Independent ecancer blogger Dr Bishal Gyawali rounds up the latest clinical oncology trial news

Is this success in CINV prevention worth celebrating?

I am a big fan of olanzapine as an antiemetic agent in the prevention of chemotherapy induced nausea and vomiting (CINV). It is cheap and effective.

Previous RCT has shown that olanzapine palonosetron dexamethasone (OPD) compared with aprepitant palonosetron dexamethasone (APD) provides similar efficacy results for complete response and better results for nausea control (See Table 3 of this review).

This RCT was very important because it showed that the cheap drug olanzapine could produce results similar to the expensive aprepitant.

Sadly though, olanzapine is not a blockbuster new drug, isn’t patent-protected in many countries, isn’t expensive–hence, this study didn’t receive the attention and importance it deserved.

Olanzapine has continually been ignored by the oncology community despite the inclusion in NCCN guidelines (but not in the ASCO and the MASCC/ESMO guidelines) for CINV prevention.

Although aprepitant containing regimen provides good vomiting control, it’s not as much effective in controlling nausea, and in this RCT olanzapine improved nausea control by more than 30% in addition to numerically better vomiting control. However, instead of welcoming this finding, many wanted to have a confirmatory trial to accept this benefit of olanzapine.

The confirmatory trial happened—but alas, it didn’t test OPD v APD.

It instead tested APD olanzapine vs. APD placebo (25% patients received other 5HT3 inhibitors and not palonosetron).

This study proved that APD olanzapine was superior to APD. This study did prove the antiemetic efficacy of olanzapine in CINV but as there was no OPD arm, the cheap agent olanzapine was not tested against the expensive agent aprepitant.

This study was published in NEJM (APD v OPD was published in journal of supportive oncology!) with all consequential hypes and media coverage - but to me, this is a sad story.

The tables 2 and 3 of this NEJM paper show a very sad finding: that despite using 4 drugs (APD olanzapine) one in four patients suffered acute nausea, more than half suffered delayed nausea and one-third suffered overall nausea.

Complete response rates in acute, delayed and overall period were 86% v 65%, 67% v 52% and 64% v 41% for APD olanzapine v APD regimens respectively. These are sorry figures.

If you see the trial of APD versus OPD, these rates are much better for both these regimens and especially better for OPD (as much as 97% complete response rate for acute period). The landmark study that established aprepitant as an effective antiemetic for CINV prevention also had much better figures.

The main problem with this study is that nausea and vomiting control was too poor in either arm. The 4 drug regimen had better control but it’s still poor compared to APD/OPD arms in other trials of CINV. So, how is this study an improvement?

Indeed, cross trial comparisons are fraught with tremendous bias and should never be considered decisive but the absolute efficacy numbers are too low in this study. The reasons for such poor figures should be sought before we hype this study.

This study is a tale of caution, not a cause for celebration: more than one-third of our patients are still vomiting (or taking breakthrough drugs for vomiting control) due to chemotherapy in the 21st century, despite being prescribed four prophylactic antiemetics!

I was pretty sad seeing such poor control of CINV and moved to the Discussion section seeking some explanations for such poor control in this study as well as discussions on how to put this study in light of much better rates with OPD in previous study.

But alas! The discussion section of this article is one of the shortest and poorly written discussions I’ve ever read for a NEJM paper. No comparisons with previous studies, no mention of the position of OPD regimen, not a single word about many patients still suffering CINV despite the use of 4 drugs. Neither was there an accompanying editorial to discuss these issues. 

I would still favour OPD as the antiemetic regimen of choice for preventing CINV and adding aprepitant on as needed basis, more so when I am working in a low-resource setting. 

Significantly unhappy (P < 0.001) with latest oncology studies

This study showed that the incidence of germline DNA-repair gene mutations in metastatic castration resistant prostate cancer was 11.8% of which 44% of total mutations was in BRCA2 gene.

This is an important finding as patients with this mutation could possibly have good results with PARP inhibitors and/or platinum.

This study showed that this incidence was higher than that reported for localized prostate cancer (4.6%) and patients without cancer (2.7%) - but I was not very happy to see that they compared these findings from different subjects and studies to say that this higher incidence was statistically significant (P < 0.001).

