The Hopes and Hypes from ASCO 2016 by Bishal Gyawali

17 Jun 2016
The Hopes and Hypes from ASCO 2016 by Bishal Gyawali

independent ecancer blogger Dr Bishal Gyawali rounds up the latest news from ASCO.

The annual meeting of the American Society of Clinical Oncology (ASCO) is the biggest annual platform in the oncology world, where the latest research and progress in cancer are presented to a global audience. The ASCO meeting this year, as always, gave us some excellent research results - providing hopes for a better future to our patients, together with a lot of hype! Hype has always been a problem in the dissemination of cancer research, with both the researchers and media playing their part in blowing the research findings out of proportion. Researchers are inherently biased towards promote their findings as extraordinary; other researchers with common (or conflicting) interests have bias to fervently support (or reject) them; and media are biased towards sensationalising the findings as extremely positive or negative to attract a wider audience. However, what our patients and public need and deserve is unbiased, undistorted truth - the reality of where we stand now, what we are aiming for and how big that gulf is. A quote by H.D. Thoreau comes to mind: "Rather than love, than money, than fame, give me truth!"

In this blog, I comment on some of the studies from the ASCO16 meeting - both the hope and hype - and attempt to make an unbiased judgment of the studies for what they really are. The studies included here are by no means exclusive, and do not indicate any priority or order.

Ten Years of Aromatase Inhibitor: What for?

Unlike in previous years, only one study from ASCO meeting was published simultaneously in NEJM this year and it’s the highly discussed MA.17R study. This trial evaluated the benefits of extending adjuvant letrozole in early breast cancer patients to 10 years versus the current standard of 5 by randomising patients who have already received 5 years of hormone therapy into additional  5 years of letrozole or placebo. This study received huge coverage and some experts even advocated that 10 years of therapy should now be a standard.

Let’s take a closer look at some facts here. The 5 year disease-free survival (5Y DFS) rate was improved by 4% (91% v 95%), HR 0.66, P = 0.01. Most of this benefit in 5Y DFS seems to be the effect on incidence of contralateral breast cancer (CBC): annual incidence of 0.49% in placebo v 0.21% in letrozole ( HR 0.42, P = 0.007). To put it in terms of numbers: out of 959 patients in each group, 13 versus 31 patients developed CBC with letrozole versus placebo and 55 v 68 patients developed recurrence of BC. This means a majority of patients will remain disease-free with placebo alone, and some patients will develop recurrence or CBC even if they take letrozole for 10 years. Only 18 more cases of CBC and 13 more cases of recurrent BC were observed among patients who stopped hormone therapy at 5 years compared to those who continued letrozole for 10 years. Even then, the risk of death remained the same: there was no difference in OS (placebo 94%, letrozole 93%).

Let’s also not forget the luxury of being off-therapy. Indeed, letrozole significantly increased the incidence of bone pain, bone fractures, new-onset osteoporosis and led to poorer quality of life. Furthermore, we don’t know whether the CBC or recurrences were early curable tumours or aggressive cancers. So what exactly do the patients gain when they take 10 years of hormone therapy versus 5?

In any case, this trial enrolled patients after 5 years on hormone therapy—that means women who have tolerated 5 years of therapy well and are willing to take another 5 years of hormone therapy. In clinical practice too, we don’t need to make this decision of 10 v 5 years at the outset. It is prudent to recommend 5 years of therapy first and at the end of 5 years, we can invite the patient for shared decision making with regards to continuing letrozole for an additional 5 years after evaluating the patient’s quality of life and willingness to continue. If the hypothetical patient is willing to go through another 5 years of treatment to live the same length of time but reduce the chances of her recurrence/CBC by a small absolute margin, she should get the treatment. If she opts to stay off therapy, we should unequivocally tell her that this would not impact her survival and would instead keep her away from the side effects of the drug.

Any point in having a cost-similar bio-similar?
A trastuzumab biosimilar showed comparable efficacy and safety to Herceptin in a phase III study of advanced HER2 positive metastatic breast cancer patients that was presented at the ASCO meeting. But many of you might not know that this drug was already in market in India in 2014, when manufacturers received a court order to first demonstrate its safety and efficacy in a clinical trial - hence, this study. This study is very important because this could not only open up avenues for women in low- and middle-income countries (LMICs) across the globe to avail themselves of this wonderful drug, but also establish a good example for other biosimilars to follow. Indeed, many patients in LMICs still have no access to this drug, which has changed the fate of many patients with HER2 positive breast cancer in the developed world.

