Independent blogger Dr Bishal Gyawali rounds up the latest publications in oncology

The journal of expensive oncology

ESMO-2016 was the most important event in oncology last month, with 6 studies from the meeting making into the NEJM. That was indicative of huge success of the conference. However, whether that’s indicative of success in patients’ outcome is another story. This lack of real palpable benefits coupled with overhyped and overpriced drugs filling the pages of NEJM irked Richard Lehman so much that he gave a new (and much cuter and more realistic?) nickname to NEJM - the “Annals of Expensive Oncology”.

Sadly, the hype usually exceeds the reality in most medical congresses. After ASCO, I published a reality-check blog on the Hopes and Hypes of ASCO. After ESMO, I had the chance to do a video interview on the reality-check of the important data that were presented at the congress. Naturally, the reality isn’t as dramatic and as outcome changing as the hype was. Please watch the video for the major hopes and hypes from ESMO 2016. The video interview I did was extempore, so here I expand on a few more points that I missed to highlight in the interview.  

3 years of Expensimumab!

The leading story from the ESMO meeting and the "Annals of Expensive Oncology" - such a catchy name! - is that of adjuvant ipilimumab for stage III melanoma. Ipilimumab is a decent drug for metastatic melanoma that can provide long term survival in a selected subgroup of patients (we don’t know who!). The price is definitely lofty and toxicities serious, but just 4 courses of ipilimumab at doses of 3mg/kg is an appropriate risk to undertake for the potential benefit it has to offer. But in this study of adjuvant ipilimumab for stage III melanoma, they have used the drug for THREE YEARS at a dose more than THREE TIMES that used in metastatic cancer (10mg/kg) to find a significant 10% better 5-year recurrence free survival and 11% better 5-year overall survival. There is no sane reason to design the trial this way, except to milk as much money as possible. This drug should be renamed "expensimumab," instead of ipilimumab. How could anyone think that 3 years of 10mg/kg would be needed to treat micrometastases while 4 courses of 3mg/kg were enough to treat macrometastases  is beyond my comprehension. Yes, there is a clear benefit in OS in this trial, but I am not sure if this regimen provides any OS advantage over 4 courses of 3mg/kg! There is also one more catch: only 16% of patients assigned to placebo went on to receive ipilimumab post-protocol. It is likely that these patients would achieve similar survival if they received ipilimumab upon disease progression. Here are 2 RCTs that must happen to guide treatment plan for our patients: 1. Adjuvant ipilimumab versus ipilimumab upon relapse 2. Four courses of 3mg/kg ipilimumab versus 3 years of 10mg/kg "expensimumab."

But, will these RCTs really happen? Who is going to fund it? Will BMS ever sponsor a study of ipilimumab versus "expensimumab?"

The story is not yet over here. Because of this overzealous dosing and duration of ipilimumab in this trial, 41.6% patients developed immune related grade 3 or 4 adverse events and 1.1% patients died due to the drug. We need to compare that against 2.7% developing immune related grade 3 or 4 adverse events and 0.0% patients dying due to the drug among patients randomized to the placebo arm.

"Foolishimumab" and "Greedilimumab"

Patients and physicians were left stunned by the results of Checkmate 026 that showed nivolumab had failed to meet the primary endpoint in the first line treatment of non-small cell lung cancer (NSCLC). They were then elated to hear that pembrolizumab met the endpoint in the same setting. Nivolumab negative, pembrolizumab positive! There are no good reasons why one drug should fail but not the other as both block the same PD-1, except for not planning the trial designs very well.

I have previously written why OS should be the primary endpoint for immunotherapy drugs. First, disease progressions with these agents aren’t well captured by traditional RECIST. Second, these agents seem to work in a “start slow, go long” fashion. There are reports of these agents showing effect even after the drug has been discontinued. Thus, it makes no sense to have PFS as primary endpoint, especially because the Checkmate 057 study in the 2nd line setting failed to improve PFS but improved OS. Although pembrolizumab also had the primary endpoint of PFS, they were clever enough to enroll only those patients whose tumors had a PD-L1 positivity of >50%; these are patients that are most likely to respond. Thus, thie examination of nivolumab was both foolish (choosing PFS, and not OS, as primary endpoint) and greedy (included all patients irrespective of PD-L1 positivity to capture the entire market). Sometimes, greed works (as it did in melanoma), sometimes it doesn’t. 

