Trastuzumab is not Roche’s HERITAGE anymore

When people hype some new me-too cancer drugs as 'life-saving', I usually get irked. But some cancer drugs are truly life-saving and trastuzumab is one of them. Unfortunately, trastuzumab - the life-saving drug for HER2 positive breast cancer - is so expensive that most patients in LMICs can’t afford it. In a study from India, only 1% of HER2 positive women received the drug. India is one of the emerging economies and at the upper tier of Middle Income Countries. So, the condition in truly LICs can only be imagined.

The recent WHO Essential Medicine List has included trastuzumab as an essential drug for the first time. Honestly, when I heard that trastuzumab was included in the EML list for the first time, I was very excited. But it was only later that I realized that inclusion in the list didn’t mean people in LMICs were going to receive the drug or the governments in LMICs were going to get subsidies in purchasing the drug or any similar benefit. So, what’s the point of all this fuss I thought! It was only later during a global cancer policy meeting at ESMO 2016 that I properly understood the implications of this inclusion. Inclusion in the WHO EML list doesn’t guarantee access but it does signify an important step towards building awareness and pressurizing government. Therefore, inclusion in EML is indeed a milestone but it’s only the first of many steps needed. The most important barrier to access was/is cost. And one scientific approach to addressing this issue was the development of biosimilars. In this context, the HERITAGE was a great study  that was properly designed and conducted. This study showed that the biosimilar was equivalent to generic trastuzumab in terms of efficacy and safety. I think this study should form a benchmark for future biosimilars study.

This study was presented at ASCO 2016. I was concerned then and I am concerned now about how this biosimilar is going to be priced. This study involves patients from LMICs. Thus, it is imperative that the drug be so priced that patients from these nations are guaranteed continued access. If long-term access to patients from LMICs is denied, the ethics of conducting such studies in LMICs should be questioned. I quote here some lines from an editorial accompanying this publication in JAMA:

“It is morally indefensible to foster a clinical trials system that recruits participants from low- and middle-resource countries primarily to benefit market competition in richer countries. The ethical conduct of biosimilar trials requires ensuring that the communities of trial participants should have realistic access to drugs they have helped to develop.”

Less is More

I have always had an uncomfortable feeling with non-superiority trials (equivalence or non-inferior trials). 'Non-inferiority design' as a tool is usually hijacked by the industry to promote their marginal products and gain market share of billions. Equivalence trials need large samples and have been unused because it’s much easier to show non-inferiority than equivalence. In oncology, I can't remember having seen an equivalence trial before. Last week’s JAMA was a surprise: I saw an equivalence trial and a non-inferiority trial and I was very happy with both. The equivalence trial is the trastuzumab biosimilar trial I discussed above. The non-inferiority trial is also equally good because it answered a question of real value. Not surprisingly, it was a government funded study. This trial tested if longer dosing interval of zoledronic acid (3 monthly) provided similar protection against skeletal related events (SRE) as the current standard of every month among patients with breast cancer, prostate cancer and multiple myeloma. Result: it did. The risk difference was -0.3% within 2 years of randomization without any difference in pain scores, PS scores, or incidence of side effects. I liked everything about this study including the clinical implications as well as balanced 'discussion'. This is a good example where non-inferiority study was of value. The next step maybe to study if a much longer dosing interval could provide similar results.

DOTATATE for Midgut Neuroendocrine Tumours

Some hi-fi endeavours do seem to work! Lu-Dotatate is octreotide that has been radiolabeled with radionuclide Lutetium-177 (don’t remember having ever read Lutetium in chemistry class, but most of the high school education has been useless anyway). Octreotide has been known to exert antitumour effects in neuroendocrine tumours besides obvious effect on symptom control, but in this case octreotide acts more like a carrier agent to help Lutetium reach the cells with somatostatin receptors and act on them. In this phase 3 NETTER-1 trial, for patients with midgut neuroendocrine tumors who had progressed on octreotide, Lu-Dotatate  showed impressive improvements in PFS (HR 0.21, 95% CI 0.13-0.33) and OS (HR 0.40, data immature) versus octreotide. Although the bar is low here because the control group is receiving octreotide only despite progressing on octreotide (due to lack of standard options, and symptom control with octreotide), other agents have failed to show good benefit in this setting. The only other agent approved in this setting is everolimus, approved last year, and it showed improvement in PFS but not OS versus placebo. So, the results with Dotatate are impressive and practice changing especially given that the side effects are fewer when given with renal protection, compared to everolimus. Furthermore, unlike everolimus that is given until disease progression, Dotatate treatment was limited to four cycles in this trial. This could potentially translate to cost savings.