As an example, you can notice that in this trial of breast cancer from India, only one of the 107 patients with HER2 positive disease had received trastuzumab - some of the saddest data I have read. After this biosimilar study, my hope is that we can see better figures for the percentage of women with HER2-positive breast cancer that have access to trastuzumab in LMICs. But wait, when an imatinib biosimilar was introduced in US, it was priced nearly the same as the branded Glivec! Maybe the case would be different for LMICs?

Alas, it seems not. This trastuzumab biosimilar was priced at 75% of the branded Herceptin price when it was launched in the Indian market in 2014 - still very expensive and out of reach for the majority of patients in LMICs. So, maybe there isn't much point in our getting overexcited about generics coming to the market. I wonder, with little R & D costs or the need for advertisement, why would a generic be priced nearly as high as the original drug. This seems inhumane, even tragic.

Is left righter than right?
This study showed that right-sided colon cancers fare poorly compared to left sided colon cancers - supported by another observational study, both of which were presented at the ASCO meeting. This study received tremendous media coverage with big headlines. However, it should be remembered that this was a post-hoc analysis of the CALGB 80405 trial, which was not conducted to answer this question. The trial results have not been published yet and we do not know what prompted the researchers to do this post-hoc analysis. Indeed, there have been other studies previously that have suggested that right sided tumours have worse prognosis than left sided tumours, but the difference in survival seen in the current study is huge - about 1 year. Further, cetuximab didn’t seem to perform as good for right sided tumours despite being RAS wild - again not a new finding. Many studies - although all limited by observational data, retrospective nature or post-hoc subgroup analysis - have indeed shown that right sided tumours have poor prognosis and do not respond well to cetuximab, which is further supported by the present study. Nevertheless, all these findings should be considered as only hypothesis-generating.

No doubt, this is an interesting research topic that should be explored in detail. As the lead study author explained, the right- and left-sided colons have different embryological origins, which could lead to different biology and mutation patterns between these two sides. Whether the observed differences in prognosis are merely a function of sidedness, or confounded by underlying differences in the incidence of prognostically important BRAF mutation status, MSI status, or genetic marker(s) as yet unkown, is a very important thesis to explore. In the meantime, there is no need or evidence yet to alarm our hypothetical patient tomorrow in the clinic, by telling him that his prognosis is poor because his colon cancer is on the right side.

On the other hand, there is also no good reason to use cetuximab therapy as first line treatment for right- sided colon cancers - bevacizumab should be the preferred antibody to combine with chemotherapy for right-sided tumors. Bevacizumab is also cheaper compared to cetuximab. In fact, Dr. Saltz explains here that irrespective of site, bevacizumab should be the preferred antibody to combine with chemotherapy in the first line treatment of colorectal cancer. 

Leave My Pathway Alone
A trial, cleverly termed MyPathway, concluded that off-label use of targeted therapies based on genetic alterations, rather than the site of origin, produced responses. This study was inappropriately hyped as "the" benchmark study for precision oncology. The idea of precision medicine is very attractive. We all want it to be achievable, myself included. But what we  would like to believe shouldn’t blind us to the evidence.

129 patients with advanced solid tumours with no curative option were provided targeted drugs based on molecular alterations in their tumour. 22 of them showed a response (1 CR) in this basket study. This is a single arm study - so you can’t compare that response with any other treatment. Also, we do not know if the increased response leads to better survival. If anything, the SHIVA trial - a randomised study comparing a personalised versus a standard approach - showed no benefit for the personalised approach in terms of survival. Also, we know that cancer treatment is not as easy as matching the name of a drug to the name of a mutation. We already know that BRAF inhibitors act well for BRAF-mutated melanoma but not BRAF-mutated colorectal cancer. Cancer biology is more complex than we would sometimes like to acknowledge. Mutations and pathways are indeed important, no doubt, but there is more to cancer than that.

I am not critical of this study; the researchers are simply testing a hypothesis – that’s what scientists do. What I am critical of is the hype the researchers, media and even ourselves lend to these results, which may confuse our patients and spread false hopes or dismay among the lay community. In a nutshell, the mutation you find in a patient's tumour may or may not affect that patient's survival. Until there is data to show that targeting genetic mutations indeed improves survival, leave My Pathway alone!

Meta-analysis of phase I trials: where does it lie on the evidence level hierarchy?
This meta-analysis of phase I trials, presented at ASCO and published in JAMA Oncology, also concluded that personalised treatment improves outcomes (RR and PFS)-- another study that was overhyped because its results fit into what we want to believe in.