Can you really do that? Compare the incidences from two different samples of two different studies and provide a P-value? If so, can we please compare the CINV control rates from the above study with other studies conducted in the past?

Formula for getting a paper published in NEJM

If you wish to get a paper published in NEJM, write anything with the combination of terms “cancer”, “immunotherapy” “PD-1” “PD-L1” “CTLA-4” “genetics” “mutations” “pathways” and “resistance” and your chances of success are much higher than those without any of these terms, or so it seems.

I actually read through this very difficult-to-read paper in NEJM that claimed “acquired resistance to PD-1 blockade immunotherapy in patients with melanoma was associated with defects in the pathways involved in interferon receptor signalling and in antigen presentation” and found that this was a study done in FOUR non-consecutive patients of which they found resistance-associated loss-of-function JAK1 or JAK2 mutations in TWO patients of which the baseline sample for ONE patient was taken not before pembrolizumab but before an earlier therapy with vemurafenib, a BRAF inhibitor. Wow! 

Not very sequential

NICE has now approved concurrent nivolumab ipilimumab for first line therapy of metastatic melanoma. Given the reputation of NICE to take cost-effectiveness into consideration and take bold steps to reject drugs that are expensive but marginally effective, this not-so-nice decision from NICE came as a surprise. There is no evidence yet that nivolumab ipilimumab improves survival over nivolumab followed by ipilimumab or ipilimumab followed by nivolumab but there is clear evidence that nivolumab ipilimumab is more toxic than either agent alone.

I was, therefore, happy to see this study comparing nivolumab followed by ipilimumab versus ipilimumab followed by nivolumab in advanced melanoma which showed that nivolumab followed by ipilimumab had better efficacy results. But this study was not a study of sequential administration in true sense.

This study assigned patients to nivolumab six doses followed by ipilimumab four doses or vice-versa followed by continued nivolumab until disease progression or unacceptable toxicities. The true clinical scenario is ipilimumab four courses followed by observation and nivolumab upon disease progression or nivolumab until disease progression followed by ipilimumab four courses.

We still have no idea about which approach is better because this study asked a question that is not asked in real clinical scenario.

Anyway, a more relevant question would be whether six courses of nivolumab alone would be as effective as nivolumab until disease progression. 

Given that four courses are enough with ipilimumab, the immune system once modulated can produce long term effects and nivolumab is very expensive, asking whether a limited course of nivolumab would be non-inferior to nivolumab until progression would be a great clinical question (a true case for a non-inferiority study).

This would save patients from toxicities and health care systems from bankruptcy. But alas, who would conduct such a trial?

Changing landscape of sarcoma treatment

In recent years, some amazing successes have been achieved in the treatment of metastatic soft-tissue sarcoma treatment, a disease that is otherwise very lethal.

Besides the anthracyclines and alkylating agents, we have pazopanib, eribulin and trabectidin added to our armamentarium.

Another agent likely to be added to that list is olaratumab, based on this phase 2 study where it has shown an OS advantage of nearly 1 year - something that has never been heard of in sarcoma! If these results are maintained in the ongoing phase 3 study, I will have absolutely no complaint about its name which sounds like an exercise in tongue twisters, especially for Japanese patients as “r” and “l” are pronounced the same in Japanese.

The Fatal Attraction of Testing

Fatal Attraction was a psychological thriller movie about the consequences of getting unwisely obsessed with someone. This study beautifully shows the obsession of oncologists to ordering CA-125 levels and CT scans for surveillance in ovarian cancer patients with the hope of detecting relapse earlier and prescribing chemo earlier despite evidences, guidelines and Choosing Wisely Campaign recommending against routine CA-125 or radiographic surveillance.

Rustin et al in 2009 showed that there was no survival benefit but poorer quality of life with routine CA-125 testing and early start of chemotherapy. This current study shows that there has been no change in practice patterns: CA-125 tests and CT scans are still routinely used for surveillance in patients with ovarian cancer.

In an accompanying editorial - which is a must read - Goodwin calls it “the fatal attraction of testing” and tries to explore the underlying psychology of this seduction. Although the study shows that the consequence of this attraction is waste of approx. 17 million dollars without any benefit, Goodwin correctly argues that cost-effectiveness is an absurd discussion for an approach that is not effective at the outset.

