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

Atezolizumab in metastatic urothelial cancer

If you find it difficult to pronounce the name of this drug, to predict whether it will work for your patient is even more so. Urothelial cancer is indeed an area of high unmet need, with virtually no standard treatment option after first-line; it's further complicated by accompanying poor renal function. So, atezolizumab showing durable response with good safety profile even in patients with poor renal function (40% patients in this study had CrCl < 60) is very exciting news—except that you can’t really predict who benefits.

Overall response in all patients was just 15%---and they tried PD-L1 status in immune cells, tumour cells, The Cancer Genome Atlas subtypes, and mutation load to see if they are of predictive utility; all of them did improve the predictive power, but there were some patients in all subgroups who responded. So you can’t really exclude patients based on any or all of these parameters. Although the FDA has already provided accelerated approved for this drug, survival data from a placebo controlled trial are desired. Patients (and physicians) are going to have a hard time predicting whether they fall into the 15% that respond or the 85% that don’t - as well as pronouncing the name of this drug that bankrupted them.

How many trials before we acknowledge that targeted drugs effective in the metastatic setting are not effective in the adjuvant setting?

Apparently, the answer is quite a lot. The failures of bevacizumab in colorectal cancer, anti-EGFR antibodies in colorectal cancer, and EGFR TKIs in lung cancer in the adjuvant settings have all suggested us that the biology of micro- and macro-metastatic diseases are different, and thus targeted drugs that control disease spread mightn’t be as effective in the search for a cure.

Yet, we see here a big study of 1943 patients with resected high-risk renal cell cancer, finding that both sunitinib and sorafenib are no different than taking a placebo - except that placebo doesn’t give grade 3 and 4 adverse effects to the patients. Oh wait, the placebo doesn’t kill patients with toxicities either - one patient receiving sorafenib and 4 receiving sunitinib died in this trial due to drug-toxicities.

Sid Mukherjee is playing it by ear

I do not usually comment on articles from lay press, but when a writer as influential as Siddhartha Mukherjee writes to the lay public evangelising non-evidence based medicine, calling for practice based on “hunches” and referring to targeted drugs as having “surprisingly minimal toxicities”, I couldn’t stay quiet.

Precision medicine, sequencing for genetic mutations, and using a drug to target those particular mutations —  it all seems very fascinating and alluring, but there is no evidence yet to support that practice. If anything, the basket SHIVA trial showed us that it doesn’t work. We shouldn’t provide false hopes and hypes to the public about precision medicine—the true reality of precision medicine is well explained here and here. Also, anyone prescribing drugs such as sunitinib or pazopanib – examples of targeted drugs that Mukherjee refers to as having “surprisingly minimal toxicities”- knows pretty well how toxic (and even lethal) they are, and how difficult it is to manage their adverse effects. Even a drug as commonly used as bevacizumab kills nearly 3 out of every 100 patients with toxic effects alone.

Treating out of guidelines based on “hunches” is simply malpractice—I really wonder what the author wanted to achieve with this piece on New York Times. It is full of hero-worshipping and encourages risky undertakings for young oncologists. What if someone was inspired by these suggestions, and wanted to experiment with - let’s say - intrathecal nivolumab for treating brain metastasis in a real patient? Is it time to peer-review medicine-related articles before publishing them in mainstream media?

Bevacizumab: The Beverly Hills of breast cancer drugs

I don’t know how they came up with such an amusing name for their trial, but this trial, termed BEVERLY-1, showed that adding bevacizumab to neoadjuvant chemotherapy for HER2 negative breast cancer patients - wait for it - doesn’t provide any clinical benefit! Was this ever in doubt? Only 19 of 100 patients achieved a pathological complete response. With all those negative trials of bevacizumab in breast cancer, I wonder why they wanted to test it again, albeit in a different setting. But wait, this trial completed enrolment in 2010 and the endpoint is pathological CR—a parameter which doesn’t require time for assessment unlike survival; so why the delay in publication? Unfortunately 50% patients developed serious adverse effects and 1% died due to bevacizumab in this trial. Bevacizumab is the Beverly Hills of breast cancer - affluent, pompous, not meaningful, and toxic!

PAZOGIST

I don’t need to check whether a trial is industry sponsored or not - I know it just by reading the conclusion. For an uncontrolled phase 2 trial (n = 81), the conclusion is that pazopanib improves PFS compared to BSC alone - but the actual PFS gain is only 1.1 months ( 3.4 v 2.3). PFS is the primary endpoint. But this mere 1.1 months benefit in PFS (OS was not different) doesn’t look something to be tremendously excited about - especially because more than one-fourth of the patients developed pazopanib-related serious adverse events, of which 6 died; of those, 3 deaths were considered pazopanib-related.