First, we should be very cautious comparing two approaches based on meta-analysis of single-arm studies. Indeed, none of the included studies were comparative studies; they were phase I, single arm studies not comparing anything. But there's more to it than that - the phase I studies are not designed to see the response rate and PFS either! Yet, the authors in this study pool the findings from lots of phase I studies that used a biomarker-based personalised approach and compared the RR and PFS with studies that didn’t use this approach or involved chemotherapies. They found that RR and PFS significantly favoured the personalised approach.

Nevertheless, if you look deeper into the study - I mean really deeper, up to the supplemental content - you will notice that a number of drug studies under the "personalised" category include drugs that we already know to be effective for corresponding mutations, such as crizotinib and dabrafenib. These drugs are already approved standard treatment options. Indeed, this study showed that the RR and PFS significantly improved if the agent was FDA/EMA approved versus not (17% v 5%, P < 0.001) which makes you wonder how much personalised approach would really be effective after excluding patients for whom personalised therapy is already known to benefit.

How can these results mean off-label personalised therapy is effective? Furthermore, some mutations can also be prognostic. How can we be sure that the better outcome is a function of the drug and not the mutation as such?

Old is the new young
This study has now confirmed the benefit of adding temozolomide (TMZ) to radiation therapy (RT) even for elderly glioblastoma patients. This study enrolled elderly patients over 65 years of age (median age 73) and found that adding TMZ to RT provided a 1.7 months median OS benefit; this benefit extending to 5.8 months for those patients who had MGMT methylated tumours. I love this study for many reasons. The important takeaways would be that clinical trials should now stop excluding patients based on age alone, and that even elderly patients should receive standard treatment based on their tolerability as assessed by geriatric assessment tools.

In fact, I find it absurd that we consider geriatric oncology to be a specialty, when in fact, majority of cancer patients are elderly. We are all geriatric oncologists by default.

Having said that, I am really not sure how much benefit (versus the toxicities) the 90 year old patients received with the addition of TMZ in this study. I notice that the age range in this trial was 65-90 and wonder whether I would be willing to take TMZ RT at the age of 90 instead of lavishing my time and money on families and wine. That brings me to another important study:

Should one really die before s/he can Rest in Peace?
This study showed that we are still causing pain to 70% of our young patients with aggressive end-of-life care during their last 30 days of life, and 1/3 patients are still dying in hospital. This is sad. We need to acknowledge that aggressive care serves no good to terminally ill patients, and prescribing chemotherapy to palliative cases is akin to delivering poison to someone who can no longer tolerate it enough to benefit from it.

Death is a tragic reality we face every day, but we need to find solace in the fact that allowing someone to have a peaceful life/death transition is a grace in itself. We know that most cancer treatments deliver marginal benefits even in the controlled setting of clinical trials and selected patients - so why do we keep believing that prescribing chemotherapy to patients even after their PS has worsened will do any good? I encourage my fellow clinicians to let such patients die peacefully in hospice, or in their homes with their families, without enforcing toxic treatment schedules - or if you do keep them in hospital, learn from the French and give them the chance to celebrate their last few days in comfort with a drink!

OS benefit of 7 months in lung cancer - and it’s not immunotherapy
Yes, a study showed a survival advantage of nearly 7 months in high-risk lung cancer patients. No, it’s not immunotherapy. It’s not even a drug. It doesn’t cost much either. Maybe that’s why you didn’t hear about it - this study was not hyped and didn’t receive as much media attention as many others. This study from France showed that the use of a web-application not only significantly improved survival, but also led to having better PS upon relapse, receiving early supportive care and lesser exposure to scans compared to standard follow-up. I eagerly await the publication of this study to check whether there were some selection bias and confounders, and to assess the global applicability of these study results. Congratulations to the authors for performing this wonderful study. My complaint: why didn’t this study deserve the superlatives that we are so quick to lavish upon new brand-name drugs?  Isn’t this equally game-changing?

Don’t envy the cheap drug prices in LMICs
This study showed that although prices are relatively lower, cancer drugs are still unaffordable in LMICs. When monthly drug prices were expressed as a percentage of domestic product per capita at purchasing power parity, cancer drug prices were too expensive in LMICs like India and China versus their prices in the U.S.A. Another study showed that the price of cancer drugs in the U.S.A. has steeply increased by as much as 44% even after adjusting for inflation. I find this baffling: what can possibly justify increasing the price of drugs years after it has gained approval? So much for Medicare not being able to not only negotiate prices, but also fix the price during approval! 