Goodwin’s piece is simply superb - a subjective, to the point, no nonsense editorial. This should serve as an example of how editorials should be written. Editorials are not research papers, and thus, they should be subjective and reflect the opinion of the non-conflicted expert. Editorials provide synopsis of the study in context, highlight the contextual importance of the study, criticize or praise it as appropriate. Editorials are short, powerful and are probably read more than the original study.

This editorial will make you think. A short glimpse here:  “But why would clinicians present the option of CA-125 testing? Shared decision making does not require that physicians present the patient with harmful options. We do not discuss heart transplants with patients who have mild congestive heart failure. Why would we discuss CA-125 testing with women who have ovarian cancer in remission?

Will the practice of obtaining routine CA-125 testing change? I doubt it. The moving target argument is too strong. There will be better tests, and more effective treatments. And studies like that of Rustin with uncomfortable results are usually not replicated. The issue is allowed to fade away. The fatal attraction of more information is too compelling."

Fatal Attraction 2: Obsession with finding positive results

Here is another study on ovarian cancer comparing farletuzumab (a monoclonal antibody against folate receptor) versus placebo with a primary endpoint of PFS which found that farletuzumab was no better than placebo. However, as mentioned by Goodwin in the editorial mentioned above, the authors of this study are fatally attracted to CA-125 testing and use it to show a positive finding when there is none.

While we have already discussed the futility of CA-125 testing, you are greeted with this statement in the introduction of this farletuzumab study: “The sensitivity of CA-125 in the detection of recurrence is approximately 90%, and low CA-125 levels are hypothesized to be associated with lower volume of residual disease”.

Why? Because they need to conclude anyhow in favour of the drug despite the overall negative results. They do this by this statement in their conclusion of abstract: “patients with CA-125 levels not more than three times the ULN and patients with higher farletuzumab exposure showed superior PFS and OS compared with placebo.” They spend considerable words in justifying CA-125 based results in the abstract but don’t consider it important enough to mention that more patients with farletuzumab (42.1%) suffered anemia versus placebo (34.9%).

Bewildered, confused and shocked at this fatal attraction to proving any new agent in ovarian cancer as positive no matter what the results suggest. I and Dr. Vinay Prasad have written an editorial regarding this fatal attraction to hailing any result as positive in ovarian cancer trials which will be online in the ecancermedicalscience journal soon.

Let me take a selfie

Bevacizumab is the first antibody to show overall survival benefit in advanced cervical cancer. 85% of patients with advanced cervical cancer live in LMICs. And one month of bevacizumab costs more than 10 times the annual GNI of LMICs. I raise the issue of this paradox and propose some solutions to combat this challenge in this commentary in JGO.

Other mentions

1. Should oncologists adapt themselves to seeing more adaptive randomization trials? My discussion on I-SPY 2 trials strengths and weaknesses are up in a separate blog here.
2. Cabozantinib has shown improved overall survival over everolimus in the 2nd line treatment of advanced RCC and thus represents a new treatment option. The safety profile of these agents are different and nivolumab has also shown better OS over everolimus in the same setting. These factors should be considered while discussing the treatment options with the patient, keeping in mind that every patient in the clinic is unique and doesn’t correspond to “most patients” reported in the studies. Dr. Lehman said “No patient is most patients” and we have now started a trend in twitter with the hashtag #Nopatientismostpatients . Please join in and help spread this important message: #nopatientismostpatients.
3. Daratumumab may interfere with compatibility testing for blood transfusion. Another lesson that we should all be careful about many unexpected effects of new anticancer drugs. It will take time for many of these effects to become apparent. A healthy balance of optimism with caution is advisable regarding every new drug that is arriving to the oncology market. Another example of what I am saying is here.
4. For patients with 1-3 brain metastasis, stereotactic radiosurgery alone provides better quality of life, less deterioration of cognitive function and similar survival compared to addition of whole brain radiation therapy. This is a well-conducted study and settles this important question for this particular subgroup of patients but other questions remain as highlighted in this editorial.

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 Dr. Gyawali's previous blogs here