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Monday, 7 July 2014

Summarizing video on Melanoma at ASCO


A good video with Jedd Wolchok:

http://www.oncologytube.com/v/1033390/asco-2014-melanoma


@ min 11: listen to relationship between PDL1 expression and response to anti-PD1 (in a nutshell, PDL1 expression is neither permanent nor evenly expressed in the tumor, so is NOT a good biomarker for response to anti-PD1 treatment)

@ min 15: the Ipi/ Nivo combo

As always, some *irritating* comments about side effects- untreated Melanoma's side effect is death, so maybe we should start looking at side effects in comparison to the positive effect of the drug: in Melanoma, no drug does not equal no side effects but death, so if Grade 3 side effects are the price to live, which patient will rather die?
Tellingly, the doctor was less worried about them than the interviewer and any speaker I've heard at ASCO said that they had gotten much better at detecting side effects under immuntherapy earlier and gotten better at treating them.


@ ca min 25: the BRAF/ MEK combo- COMBI-D trial from GSK

I had hoped for a personal opinion on why the latest data about the BRAF/MEK combo versus BRAF alone somehow all of a sudden seems to show that the BRAF mono therapy is *better* than in the Phase 2 trial.

Now, drugs in later stage trials somehow always tend to do *worse* than initially assumed, there are articles out there on how early trials tend to overestimate efficacy and underestimate side effects, so now all of a sudden having a drug being *better* is a bit of an oddity and requires an explanation.

There are a number of possibilities out there- including patient selection, differences in evaluation and the time-point of when a patient is taken off a trial- all of them are relevant to patients, because they could tell us things like which patients are more likely to respond or whether PFS (progression-free survival) as a surrogate marker in clinical trials is influenced by the general treatment options available because one of the possible explanations is that doctors kept their patients as long as possible on the trial because there simply were no other treatment options around (the no scan, no progression option).

So simply saying 'we have to wait for more results in the future' is also a way of chickening out- and picking on Jeff Wolchok now is grossly unfair because that's the general refrain.
However, Melanoma patients continue to die and our patients have already lost their lives on these trials, so they deserve the most open trouble-shooting discussion everyone can come up with.
Science is by definition not a straight path but trial and error- but progress depends on the quality of the trouble-shooting. While expecting that every experiment succeeds is unrealistic, patients can expect that there is an open and constructive discussion about what didn't work to ensure the fastest progress possible- because they paid and continue to pay with their lives for that very research.

As Helsinki states
…..
6.         The primary purpose of medical research involving human subjects is to understand the causes, development and effects of diseases and improve preventive, diagnostic and therapeutic interventions (methods, procedures and treatments). 
……

The fastest way of understanding is not to NOT talk about it!







Sunday, 29 June 2014

Basket trials

A new type of trials that was mentioned a number of times at ASCO- BASKET trials.

The idea behind a basket trial is to match a patient whose tumor shows a specific mutation- like BRAF or NRAS- to a drug that is know to work on that mutation. So a Melanoma patient with a BRAF mutation could be on that trial as well as a colon cancer patient with a BRAF mutation.

You can find an article on the topic here: http://goo.gl/JqfGs8


This type of trial will become increasingly important the more we learn about the genetic make-up of tumours and as the article says:

'Though randomized clinical trials are the preferred gold standard for FDA approval, the design is often not feasible in a timely manner for rare mutations and patients with rapidly advancing malignancies.  - See more at: http://www.oncotherapynetwork.com/conference-report/basket-design-novel-approach-cancer-clinical-trials?GUID=5613AAF4-725E-4285-8C2F-CEDE506C383F&rememberme=1&ts=29062014#sthash.J1uzYQxP.dpuf'



Saturday, 7 June 2014

On the value of PDL1 as predictive biomarker for response to anti-PD1- OR RATHER NOT



For those of you who remember, I was rather irritated by the AACR press release in April

'Biomarker Identifies Melanoma Patients Who May Respond to Immunotherapy MK-3475'

http://www.aacr.org/home/public--media/aacr-press-releases.aspx?d=3307

on the value of PD-L1 as biomarker for response to anti-PD1.

A GOOD biomarker would be: you have it, you respond, you don't have it, you don't respond (or the other way around: you don't have it, you respond, you have it, you don't respond).

The crunch point of the AACR data about MK-3475 presented was

'Similarly, 86 percent of the patients whose tumors were PD-L1-positive were alive after one year, compared with 72 percent of those whose tumors were PD-L1-negative.'


For comparison, on Ipi 3mg/kg: 45.6 percent are alive after one year ( Phase 3 study, Hodi et al. 2010
Read the original publication here ).

Now, Mario Sznol suggested in a session last Saturday at ASCO (see details below), that there might even be no difference in overall survival for patients on anti-PD1 whose tumours are PDL-1 positive and those whose tumours are PDL-1 negative.



