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

This blog provides a summary of the important oncology studies, excluding immunotherapy studies, from the month of November. There were quite a number of important immune-oncology studies last month which I will describe in a different blog.

What’s new here, New England?

The New England Journal of Medicine prides itself in publishing “new” practice-changing research. But I can’t yet figure out what exactly was new with this report of PALOMA-2 published last month. Palbociclib plus letrozole as a first line therapy for hormone receptor positive breast cancer has already been given accelerated approval by the FDA based on improved PFS in a randomised phase 2 trial PALOMA-1 previously published. Thus, we already know that palbociclib plus letrozole improves PFS compared with letrozole alone in this population. What we don’t know yet whether it improves OS or not. 

This new report, published in NEJM, provides us with the same information that palbociclib improves PFS. OS follow-up is ongoing and will be reported later, apparently. What I didn’t understand was the haste in publishing PALOMA-2 results without having any OS data to report on, especially because palbociclib is already in market. What I didn’t understand more was what “new information” did the journal find to publish this. I further didn’t understand why they decided PFS, and not OS, as the primary endpoint of this phase 3 trial when PFS prolongation was already proven in a randomised phase 2.

I have been intrigued by the clinical trials of new drugs for advanced breast cancers for a long time. They seem to dramatically improve the PFS: bevacizumab prolonged PFS by nearly 6 months and everolimus by 4 months-both of which were highly significant. Palbociclib also prolonged PFS by 5.4 months in second-line setting. Of these 3 agents, OS data for bevacizumab and everolimus are known and they are negative. It remains to be known whether palbociclib prolongs OS in both first and second line settings. But, significantly prolonging PFS without benefiting survival baffles me. Now before someone argues that crossover could have diluted the survival benefit, let me tell you that crossovers weren’t allowed in all these three trials. Further, if a drug is really good, it prolongs OS despite crossover as we have seen with pertuzumab in the CLEOPATRA study. Thus, even though PFS benefit with palbociclib in PALOMA-2 and PALOMA-3 have been impressive, there is no guarantee that it would lead to OS prolongation. We have discussed these issues in further detail here.

There was another similar trial of a similar drug in a similar setting published in NEJM last month. Ribociclib plus letrozole significantly improved PFS with an hazard ratio of 0.56 compared with letrozole alone in the MONALEESA-2 trial, with toxicity profile similar to that of palbociclib. Of course, they belong to the same class of drugs and therefore have similar efficacy and toxicity profile in similar settings. It’d usually be considered a good thing to have many options for the same indication, because prices would go down due to competition. But welcome to the oncology world where every Tom, Dick and Harry “me-too” drug can proudly boast a price tag higher than its competitors. I am sure that ribociclib will cost no less a fortune than does palbociclib (~$10,000 a month) even though both these drugs are just a me-too of each other.

The Primary Outcome Failed? Do this!
There was a controversial paper in NEJM a couple of months ago titled: “The Primary Outcome Fails — What Next?”

 But here you have a real-life example of how to manipulate the readers when the primary outcome fails, but a market of $13,000 per month per patient is at stake. This is the conclusion of the trial of olaparib maintenance monotherapy in ovarian cancer:

“Despite not reaching statistical significance, patients with BRCA-mutated platinum-sensitive recurrent serous ovarian cancer receiving olaparib maintenance monotherapy after platinum-based chemotherapy appeared to have longer overall survival, supporting the reported progression-free survival benefit. Clinically useful long-term exposure to olaparib was seen with no new safety signals. Taken together, these data support both the long-term clinical benefit and tolerability of maintenance olaparib in patients with BRCA-mutated platinum-sensitive recurrent serous ovarian cancer.”

Negative trials in colorectal cancer: Is there such a thing as too much optimism?
Our editorial in ecancermedicalscience titled “Negative trials in ovarian cancer: is there such a thing as too much optimism” received quite a lot of response in social media. In an interview with the journal, I said “this editorial must have struck the chord of many oncologists because this phenomenon is not specific to ovarian cancers but is an underlying theme to many other cancer trials”.

Reading the results from QUASAR-2 was a nice reminder that this indeed was a problem in colorectal cancer too. The AVANT and NSABP C-08 trials have already shown that bevacizumab in the adjuvant treatment of colorectal cancer is not only futile but can be harmful. As the results of harms from these two trials arrived, should the QUASAR-2 trial have been allowed to run to completion? Doesn’t this violate the Primum Non Nocere? We are asking patients to enrol in this trial to receive a drug that is toxic - and sometimes fatal - when two other studies have clearly shown that this approach provides no benefit! How can this be in accordance with the Declaration of Helsinki?

On a positive note, the accompanying editorial by Dr. Saltz is wonderful. When most of the editorials are biased and smell of conflicts of interest, Dr. Saltz’s editorials always provide a pleasant break.

Unethical expensive cancer industry?
This is the first time I am discussing a paper from the BMJ and what an important paper it is! An analysis paper published in the BMJ questions some important issues surrounding oncology drugs, practices, trials and ethics. This paper asks the meaning of approving expensive cancer drugs that improve survival by less than 3 months but cost a fortune and the ethics of approving without meaningful gains in patient outcomes and not providing enough information on treatment toxicities to the patients. I don’t want to spoil the fun by summarising everything here. It is a short and nice commentary which I suggest you to read for yourself and ponder. If you do want to read my commentary on this paper, you’ll find it here.

Financial toxicity: it’s not a Global-South problem
In this important study from Italy, Perrone and colleagues show that financial toxicities measured as worsening of financial burden scores on EORTC questionnaires are associated with patient outcomes such as survival and quality of life. This is a surprising finding, given that Italy has a public health system where patients don’t need to contribute to drug expenses with any co-payments. Further, this was an analysis done among patients on trials and trial patients are usually privileged with some benefits that don’t exist under routine practice.  This study thus shows that financial toxicity is a real problem and not an imaginary creation of anti-industry group as some people still tend to think. Also, I sometimes come across some colleagues who equate financial toxicity with global oncology meaning that financial toxicity is a problem of the global south. As this study clearly shows, it isn’t. Financial toxicity is a real and palpable problem and unless we do something about it together, financial toxicity will soon become the leading cause of cancer deaths across the world.

Let me take a selfie
In a meta-analysis published in Annals of Oncology, we have shown that sorafenib treatment is a double-edged sword. Sorafenib has shown some benefit in a few cancers, but it also significantly increases the risk of serious adverse events (SAEs) and fatal adverse events (FAEs) compared to control. The risk for SAEs increased by 49% and FAEs by 82%. This is a substantial increase in risks and patients should be clearly informed of these increased risks at the time of shared decision making. With drugs such as these that don’t cure but modestly improve survival, proper knowledge on risk-benefit tradeoff is important to make an informed choice. Importantly, we have shown that the risks are higher when the drug is used in settings other than the approved indications (the off-label use). I further discuss these results in a video interview here.

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 http://twitter.com/oncology_bg@oncology_bg. Dr Gyawali is an independent blogger and his views are not representative of ecancer. Read his previous blogs here.