Latest Article on IP/NIVO failure.

Hi Trent, checkmate 915 trial looked at a totally different patient population than you are in. They were trying to see if the combination was better than pd-1 nivo in adjuvant patients after surgery, which means starting with zero tumor burden on scans. They are also doing neo adjuvant trials where they use combination of Ipi/nivo before surgery,trying to reduce tumor size before cutting or maybe not having to have surgery at all if tumor shrinks. 915 results answer a question for those specific adjuvant type patient and shouldn’t be used for stage 4 patients who progress which is your current situation. Progression on nivo has very little data but I shared some new retrospective findings with you a few post ago, and adding Ipi to nivo for those who progress on pd-1 monotherapy works way better than Ipi alone based on small retrospective data set. The 915 trial won’t be the only negative trial in the future, mainly because the standard of care drugs, in this case nivo (pd-1) works really well!!!!

When I saw this article – I was SOOOOOO afraid this would happen. Okay. Deep breath. When you look at articles talking about research reports you have to figure out their slant!!!! Super important. Are they someone writing for or representing the perspective of an institution? A group – like the AHA? Or – in this case – financial investors? In the “about us” section of the FiercePharma website they note: “Our aim is to analyze the day’s news, showing readers not only what they need to know, but why they need to know it. Beyond the daily, the FiercePharma team produces special reports that take stock of the industry’s products and finances, and shed new light on industry trends.” In other words, while they do share data from research, it is mostly from the prospective of financial investment.

NOW – what were they really writing about? They were writing about this study: CheckMate 915 Here is a synopsis of the results of that study:

“Updated results from the randomized, phase 3 CheckMate-915 trial found that nivolumab (Opdivo) plus ipilimumab (Yervoy) did not result in a statistically significant improvement in recurrence-free survival (RFS) in the intention-to-treat population of participants, according to Bristol Myers Squibb, the developer of the agents. The study is evaluating the nivolumab-ipilimumab combination versus nivolumab alone in patients who have had a complete surgical removal of stage IIIb/c/d or stage IV melanoma. “We are proud of our legacy in melanoma with both [nivolumab] and [ipilimumab],” Sabine Maier, MD, vice president and head of Oncology Clinical Development at Bristol Myers Squibb, said in a press release. “They have each brought significant benefit as monotherapies for appropriate melanoma patients in the adjuvant setting, and as a dual immunotherapy regimen in the metastatic setting.”

“In CheckMate-915, we evaluated adding [ipilimumab] to [nivolumab] against [nivolumab] – an established, active comparator and current standard of care in the adjuvant setting. We designed this study to determine if dual immunotherapy has the potential to bring additional benefits to patients in this setting, understanding the high benchmark we would need to exceed with this trial,” Maier continued. “We remain committed to continued research in melanoma, both to further understand the potential benefit of [ipilimumab] in combination with [nivolumab] to treat high-risk melanoma patients in the earlier stages of disease, as well as to study additional novel combinations in various settings.”

The randomized, placebo-controlled, double-blind, phase 3 study enrolled patients who had no prior systemic anti-cancer treatment for melanoma, except surgery for melanoma lesion(s) and/or adjuvant radiation therapy after neurosurgical resection for central nervous system lesions. Overall, 1943 patients were randomized to receive either 240 mg of nivolumab intravenously every 2 weeks and 1 mg/kg of ipilimumab every 6 weeks or 480 mg of nivolumab every 4 weeks for up to 1 year. Notably, Bristol Myers Squibb previously announced in November 2019 that a statistically significant benefit was not reached for the co-primary end point of RFS in patients whose tumors expressed PD-L1 <1%.

CheckMate-915 reinforced the already established benefit of nivolumab monotherapy as a standard of care in the adjuvant setting. The safety profiles for nivolumab monotherapy and the combination of nivolumab plus ipilimumab were consistent with previously reported studies at the aforementioned dose and schedule, and no new safety signals observed.

Bristol Myers Squibb indicated that it will complete a full evaluation of the CheckMate-915 data moving forward and will also work with investigators to share the results at an upcoming medical conference."

OKAY. SO - this was a study of the ipi/nivo combo in Stage III and IV melanoma patient who had already had their obvious melanoma REMOVED or zapped. In other words, they were NED. They were using the combo as adjuvant. That is a very different thing than using the combo when there is active disease. In this sample of patients, using the combo as an adjuvant therapy, they found that the patients did no better than those treated with nivolumab (Opdivo) as a single agent in regard to recurrence free survival. This is important stuff. If the combo, with its increased rate of side effects, does no better than nivo alone for patients in need of adjuvant treatment, then why put them through it. So - good to know. From a financial perspective, this means that BMS (Bristol Myers Squibb) can't make money on both products for another application.

