Weeks 142 & 143: Recovery and research time

Written by Lars Haakon Soraas
23
May

Weeks 142 and 143 in the war on cancer have passed. First of all: apologies for the delayed update. Have been a bit recovery/exam/research focus here. Here is an update on the last couple of weeks:

  • The most important development is that Dyanne is in much better shape now than when we checked out of the hospital in Bergen three weeks ago. She is eating well, has put on 1.5 kg in weight and is physically in much better shape too. The nausea disappeared two and a half weeks ago, but has come back a bit in the last week or so.
  • A bit more than a week ago, Dyanne started feeling like the ceiling was moving when she looked up or laid down. It seems the most likely explanation is that she has gotten something called benign paroxysmal positional vertigo (BPPV). Even if it is annoying, anything that starts with “benign” is a lot better than things which start with “malign”. She went to her physiotherapist who did some special movements with her head, and this helped quite a bit. But she is not yet completely rid of it and we will try to soon see an ear-nose-throat specialist to hopefully completely get rid of it.
  • Dyanne did an MR scan of the brain on 16th May. We should learn results of this scan later this week. Crossing our fingers it shows everything is ok.
  • We have gotten some more immunomonitoring results from the place that does the personalized vaccine for Dyanne in Germany. It shows that, as measured in blood, there is an increase in both the breath and potency of the immune response that has been triggered by the vaccine. One cannot conclude that this means that the vaccine has triggered immune cells to kill cancer cells. However, it is a, somewhat, hopeful development.
  • We measure a tumor marker called CEA every week. CEA is a simple blood test and studies have shown that it can correlate well with development of some cancers, including EGFR mutant lung cancer. It should, however, be mentioned that it does not correlate perfectly. So both false positives and false negatives are possible. In any case, it seems there has been a rise in Dyanne’s CEA level lately. Attached to this post is the chart. The increasing trend may signal that the cancer is progressing. Or it may signal some other, more benign, developments. We will monitor this in the weeks to come to see how the trend develops.

CEA chart: blue line is measurement from Oslo University Hospital, red line is measurement by Fürst (a private laboratory)

In other news: one of the world’s largest cancer conferences, the ASCO annual meeting, will take place in early June. In preparation of the meeting, around 5000 abstracts with new research has just been released. I have spent a lot of time pouring over the data to see if there is anything of relevance for EGFR mutant lung cancer. Based on what I have been able to find so far, here are some highlights:

