizard break it down - Now, this:
I seems that you can already have had anti-PD-1, or not, and still qualify. Folks with NSCLC, urothelial carcinoma or melanoma may enter. Initially, it is a just a dose limiting study...how much can you give without making folks grow 2 heads?...but then they are also going to look at the impact on the tumors as well. Early days for this one, but....
#4: TNF is tumor necrosis factor is a protein that plays a role in cell life, differentiation, growth, and death and has a lot to do with inflammation in our bodies. In cancer, it's even more complicated. In this article, the authors note: "In regard to cancer, TNF is a double-dealer. On one hand, TNF could be an endogenous tumor promoter, because TNF stimulates cancer cells’ growth, proliferation, invasion and metastasis, and tumor angiogenesis. On the other hand, TNF could be a cancer killer. The property of TNF in inducing cancer cell death renders it a potential cancer therapeutic, although much work is needed to reduce its toxicity for systematic TNF administration. Recent studies have focused on sensitizing cancer cells to TNF-induced apoptosis through inhibiting survival signals such as NF-κB, by combined therapy."
Now, there's this:
Knowing that TNF is "upregulated in the intestines of patients suffering from colitis" due to ipi/nivo, these researchers gave mice a TNF inhibitor BEFORE treating them with ipi/nivo. Per this report, blocking TNF improved episodes of colitis and hepatitis caused by ipi/nivo in these poor mice AND the ipi/nivo was still effective against their tumors. Let's hope it works in real live ratties!!
#5: TIL is complicated in lots of ways. I posted this in 2016: TIL - Tumor infiltrating lymphocytes writing in part:
"What is TIL? TIL (Tumor infiltrating lymphocytes) are used in an ACT (adoptive cell transfer) therapy like this: A tumor is removed from the patient's body. Lymphocytes are collected from it. Those lymphocytes are tested in order to identify the cells that show the greatest anti-tumor activity. Then....those particular cells are grown in a lab for several weeks. If the TIL cells grow sufficiently, the patient is given a body pounding dosing of chemotherapy to rid the body of other lymphocytes so that the new TIL batch will be accepted more readily when they are infused with no other immune cells there to attack them. The newly grown lymphocytes are then returned to the patient in an infusion along with a cytokine (immune stimulating agent) like IL2 (interleukin 2). In numerous studies TIL demonstrates a 50% response rate in patients with metastatic melanoma."
"So....basically. A tumor is harvested. T-cells are extracted from it...with the idea that they were good soldiers who had already recognized and were in the process of attacking that tumor. To increase their numbers...they are grown in a dish. To further their interests...the patient (ie the battlefield) is injected with bad stuff (IL-2, IL-21, or cyclophosphomide and fludarabine, are frequently used) to kill off T-cells that might try to block their fight with the tumor...and/or support the good T-cells...which are then sent back into battle (ie injected into the patient)!"
Further, I posted this earlier this year: Baseline levels of IL-9 predicted response to Adoptive cell therapy (ACT) using TIL in melanoma and a complete response in TIL paired with nivo (a case study) Where it was noted that: "Best overall response for the entire cohort was 42%; 47% in 43 checkpoint naïve patients, 38% when patients were exposed to anti-CTLA4 alone (21 patients) and 33% if also exposed to anti-PD1 (9 patients) prior to TIL ACT. Median overall survival was 17.3 months; 24.6 months in CTLA4 naïve patients and 8.6 months in patients with prior CTLA4 blockade. "
Growing useful cells to be injected back to the patient is tricky and just one of many obstacles in TIL therapy. As the process has advanced, it has diverged into a variety of techniques and methods that can be utilized. Now, there's this:
Here 55 Stage III/IV melanoma patients previously treated with anti-PD-1, ipi, and/or BRAF/MEK, with progressive disease and high tumor burden were given "cryopreserved lifileucel" derived from "tumors resected" at several institutions, then "processed" at a central facility for "TIL production in a 22-day process" then "cryopreserved and shipped to sites". As is typical with TIL therapy, patients were given one of the nasty pre-treatment concoctions to kill off their existing lymphocytes, were then given a single infusion of lifileucel, followed by up to 6 doses of hell (I mean IL-2). ORR = 38%. Of 21 initial responders, 4 have progressed over the f/u of 7.4 months. Overall disease control was 76%. Both folks who had progressed on anti-PD-1 and those with PD-L1 negative status were among the responders. Based on this result, a new cohort is recruiting.
#6: The "microbiome" craze is not exactly 'new' as it has taken over the universe! BUT!!! How much is hype? How much is real? How can we drill down on the details? How can we harness what we know to impact treatments such that patients benefit? The next 3 posts address this topic. Now, there's this:
Here, researchers are going to give the first 12 patients with solid tumors who have progressed on anti-PD-1, Pembro every 3 weeks along with a capsule of MRx0518, a "live biotherapeutic", taken by mouth, twice a day for one 21 day cycle. In part b, the plan is that 30 patients could be given the same for up to 35 cycles or until disease progression. My only concern here would be the fact that we've found that folks who took probiotics from a bottle did not do so well, while those that got their cooties from foods like Kefir, kimchi, yogurt, sauerkraut, etc. - did better. If I were to consider participation in this study, I'd be asking my doc about that.
#7: As I noted above, these last two reports are more along the lines of ~ "What once was old is new again!" I've been talking about the Cooties in our Gut since 2015, putting it all together in this post from 2018: Microbes again...and how they may be associated with improved response to anti-PD-1 for melanoma patients...and you might even laugh!!! Still, there is much we don't understand about how all this works. Now, there's this:
So, a lot of fancy words to say that mice with a certain microbiome component (less UPR expression) responded better to immunotherapy. Further, when those mice lived with mice whose gut initially did not possess those properties, researchers found that they too developed an altered gut flora and a greater ability to restrict the growth of melanoma. Bottom line: Live with somebody who has the right cooties! (If you can figure out who exactly that is!!!)
#8: Given the fact that a certain "microbiome" aids our responses to immunotherapy while a different one does not, it makes sense that antibiotics, which kill off bacteria that are trying to do us harm as well as those who may do a body good, could be problematic when trying to foster cooties that improve our response to immunotherapy. Here are some earlier articles and explanations:
This from 2017: Antibiotic use MAY decrease effectiveness of immunotherapy?????
And this from April of this year: DECREASED progression free survival in melanoma patients treated with antibiotics prior to or at start of immunotherapy!!!! In that study it was noted that, despite - "Small numbers. ..the 10 folks, from the 74 advanced melanoma peeps examined, who were given antibiotics within 30 days of their immunotherapy, had more resistance to treatment, a shorter length of progression free survival (2.4 vs 7.3 months) and overall survival was shorter at 10.7 months vs 18.3 months."
Now, there's this:
In this retrospective study of 108 melanoma patients treated with immunotherapy, it was noted that 46 were given antibiotics at some point between 6 months prior and 1 month after starting their immunotherapy treatment. PFS was 88 days in those who took antibiotics and 322 days in the group who didn't. OS was 294 days in the antibiotic group - 573 days in the non-antibiotic group. Response rate was 8.7% in the group that had taken antibiotics vs 12.9% in the group that had not been exposed to antibiotics. As I wrote in the post I put up in April: "So...if you really NEED antibiotics, they may save your life and will certainly decrease misery. BUT, if you DON'T really NEED them...they can cause harm, in lots of ways."
WHEW!!! Melanoma is a lot. A lot of crap. Ad an actual crap shoot for far too many! But, just like today...
...there is still beauty, despite the storm.
More to come. c