Credit to BMS, they sensibly put OS as the primary endpoint for their Nivolumab trial in recurrent head and neck squamous cell cancer and got positive results: OS improved significantly by 2.4 months. I am sure you won’t be surprised to know that Nivolumab had a shorter PFS in this trial: 2.0 months versus 2.3 months in the control group. Imagine if they had chosen PFS as their primary endpoint!

Cold waters on screening

I recently wrote a paper where I suggested low- and middle-income countries (LMICs) shouldn’t spend their limited resources on mammography screening. Naturally, low-income countries didn’t take this in a positive way. There are many institutions-doctors, hospitals, NGOs, INGOs, volunteering organisations- who want to make money, fame, reputation, power, political career by fear mongering. Spreading the fear of breast cancer among public and following that up with their generosity in providing mammographic screening campaigns is one of their most marketable products. They will definitely not take it positively when you go out and shout: "hey, mammography is useless!"

But, I will now raise my voice, because here’s more evidence to suggest that mammographic screening leads rather to overdiagnosis than to earlier detection of a tumour that was destined to become large. To be clear, the paper’s argument and mine too, is not that mammographic screening is useless to a particular woman-she should make her own risk-benefit judgment and decide accordingly. Our argument is against performing population- level mammographic screening as public health intervention or campaigns.

The case with PSA screening for prostate cancer is also not very different, as this editorial eloquently concludes: “In summary, although we cannot emphatically endorse population-wide annual PSA screening on the basis of available evidence, we also cannot dismiss the fact that, when done properly, screening confers a survival benefit. As we go forward, we will no doubt develop new evidence that will identify personalized screening strategies that maximize the benefits of screening and minimise harms. In the meantime, let us not throw the baby out with the bathwater.”

Poking A Nose into China’s research

Clinical researches from China, especially drug trials, have been met with big skepticism lately after the publication of a report claiming up to 80% of data in clinical trials from China are fabricated. This trial of recurrent nasopharyngeal carcinoma, however, is no such thing. Nasopharyngeal carcinoma is a rare tumour in other parts of the world but very common in China, and I am really glad that they have conducted this nice phase 3 trial, which would have been very difficult to conduct in other parts of the world. Now, thanks to the Chinese, we have evidence to treat these patients with gemcitabine-cisplatin combination rather than a 5-FU-cisplatin combination. I was very happy to see this trial in the Lancet, not only because it could begin to redeem a country’s lost credibility in academia, but also because I believe that LMICs should focus on such research topics that are unique to their context but provide evidence to the global community.

MAPIE is not HAPPIE

Osteosarcoma is a very difficult-to-treat cancer with urgent need for better treatment strategies. In this commendable collaborative efforts from investigators in various countries, intensifying the postoperative treatment by adding ifosfamide to the standard MAP regimen in those patients who responded poorly to the preoperative treatment led to added toxicity but no better clinical outcomes.  Thus, MAP - not MAPIE - should remain the standard post-operative regimen irrespective of response to preoperative MAP.

The BATTLE of Precision Medicine

We now have strange trial designs such as umbrella and basket designed to test the precision medicine. Precision medicine is still under trial, and hasn’t yet delivered the promise it was hyped to deliver. BATTLE-2 is an umbrella trial that tested the precision medicine approach for non-small cell lung cancer, but the most important take-away messages from this trial are nicely put in this editorial by H.J. West.

Let me take a selfie

“As oncologists, however, we should push for uniformity in the interpretation of clinical trial results and try to achieve as much consistency in our practice as possible. Consistency would be a virtue for cancer care.”

This is what my co-authors and I conclude in our commentary in JCO titled “Same data; different interpretations”. In this commentary, we provide some examples of similar data interpreted differently by the oncology community. This inconsistency in integrating trial data into clinical practice is baffling to both physicians and patients. We highlight this discrepancy and offer some possible explanations.

Finally, there is also a video interview at ecancer where I talk about the positive lessons from negative trials in relation to our one of the most read editorials “Negative trials in ovarian cancer: is there such a thing as too much optimism?”.

Bishal Gyawali (MD) is an independent blogger. 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. Dr Gyawali is an independent blogger and his views are not representative of ecancer. Read his previous blogs here.