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:

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:'

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'

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:

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.

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


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.

Does Vemurafenib work on brain mets?

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

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

Sunday, 1 June 2014

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 study

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.

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.