  1. Abstract 9002: For the first time a randomized immunotherapy trial seems to show some promise for EGFR mutant lung cancer patients. The combination of chemo, bevacizumab and atezolizumab (an immunotherapy drug) seems to have increased survival compared to just chemo and bevacizumab. And, contrary to many other trials in this field, this finding seems to hold true also for the EGFR mutant patients that were included in the trial. Roche has only released detailed data from arms B (chemo+bevacizumab+atezolizumab) and C (chemo+bevacizumab) in the trial. For arm A they have only released rudimentary data. No data on EGFR patients in arm A has been released. Furthermore, no direct comparison of arms A and B have been presented (only arms A and C have been compared). For EGFR positive patients, it is thus difficult to say whether the inclusion of bevacizumab is useful or not. Patients, and their doctors, worldwide are then left not knowing whether one should add a toxic and expensive bevacizumab to the treatment regime of patients who would like to test out this new, and promising, immunotherapy combination. That Roche has a rather poor track-record for releasing data from the trials they sponsor is, sadly, evident from data gathered as part of the AllTrials initiative: http://policyaudit.alltrials.net/companies/roche.html.
  2. Abstract 9005: A randomized phase 3 trial from Japan has tested whether the combination of gefitnib and chemo as first line treatment for EGFR mutant lung cancer is better than gefitinib monotherapy. The results show that patients who got the combination lived for a median of 53 months. Patients who got only gefitinib lived for a median of 39 months.
  3. Abstract 9007: A randomized phase 2 trial, also from Japan, that has tested whether the addition of bevacizumab to erlotinib could help improve outcomes in EGFR mutant lung cancer. The overall survival results shows that there was no difference in survival between the two arms in the study (i.e. the arm testing bevacizumab and erlotinib and the control arm where erlotinib monotherapy was given). There was, however, a difference in the metric called “progression free survival” (PFS). Patients who got the combination had a longer time without progression of the disease compared to those who only got erlotinib. Furthermore, it seems most patients who took part in this trial lived long, at least compared to historical standards: the median survival was around 47 months. Is this because these were generally healthy patients to begin with? Or because Japanese lung cancer patients tend to live longer than Caucasian lung cancer patients? Or because patients who initially only got erlotinib later in their treatment also got bevacizumab? With the data released, these are impossible questions to answer. I have, however, been in contact with Roche and gotten data on how many patients in the erlotinib monotherapy arm got bevacizumab as part of their later treatments. It turns out around 30% of the patients did. It thus seems unlikely that bevacizumab given in later treatment lines is what has driven the good OS numbers in the erlotinib monotherapy arm. My conclusion is thus that it bevacizumab probably does not add much to the overall survival of EGFR mutant lung cancer patients.
  4. Abstract 9013: A small, randomized, phase 2 trial in Mexico tested whether the combination of a standard EGFR TKI (e.g. erlotinib or gefitinib) and the common diabetes drug metformin was superior to EGFR TKI monotherapy. The trial shows that patients who got the combination lived longer (27 months vs. 19 months). One question about this trial is why there were more patients in the EGFR TKI arm (67 patients) than the combination arm (only 49 patients).
  5. Abstract 9023: Although not specific for EGFR mutant lung cancer patients, this trial from the Netherlands tested whether giving stereotactic radiation (3 x 8 Gy) just before immunotherapy (pembrolizumab) could improve outcomes for lung cancer patients. The patients who received radiation had a higher response rate (41% vs 19%) and a longer progression free survival (6 vs 2 months) than those who only got pembrolizumab. Overall survival results have not been published.

There is lots more research published too. A good place to search and browse through abstracts is here: http://abstracts.asco.org/214/IndexView_214.html.

Finally, I was invited to Roche here in Norway to give a talk to their employees about clinical trials. The presentation, which I held yesterday, can be found here (but note that it is in Norwegian). [Disclosure: I did not receive any compensation/payment for the talk, but Dyanne has previously received a free Foundation Act test from Roche.] Among my suggestions to Roche and their emmployees was that they should stop propagating the lie that high drug prices are due to high development costs (the truth is that drug prices are high because we are willing to pay a high price; drug development costs is a sunk cost that does not affect the pricing decision), and that they should join the AllTrials initiative and report MUCH better from the clinical trials they run (their lackluster reporting has direct negative consequences for patients, including Dyanne). Finally, I also suggested that their employees, if they come across unethical behavior, should follow the footsteps of Edward Snowden and leak information to WikiLeaks or the media. Among the data it would be nice if some Roche employees could leak is the missing data from trials where bevacizumab has been tested in lung cancer.

My suggestions caused many questions and comments from the audience, and we had a good and frank discussion. I have no doubt that there are many smart, good and hard-working employees in Roche. The problems arise when a profit maximizing entity, like Roche, meets and interacts with a poorly organized, poorly incentivized, poorly managed public health care system in a poorly regulated environment. When this happens outcomes are, unsurprisingly, sub-optimal.

With that, best of wishes to everyone from Oslo!

CORRECTIONS
1. An earlier version of this post stated that Roche had not released any data from arm A (the chemo + atezolizumab arm) in the IMpower150 study. This was incorrect. Some, rudimentary, data from this arm was released at the ESMO ImmunOncology meeting in Geneva in November 2017. The blog post has been updated to reflect this.

2. An earlier version of this post stated that Roche had deliberately withheld overall survival data from a trial that tested the combination of erlotinib and bevacizumab vs erlotinib monotherapy. It turns out that this OS data actually was published in 2016 as part of an assessment that the European Medicines Agency (EMA) has done of this treatment combination. The overall survival figures from this trial were can be found on page 28 in the EMA report that can be found here.

I apologize to Roche for these mistakes.

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