However, the report highlights instead on the more impressive figures of difference in PFS rates at 4 months: 45% v 17%. Something is going crazy with the sarcoma community: they recommend PFS at 12 weeks as good enough endpoint to determine whether they should pursue a phase 3 trial, but end up using it as a primary endpoint in phase 3 trial itself, discovering that PFS and OS are discordant in two big phase 3 trials and now using 4 months PFS as appealing data for GIST. It’s already clear that such haphazard survival data at a fixed time point is meaningless for making comparisons, and that they are not correlated with survival. Amen!

Pharma can do good too

Regarding the limited access to anticancer drugs in low-middle income countries (LMICs), I have previously called upon the pharma industry to realize their corporate social responsibility and provide cancer drugs for a very low cost in LMICs. So, you can understand my happiness when I read this editorial in the Lancet Oncology. GlaxoSmithKline (GSK) said it won’t patent cancer drugs in LMICs! That’s a great news for patients and physicians in LMICs; and gives us a glimpse of how inspiring the world could really be if we all focused more on providing care than earning money! I hope other pharmas follow this lead. I just want to say, thank you GSK!

Fertility issues in childhood cancer survivors
The tragedy with having cancer during childhood is that patients don’t really understand the risks and benefits of treatment and can’t really give their informed consent. The toxicities of treatment kick in many years later, in some cases in the form of inability to conceive, at which point nothing can be done about the situation. This study, therefore, provides very important information on the reproductive outcomes in survivors of childhood cancer treated with chemotherapy alone (radiotherapy excluded) and the news is not very good: only 38% of cancer survivors reported having or siring a pregnancy compared with 62% of siblings; the risk of not having or siring a pregnancy being greater for male survivors (HR 0.63) than female survivors (HR 0.87).

Cyclophosphamide, Ifosfamide, Procarbazine and Cisplatin were associated with reduced likelihood of pregnancy in males while only busulfan and lomustine were associated in females. Cyclophosphamide equivalent dose had a linear relationship with reduced likelihood of pregnancy in males ( HR 0.82 per 5000mg/m2 dose) but not in females where cyclophosphamide equivalent dose was associated with risk only at the upper tertile dose. The key message is that receiving treatment with cytotoxic drugs in childhood has a detrimental impact on later pregnancy, more so for males, and thus fertility preservation options should be actively encouraged in all paediatric cancer patients with the reference of these data. Please refer to the table of the study for the detailed risk of different agents at different dose levels for informed decision-making. For female patients already treated in childhood with cytotoxic agents, it is reassuring that besides busulfan and lomustine, other drugs didn’t have much detrimental effect.

EPIC Failure?
This study - labelled as EPIC - comparing ponatinib with imatinib for the first line treatment of CML was terminated early because of the accumulation of arterial occlusive events with ponatinib use in clinical trials. The authors conclude their abstract with: “The efficacy of ponatinib treatment of newly diagnosed chronic-phase chronic myeloid leukaemia compared with imatinib could not be assessed due to trial termination, but preliminary data suggest there might be benefit, although with more arterial occlusive events than with imatinib at the doses studied. Because the EPIC trial was terminated early, efficacy of ponatinib in this setting remains to be established.”

But my conclusion would be very different: “Ponatinib should not be used in the first-line treatment of CML patients. These patients need to take TKIs for the rest of their lives, and therefore these increased risks of vascular adverse events with ponatinib are of grave concern. Imatinib, already in use for many years, has a known safety profile and is already very efficacious. Thus, we can reserve hazardous drugs like ponatinib for later lines of therapy when patients develop resistance to imatinib."

(By the way, did I mention that this trial was industry-sponsored?)

How statistically significant!
This one is hilarious. In the LUX-Lung 7 trial, in the authors’ own words “Afatinib significantly improved progression-free survival” compared to gefitinib. Well, looking at the data, the actual prolongation of survival is by a margin of  – wait for it — 3 days! Yes, that’s right. A median PFS of 11.0 months with afatinib versus 10.9 months with gefitinib. But it indeed is statistically significant, with P = 0.017. And the authors conclude, “These data are potentially important for clinical decision making in this patient population”.

No comments. But it did remind me of P-hacking- no, not Phacking, as John Oliver puts it!

Apatinib in Gastric Cancer
When countries like China publish good phase 3 trials, I am delighted. Slowly, but surely, the LMICs are trying to keep pace with the oncological advancements of the developed nations. This trial found that apatinib, a VEGFR2 inhibitor, significantly prolongs both OS and PFS in metastatic gastric cancer patients who have failed at least 2 lines of therapy. Angiogenesis inhibitors have a strange relationship with gastric cancer - bevacizumab failed, ramucirumab worked, and now apatinib has shown good results.