Practical Considerations in the Design of Clinical Trials of Targeted Therapies and Immunotherapy
Saturday, May 31st
….
1:55 PM - 2:15 PM
One Size Does Not Fit All: What We Have Learned from Immunotherapy Trials
Mario Sznol, MD Disclosure
Yale Cancer Center


One obviously has to be careful when comparing data from early Phases (like now PD1) with later Phases (like for Ipi), because there tend to be very few patients in the early Phases and the dose of the drug might not be optimal- as the point of a Phase 1 trial is to find that out. So results can be the sum of patients who have received different amounts of drugs- it pays off to read the details.

Nevertheless, we've never had such a high survival in a Phase 1 on any of the other drugs, so while the final data might be a little less grand- 86 or even 72 percent are just still SO many more than the 45.6 percent of patients on Ipi alive after one year that this will be very hard to explain purely by bias in the patient selection or simple coincidence.
This makes me feel that any comment suggesting that a Melanoma patient should rather die waiting until the final PD1 results are in (or maybe participate in a trial along the lines of PD1 versus DTIC- anyone?!) reveals a deeply cynical attitude towards the suffering of Melanoma patients. Metastatic Melanoma is horrendous, we are loosing young patients and our goal should be to save as many as we possibly can and living through the first year would be a good start!

Take home messages-
- don't bother about PDL-1 status, in any case, survival chances on anti-PD1 look better than on anything else out there.
- follow the updates on the early phase trials for anti- PD1 because they will tell us how good these drugs actually really are



Monday, 2 June 2014

ASCO- the best I've seen: Nivo plus Ipi


And this is the best I've seen this ASCO-

M. Snzol presented the overall survival on the Nivo plus Ipi combo

at Nivo 1 mg/kg and Ipi 3 mg/kg


94% of patients are still alive after 1 year 
88% after 2 years


If you look at the data, you will see that the patient groups are very small and that especially for the higher doses, the proportion of BRAF negative patients is higher. As those do overall better than BRAF positive patients, this result might look less good for BRAF pos patients.
As the numbers are small, one has to be careful but still, this is OVERALL SURVIVAL in an so far unseen magnitude (for comparison, on Ipi 45.6 % of all patients are still alive after 1 year, Hodi 2010, read the paper). The side effects can be severe but still, people LIVE!!!

So there is hope in Melanoma!

Primary overall survival under T-Vec



This is a study comparing the injection of GM-CSF subcutaneous versus T-Vec intra-lesional in
277 patients with 2116 lesions. There was an interesting by-stander effect on un-injected skin lesions was roughly half the size of the response in injected lesion, but visceral lesions respond less well.
The median overall survival was 23.3 months on T-Vec versus 18.9 months on GM-CSF, and especially benefitting appear patients with Stage 3B/C, 4M1a disease who had had no prior adjuvant therapy. Side effects are rather local, so the therapy is rather well-tolerated.

The abstract can be found here:
http://abstracts.asco.org/144/AbstView_144_133898.html

So this could look like a therapy option for patients with Stage 3B/C and 4M1a Melanoma who have mainly skin metastases rather than visceral lesions.

As this is a treatment for Stage 3 patients who might or might not progress, side effects are an important topic as taken up by the last speaker of the session- so I think there will need to be a very careful stratification into groups of patients who will  benefit from receiving e.g. Ipi and where the associated side effects are 'worth' the benefit (overall survival benefit is not available yet in the EORTC study) and others who might be better off with e.g. T-Vec with less side effects….in conclusion, it seems that doing something instead of simply waiting might be a smart patient strategy.


Ipi versus placebo after fully resected Melanoma- Eggermnont presentation at ASCO



A. Eggermont presented the results of the EORTC study for Stage III Melanoma- Ipi 10 mg/kg (induction plus maintenance) versus placebo in about 1000 patients with nearly fully-resected Melanoma in a high-risk patient population for relapse.

Results:
relapses in 234/ 475 with Ipi versus 294/ 476 with placebo, after a median 26.1 versus 17.1 months respectively.

Especially profiting appear patients in stage 3b and 3c and the ones with ulcerated tumours, while the data is too immature for 3a patients who might or might not profit.
Side effects were comparable to the ones known for Stage IV Melanoma, so this is unfortunately not a treatment without problems.


                                                        Pbo                 Ipi
No. RFS events294234
3-Year rates (SE)34.8% (2.4%)46.5% (2.5%)
Median (mos)17.126.1
HR (95% CI)0.75 (0.64–0.90)
Log-rankP = 0.0013
RFS: recurrence- free survival

http://abstracts.asco.org/144/AbstView_144_130118.html

LBA9008

Upon resistance, plasma concentrations of Vemurafenib are lower than at the begin of the therapy




A finding that could suggest that low levels of Vemurafenib in the blood are a reason that the tumours no longer respond…. Drug concentrations can become lower when the body e.g. makes more of the enzymes that degrade those drugs.

http://abstracts.asco.org/144/AbstView_144_129906.html