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!

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'

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

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

http://abstracts.asco.org/144/AbstView_144_126008.html

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 events	294	234
3-Year rates (SE)	34.8% (2.4%)	46.5% (2.5%)
Median (mos)	17.1	26.1
HR (95% CI)	0.75 (0.64–0.90)
Log-rank	P = 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

Does Vemurafenib work on brain mets?

Kim Allyson discussed in this morning's session real-world data: Does Vemurafenib work on brain mets?

http://abstracts.asco.org/144/AbstView_144_131583.html

This analysis included 275 patients and showed that Vemurafenib worked on brain mets similarly to tumours outside the brain, maybe a bit less well and less long.

14% patients had a complete response and 34% a partial response.

So yes, Vemurafenib work in the brain!

Worth getting your BRAF status re-checked over time

This was a very interesting poster at this morning's poster session- the scientist rechecked the BRAF status of patients in the original tumor, lymph nodes, liver mets and the blood and it turned out that tumours in the same patient could be both BRAF positive and negative.
They hadn't tested many patients yet, but interesting there were 2 patients who were BRAF positive in the original tumor, lymph nodes and blood but NOT in the liver.

This means that if you are BRAF negative at onset, it is worth to recheck the status later and if you want to pass this on to your oncologist, the reference to the poster is here:

Abstract 9017, ASCO 2014

http://abstracts.asco.org/144/AbstView_144_132370.html

GSK Dabrafenib/ Trametinib combo versus Dabrafenib alone

This was a very interesting session and of relevance to all patients with BRAF mutant Melanoma

Keith Flaherty presented an update on the combo versus mono study from the GSK Phase 1/2 studyhttp://clinicaltrials.gov/show/NCT01072175:

http://abstracts.asco.org/144/AbstView_144_134903.html

The overall survival for the combo was 25 months- I know the abstract says 23.8 but I noted 25 several times, so once I will get the presentation, I'll post more details of the data, against 20.2 for mono therapy. The authors argue that the data for Dabra alone could be confounded because many patients moved on to the combination- so it is most likely rather less.

Interesting to note was that after 2 years on combo

83% patients who had had a complete response

51% who had had a partial response 

35% who had had stable disease

were still alive- so survival depends on how complete one responds to the therapy.

I will post the data but he showed data that patients who first got a BRAF inhibitor and those who were permitted to cross over from the mono to the combination arm were doing WORSE. So that means one should get the combo from the onset, not after progressing on mono therapy. It always means that even allowing for cross-over is not fair for patients- because they will do worse.

This is very important data as it is overall survival data- and that is considered the 'hard' data- especially in the face of the early results from the GSK Phase 3 study presented in the next session.

Have to run, more later!

Updated on targeted therapy in NRAS mutated Melanoma

This morning, J. Sossman gave an update on the Novartis trial testing a combination of a MEK inhibitor with a cell cycle inhibitor in patients with NRAS mutated Melanoma.

http://abstracts.asco.org/144/AbstView_144_130034.html

15-20 % of all Melanomas carry a NRAS mutation and currently, there is so far no approved targeted therapy (like Vemurafenib or Dabrafenib for BRAF mutant Melanoma) available for these patients.

Analysis of NRAS mutant Melanomas has shown that they have an overactive MAPK pathway as well as cell-cycle check point dysregulation (cell-cycle check points usually control that cells don’t divide uncontrollably) which was the motivation for this trial.

There were only 22 patients on this study, so one needs to be cautious with the results but so far, 33% of patients had a partial response and 68% had clinical benefit from the treatment. So while this is maybe not the BIG success, it is an encouraging start so that maybe one day, we'll have an equally efficient targeted therapy available for patients with NRAS mutant Melanoma like we have in BRAF mutant Melanoma today.

Value in Cancer Care- ASCO session

I went to the industry and oncologist perspective on value in cancer care- very insightful!

While the speaker from industry stressed the need for return for investment, he also acknowledged the need for a re-thinking of the system. There are already a number of interesting pricing systems out there, e.g. only paying if a therapy works- need to look into that.

The oncologist made the point that oncologists have the responsibility to try and save unnecessary costs (like unnecessary imaging) to reduce health care cost, before limited budgets lead to the limitation of access to potentially beneficial treatments. He made very insightful comparisons about the size of the health budgets- if you think it's enormous, it is even more than that! He didn't have slides but I will see whether I can get the clip, I really liked the examples he gave but want to double-check before posting!

Unfortunately, I couldn't make it to the first part of the session but will definitely watch them later as I think that this is an important topic.
The theatre was packed demonstrating the interest in the topic- the last speakers said: 10 years ago such a session wouldn't have existed- and I think the BIG point here is to get all stakeholder together and to discuss this problem while respecting everyone's perspective because let's face it, things will only change if everyone gains in the process!

What I think what is increasing is the recognition that there must be an incentive for innovation (why do it otherwise?) and this is something we as advocates will have to think harder about as well.
If Melanoma patients and others with similarly desperate cancers want to live- and there is no doubt about that- they need new therapies. While in times of unlimited resources, 'just' throwing money at the problem might have looked like a solution (but even then, we need the RIGHT new drugs, not just new drugs), we all know that this is not the reality but that we have to accept a limited budget (besides, who even as a patient wants to pay even more health insurance?).
So we have to find a way to get new therapies that are BOTH profitable AND affordable- to make sure that we get new therapies coming in the first place and then actually also get access to them- now that would be something to advocate for.

Somehow I think that the economy of innovation will be a topic to work on :-)



The program below, I will see whether there is a way to access the clips from the sessions-

Can We Find Common Ground? Stakeholder Perspectives on Value in Cancer Care

Presentations

3:45 PM - 4:05 PM

Value in Cancer Care: What's the Problem?

Neal J. Meropol, MD Disclosure

University Hospitals Seidman Cancer Center and Case Western Reserve University

 View other publications from this presenter

4:05 PM - 4:25 PM

Defining Value: An ASCO Initiative

Lowell E. Schnipper, MD Disclosure

Beth Israel Deaconess Medical Center

 View other publications from this presenter

4:25 PM - 4:45 PM

The Patient Perspective

Diane Blum, MSW Disclosure

CancerCare

 View other publications from this presenter

4:45 PM - 5:05 PM

Using Value for Coverage

Lee Nisley Newcomer, MD Disclosure

United Health Group

 View other publications from this presenter

5:05 PM - 5:25 PM

Industry Perspective: Drug Development, Costs, and Return on Investment

Gregory P. Rossi, PhD Disclosure

Astrazeneca UK

 View other publications from this presenter

5:25 PM - 5:45 PM

How Should Oncologists Become Value-Based Providers?

Ezekiel J. Emanuel, MD, PhD Disclosure

Perelman School of Medicine and The Wharton School, University of Pennsylvania

 View other publications from this presenter

5:45 PM - 6:00 PM

Panel Question and Answer

Panel Discussion