INGLORIOUS GLARIUS
We have had two big trials of bevacizumab in glioblastoma multiforme and both these trials unequivocally showed that bevacizumab doesn’t improve OS. But here comes another trial that studied the same thing, albeit in a subgroup of MGMT non-methlyated tumour, which found the same thing: bevacizumab doesn’t improve OS! The authors cite high crossover rate for this lack of significance in OS despite the significant benefit in PFS — but maybe they should have first read this and this before resorting to crossover to explain their findings. How can you deny the increased off-target deaths with bevacizumab in this trial especially when the OS with bevacizumab is shorter than the control? ( 16.6 v 17.5 months). The last few words of this report are “BEV, nevertheless, could be an interesting experimental alternative to TMZ in this particular subgroup”. Very interesting indeed!

STAMPEDING Guidelines
I should have included this in April’s post, but it’s better late than never. There is an interesting rebuttal letter from the experts who penned the ESMO clinical guidelines for prostate cancer (PC) in April issue of Annals of Oncology.

Prof. Tannock - the famous prostate cancer expert who also led one of the first trials that established docetaxel (DTX) as the first chemotherapy to improve survival in PC- had earlier written a letter against the ESMO recommendations that all patients with hormone sensitive PC receive upfront chemohormonal therapy (DTX androgen deprivation therapy). The CHAARTED and the STAMPEDE trials have established the benefit of upfront chemohormonal therapy ( OS benefit of nearly 1 year). It is, therefore, understandable that the authors of the ESMO guidelines recommend DTX addition to all eligible patients. However, Prof. Tannock strongly opposes against recommending upfront chemohormonal therapy to all patients. Indeed, these trials have shown that the OS benefit is not significant among patients with low volume disease.

These patients also represented only a minority of the study population. So, given the adverse effects including occasional mortality with DTX, patients with low-volume disease should be spared upfront DTX—Prof. Tannock writes strongly in his letter asking for a correction in the guidelines; but the authors of the guidelines discard this as a casual subgroup observation. It is noteworthy that Prof. Tannock had himself co-authored a consensus-based guideline – published in the same journal earlier - where the majority voted against using DTX upfront for low-volume disease. I personally don’t favor upfront DTX for low-volume disease, not only because of lack of significance and longer natural survival for this subgroup, but also because many options are now available in later lines of therapy that weren’t available when these studies began. In any case, the major dissent against the ESMO recommendations would be the strength of the recommendation - it gets a (I,A) which means strong evidence and highly recommended.

For low-volume disease, with so much disagreement going on, I don’t think (I,A) is an appropriate recommendation. I also want to raise another important issue in this context—that of subgroup analysis. Whether subgroup analysis can be taken as reliable evidence is a big apple of discord among oncology community. The high volume versus low-volume subgroup analysis in CHHARTED was pre-planned. Dismissing the lack of benefit among low-volume PC as a mere subgroup observation while upholding bevacizumab as efficacious in poor-prognosis ovarian cancer patients based on a sub-group observation alone is a double standard by the oncology community.

Let me take a selfie
Self-citation is considered to be the "selfie" of academicians. Please allow me to take a selfie and inform you here that last month my colleagues and I published what we believe to be the first case-report of a CML patient developing pure red cell aplasia with both imatinib and nilotinib. Luckily, with steroid and cyclosporine support, we were able to continue TKI in this patient.

Acknowledgments
First of all, I would like to thank you all my dear colleagues and readers for your overwhelming response to the first blog post last month. This blog is a product of inspiration from reading Dr. Richard Lehman’s blogs in the BMJ where he reviews major medical journals weekly—it’s a treat to read and if you haven’t followed it yet, please do. Because there are many important oncology articles published every month that an oncologist should stay informed about, I started this blog to provide an unbiased critical commentary of major oncology papers from the month--inspired by Dr. Lehman’s blogs and encouraged by Dr. Vinay Prasad. I would like to express my big thanks to them. Indeed, Dr. Lehman has already cautioned me that this activity could age me sooner and use up my weekends; but I hope it’s worth it.

Last, but not the least, I am very grateful to the ecancer team for their extremely positive and enthusiastic support from the very beginning. In particular, it was the encouraging feedback from Prof. Gordon McVie, the editor-in-chief of ecancer, and the very energetic collaboration with Audrey Nailor, the journal editor of ecancermedicalscience, that made this idea of blog shape into reality. Thank you.

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.