Some other important studies presented at #ASCO16

  1. The CATNON study showed that the addition of adjuvant TMZ to RT improved OS in anaplastic glioma without 1p/19q co-deletion. This is already a standard treatment in glioblastoma and the results of this study confirm the use of this strategy in anaplastic glioma too, but full publication of the results is important to look at the details of the study design and results.
  2. This study showed that anthracycline-containing regimen should remain the standard for the treatment of high risk, HER2 negative early breast cancer patients.
  3. The ESPAC-3 trial reported that adding capecitabine to gemcitabine improves survival compared to gemcitabine alone in patients with resected pancreatic cancer. The survival is by two and a half months, but for a disease like pancreatic cancer, any progress is important. However, another trial - JASPAC 01 - by the Japanese group has recently been published in the Lancet, and this shows that adjuvant S-1 also improves OS significantly compared to gemcitabine alone. And this OS advantage is not trivial: a 21 month benefit! Yes, that’s not a typo: median OS of 46.5 months with S-1 versus 25.5 months with gemcitabine with an HR of 0.57- quite amazing statistics for a non-inferiority trial and an unprecedented survival benefit for pancreatic cancer. Although it remains to be seen how S-1 would perform against gemcitabine-capecitabine combination, given the enormous survival benefit with S-1 in the JASPAC 01 trial, S-1 should definitely be given another chance in the Western world. In Japan, it is already a standard of care both in the adjuvant and metastatic setting. 
  4. The J-ALEX study from Japan has shown very impressive results with alectinib versus crizotinib for first line treatment of ALK-positive non-small cell lung cancer patients with an HR of 0.34 for PFS and better safety profile. OS results are pending, but given the magnitude of benefit, this looks very promising. It would be interesting to know whether crizotinib-alectinib sequence would provide similar results to alectinib upfront. Another question would be the use of crizotinib post-progression in these patients who received alectinib first-line. The global ALEX study is ongoing to confirm this benefit in the global population.
  5. How long should docetaxel (DTX) be continued in a patient with metastatic castration resistant prostate cancer is a matter of big debate with no clear evidence. I recently published a review of studies assessing continuous versus intermittent DTX in this setting and found that most of the studies are heterogeneous and of poor quality. The intermittent approach is attractive because it provides periods of "chemo holiday" and thus relieves patients from chemotoxicity, expenses and taking leave from work to receive chemotherapy. However, the concern for inferior survival with chemo holiday is valid - hence, a phase 3 trial was highly desired. PRINCE, presented at this year’s ASCO, was a very important study that directly addressed this question and found that intermittent DTX was non-inferior to continuous DTX in terms of one-year survival-the primary endpoint. But, this study was limited by incomplete recruitment, small sample size and the inability to demonstrate non-inferiority for OS in a post-hoc analysis. The median chemo holiday duration was 15 weeks (max. 69 weeks). Based on this study, there should be no hesitation to propose intermittent DTX for eligible patients who want to stay off chemo.

A final note on immunotherapy trials
A huge number of immunotherapy drugs are in development and reports of phase I, II trials of these agents dominated most of the ASCO meeting. Every pharma wants to have a share in this goose that is laying golden eggs. Most of the drugs are just “me-too” versions of nivolumab or ipilimumab. There is a real big concern with these mushrooming immunotherapy trials – industry and researchers are losing their focus on other potential drug targets that could benefit patients and recruiting patients in clinical trials of other agents is getting increasingly difficult. When will this race, if ever, end?

Bishal Gyawali (MD) is an independent blogger and his views are not representative of ecancer. Dr Gywali reports no conflict of interest. He is undergoing his postgraduate training in medical oncology at the Graduate School of Medicine, Nagoya University, Japan, where he is also a PhD candidate under the Japanese government scholarship. He also serves as visiting faculty at the department of Hemato-Oncology in Nobel Hospital, Kathamandu, Nepal. He graduated in medicine from Institute of Medicine, Tribhuwan University, Nepal in 2011 with seven gold medals for his academic excellence. He has been honoured with “Student of the Decade award” and “Best Student Award” for his academic excellence in Nepal. His areas of interest include evidence-based oncology practice, cost-effectiveness of cancer therapies and economic feasibility of cancer management in low-income countries. Dr Gyawali tweets at @oncology_bg

Read his previous blog entries here and here.