Current Immunotherapy (also referred to as Check Point Inhibitors)
From the November 2015 link - Here are more ways Opdivo has been approved and is helping others:
- Advanced renal cell carcinoma (11/23/2015)
- Advanced non-squamous non-small cell lung cancer - after platinum based chemo (10/9/2015)
- In the Nivo/Opdivo with Ipililmumab/Yervoy combo for BRAF V600 advanced melanoma (10/1/2015)
- Advanced non-small cell lung cancer - after platinum based chemo (3/4/2015)
- For melanoma, after failing ipi, and if BRAF positive, BRAFi (12/22/14)
Response rate and side effects for advanced melanoma patients:
Both anti-PD-1 drugs effect about a 40% response rate in melanoma. They can work in the brain and the body. Median time to response is about 3 months. But, there are outliers, with documented responses, that do not occur until 6 - 9 months. Here's a cool graph...
|Here's a post with more info: Time to Response...Ipi vs Nivo and ipi|
Side effects are similar for both drugs and are those typical for immunotherapy, but less severe than those encountered with ipi. On the topic of side effects...they SHOULD be treated!!! As quickly as possible, often with a break from medication and immunosuppressive drugs as required. While oncologists not familiar with immunotherapy may fear decreased therapeutic response if steroids are used...THIS IS NOT THE CASE!!! Here's a post (with multiple links within related to treating immunotherapy side effects: Yep! Immunotherapy can work in the brain...and pseudoprogression can be real!!
Pembro is dosed at 200 mg IV every 3 weeks. Nivo is dosed at 240 mg IV every two weeks or 480mg IV every 4 weeks, endpoints vary per doc, patient and institution. When ipi is combined with nivo, response rates in melanoma rise to 50+%, though side effects do as well, though mostly due to ipi. For the combo, dosage is: nivo at 1 mg/kg followed by ipi at 3 mg/kg on the same day, every 3 weeks for 4 doses, then nivo alone at 240 mg q 2 wks or 480 mg q 4 wks. Many patients cannot tolerate all 4 doses of the ipi/nivo combo due to side effects. However, outcomes can be good even if you have to stop early. Here's a report from ASCO 2016: Nivo plus ipi, CheckMate 069 trial....18 month OS similar even if you stop meds due to side effects!!! Additionally, most folks can go on to tolerate nivo alone, once their side effects are brought under control with a medication break and/or steroids. Pembro in combination with ipi is being studied.
At this point in melanoma, the only approved targeted therapy is for patients whose tumor is positive for the BRAF V600 mutation. About 50% of melanomas are. However, researchers are looking at drugs that could target other points in the molecular pathway of melanoma. This diagram shows what I mean by "pathway"...
|A Melanoma Molecular Disease Model (See the link below for credit and more info)|
Here's just one example from March of this year: What tangled 'paths' we weave: Nilotinib for KIT mutated melanoma and Buparlisib for the PI3K pathway in melanoma brain mets
But....for current purposes....I am focusing on the BRAF mutation. Here's a post I made a bit ago that really breaks down what BRAF is, what it means in melanoma, and how the drugs work: BRAF inhibitors for melanoma: Dabrafenib, Vemurafenib, Dabrafenib/trametinib combo. Answers!!!!!
Usually when we combine drugs, we end up with increased side effects. However, in the case of BRAF targeted therapy we now know that BRAF inhibitors should ALWAYS be given with a MEK inhibitor. Strangely enough, when the combo is given, patients experience better response rates, DECREASED side effects, and DECREASED rates of tumor work-around.
DRUGS, administration, and side effects:
BRAF inhibitor (BRAFi) drugs include: Vemurafenib (Zelboraf), Dabrafenib (Tafinlar), Sorafenib (Nexavar), and Encorafenib
MEK inhibitors (MEKi) include: Trametinib (Mekinist), Cobimetinib (Cotellic) and Binimetinib (not yet given a brand name)
These drugs are administered orally. So that's super cool. Dosing depends on the particular drug.
Side effects include joint pain, rashes, extreme sun sensitivity, development of benign skin cancers, fevers and sometimes liver toxicity.
EFFECTIVENESS and tumor work-around:
For patients who are BRAF positive, BRAF inhibitors combined with a MEK inhibitor have impressive response rates, clearing tumors rapidly, and often completely, in about 70-80% of patients and are effective in the brain and body. However, those responses are not very durable, with most tumors learning to work around the inhibition in about 7-9 months. BUT!!!! By using an "alternate dosing schedule" (one that is varied, rather than absolute with an 'every so many hours daily' dosing pattern), combining BRAFi with MEKi, as well as the development of the newer drugs (Here's a post out of ASCO this year: Encorafenib/binimetinib, a BRAF/MEK combo = 14.9 month PFS) that time can be stretched out a bit. Furthermore, despite the statistics, there are some melanoma peeps whose melanoma has been successfully managed for years on BRAF/MEK combo's!! Finally, some melanoma specialists use BRAF/MEK combo's in BRAF positive patients, to rapidly decrease the tumor burden, then switch the patient to slower acting, but more durable immunotherapy. And...in the realm of 'the latest and greatest', researchers are working on combining BRAF/MEK with immunotherapy. Here's a recent post on the topic with more links within: ASCO 2017: Atezo (anti-PDL1) with Cobimetinib (MEKi) and Vemurafenib (BRAFi) for BRAF V-600 melanoma
DECIDING on immunotherapy vs targeted therapy in the BRAF positive patient - can be tricky! Here is a post addressing that issue via a discussion between melanoma experts: Pick your poison: Weber and Agarwala discuss combination therapy for melanoma
INTRALSIONAL (also referred to as 'intratumoral') THERAPY
Intralesional drugs include (but are not limited to):
CAVATAK - derived from the Coxsackievirus
T-VEC - also called OncoVEX, Imlygic, or Talimogene Laherparepvec - uses the herpes virus with GM-CSF
PV-10 - derived from Rose Bengal
HF10 - also derived from HSV
SD101 - a TLR9 agonist
IL-2 - see note above, is also being used
These drugs are injected directly into a relatively superficial melanoma tumor. They have been found to be effective in not only eradicating the tumor into which they have been injected, but 'by-stander' lesions as well. Researchers feel that they have the most promise when they are combined with a systemic treatment like immunotherapy. I summarized response rates, side effects, and pretty much everything else current about these drugs in this post from this year's ASCO reports on all of them: All things intralesional/intratumoral
FUTURE TREATMENT OPTIONS
Despite the success that these therapies have had for many melanoma patients, myself included, they are insufficient for far too many! Luckily, research and drug development continues. Many researchers have noted that combo's are likely to be the future of melanoma treatment. Work is ongoing on IDO inhibitors, ERK inhibitors, vaccines (though I fear we are not there yet), new anti-PD-1 and anti-PD-L1 drugs, anti-LAG-3, CD47 blockers, HDAC inhibitors, and more.
I hope this primer will be helpful. What has served me best in attaining effective treatment for my melanoma has been seeking out a melanoma specialist and never being afraid to ask questions. Asking this question of my doctor may have been the most beneficial: "What treatment would you recommend if it were YOU or your brother, sister, wife, father, mother.... in need?"
I wish you all my very best. Hang in there. And....thanks, ratties! - love, c
P.S. If all the acronyms are driving you crazy, here's a post that defines at least some of them: Melanoma abbreviations ~ and random thoughts on posting melanoma crap-ola....
P.S.S. A sense of humor really does help!! - c