NOW - for the elephant in the melanoma forum. THIS DOES NOT CHANGE THE FACT THAT THE IPI/NIVO COMBO IS STILL THE BEST THING GOING FOR STAGE IV PATIENTS WITH ACTIVE DISEASE!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!! Has nothing to do with that. I still hope for even better therapies to evolve. And I think they will. But all the data regarding the ipi/nivo combo for Stage IV patients with active disease, it still intact!!!

We have tons of data that those who progress or fail to respond to nivo alone, can respond when treated with the ipi/nivo combo. We have tons of info that compares patients on nivo alone vs those treated with the ipi/nivo combo. Those with active disease do better on the ipi/nivo combo. Here are 9 bazillion reports if you are interested: https://chaoticallypreciselifeloveandmelanoma.blogspot.com/search?q=ipi%2Fnivo
Many of these reports have pretty good charts and graphs that demonstrate the improved efficacy of the combo compared to either ipi or nivo as single agents. Researchers had hoped that the combo would demonstrate that improvement as an adjuvant treatment as well, but that didn't pan out.

No need for any additional depression. Between melanoma, a pandemic, world events, leaders who don't lead - LORDY - we got enough!! Hope this attempt at an explanation helps. Hang in there. You have every reason to hope to reap benefits from your current treatment. Yours, celeste

I was part of the Checkmate 915 on the – as it turns out – Nivo-only side, which didn’t work for me, as I had progression. Unfortunately, sounds like the other arm had just as many progressions (or not significantly less). Kind of surprises me, but everything is local. Anyway, I seem to be having more success with the combo, so – yeah – progression on nivo doesn’t mean that nivo/ipi won’t work better. And then there are more options after that (none of them fun though, I’m sure).

Oh, Gopher and Threefitty! So sorry for what you’ve endured and very glad you both seem to be responding to the combo. It will be “interesting” to hear in the coming bit what Melanoma Big Dogs think was going on here. I was lucky to respond to nivo as a single agent as a Stage IV NED patient back in 2010. In our study, it was reported that MDSC (myeloid derived suppressor cells) played a big role in response – if you had a high level you were less likely to respond. Here are a bunch of articles – https://chaoticallypreciselifeloveandmelanoma.blogspot.com/search?q=MDSC

Then there is the issue of what difference the presence of PD-L1 on tumors makes. We know that folks with and WITHOUT that marker can respond to anti-PD-L1 products (niv0-Opdivo and pembro – Keytruda) but is this factor part of the key to the results of the CheckMate 915 study?
Here is a report from 2015 – http://chaoticallypreciselifeloveandmelanoma.blogspot.com/2015/07/combos-looking-goodbut-if-pd-l1.html
The conclusion boiled down to this – Combo immunotherapy: CheckMate 067 showed us PFS of 11.5 months on the ipi/nivo combo vs 2.9 months on ipi alone and 6.9 months on nivo alone. BUT!!!!! In PD-L1 positive patients PFS was 14 months on just nivo vs 3.9 months for ipi. In PD-L1 negative patients the ipi/nivo combo was better than either monotherapy. SO! Since the ipi/nivo combo has more side effects but gives you no better results if you are PD-L1 positive….it probably makes more sense to just do nivo alone!
On that same subject, Weber and Agarwala had this discussion, also in 2015: https://chaoticallypreciselifeloveandmelanoma.blogspot.com/2015/09/pick-your-poison-weber-and-agarwala.html
In it they also note: “Folks with tumors that are positive for PD-L1 respond better to anti-PD1 products. However, many problems remain with the clarity of the test, availability of the test, consistency of results, etc. Therefore, it is a useful…though not a predictive…marker.” And – “In PD-L1 positive patients: those in the combo had a 58% overall response vs 18% ORR to ipi alone. PD-L1 negative patients: had an ORR of 55% to the combo vs 4% ORR to ipi alone.”

I worry that we learn bits and bobs, but then fail to go through with really checking them out in real time with real live ratties. Perhaps these points were examined, along with many others, in your study. I long for a day when a simple blood draw could point melanoma peeps in the right direction. Indicating a need perhaps for pretreatment with ‘x’ before carrying on with treatment ‘b’. OR – clear indications for a response, if the patient is treated with ‘c’.

Pie in the sky dreams, perhaps. But, I think it can be done. Hang tough. Thanks for leading the way. Ratties rock. – les