The OAK looks strong from the outside but how robust is it really?

The OAK trial testing atezolizumab versus docetaxel has shown prolongation in overall survival (OS) in the second line treatment of non-small cell lung cancer (NSCLC) including both squamous and nonsquamous types.  The TC/IC 0,1,2,3 categories were defined based on PD-L1 positivity of 0,1,5 and 50% cut-offs, and OAK showed that atezolizumab gave nice OS improvement across all the subgroups. However, PFS was actually longer with docetaxel and this again reflects why OS and not PFS should be the primary endpoint with immune checkpoint inhibitors. All good except when you look into the subgroup comparisons by PD-L1, the subgroups are divided into four categories: TC/IC 0, TC/IC 1,2,3, TC 2/3 and TC 3. Atezolizumab shows benefit across all these subgroups. However, as Vinay Prasad tweeted, if you test TC/IC 0 , TC/IC 1, TC/IC2 and TC/IC 3 separately, the benefit doesn’t look as good especially for TC/IC2 population (PD-L1 positivity between 5-50%). Clearly, PD-L1 is not an ideal biomarker and atezolizumab does seem to be a good drug, effective even in PD-L1 negative population, but why not just present data for each subgroup and gain credibility too?

Regorafenib: expensive and toxic sorafenib?

I’ll be honest: I am not a big fan of regorafenib. No, I have no prejudice or conflicts against regorafenib but I just find that it is very toxic to patients. Regorafenib is almost similar to sorafenib in structure and mechanism but costs more (almost twice) and is more toxic. Sorafenib in itself is not a cheap or safe agent: a recent meta-analysis has shown that sorafenib increases the risk of serious adverse events (SAEs) and fatal adverse events (FAEs) by 49% and 82% respectively. Sorafenib was the first drug to show improved OS in advanced hepatocellular carcinoma. In the REGOSARC trial regorafenib improved OS among those patients who had progressed on first line sorafenib. Usually, I don’t have problems when drugs improve OS. But anyone who has used regorafenib for colorectal cancer/GIST knows that liver toxicity is severe with regorafenib. In this case, we are trying to use regorafenib in patients whose liver function is clearly bad because first, they have liver cancer and second, their liver has already been somewhat damaged by sorafenib used in first line. In this big trial of 573 patients with good liver function who had tolerated sorafenib well in first line and had Child score A, regorafenib improved survival by 2.8 months. These OS results are important given the lack of other treatment options. However, I fear that when approved, people with poorer liver function will want to use it with very detrimental outcomes. Keeping in mind that this was a trial done on patients with good liver function, a key data to note is “adverse events were reported in all regorafenib recipients (374 [100%] of 374) and 179 (93%) of 193 placebo recipients.” Also, the incidence of FAEs in regorafenib group was 2%. These data are among patients with child A liver function in the setting of a clinical trial. A note of caution would be sensible when using this drug to those with less than ideal liver functions.

MARIANNE is not happy, she needs a taxane

The phase 3 MARIANNE study compared trastuzumab plus taxane versus T-DM 1 versus T-DM1 plus pertuzumab in patients with locally advanced or metastatic HER2-positive breast cancer. It found both the latter two regimens were non inferior but not superior to trastuzumab plus taxane. Clearly, the current standard is not trastuzumab plus taxane, but dual HER2 blockade with trastuzumab plus pertuzumab plus taxane, based on unprecedented OS benefit of 16 months in CLEOPATRA trial. I had to check the trial dates to make sure this was an ethical randomization (it was, the trial began before pertuzumab was approved but after pertuzumab showed clear OS benefit, was it ethical to continue with the less than ideal controls? Would love to hear from experts on trial ethics). But what was shocking was T-DM1 plus pertuzumab didn’t outperform trastuzumab plus taxane! T-DM1 plus pertuzumab represents dual HER2 blockade and should have shown superior results to trastuzumab plus taxane based on extremely good results in CLEOPATRA. But it didn’t, which is puzzling. Maybe taxane is THE key drug far more important than we had imagined! There goes precision medicine again - taking all the stick!

Bishal Gyawali, (MD) is a postgraduate trainee in medical oncology at the Graduate School of Medicine, Nagoya University, Japan, where he is also a PhD candidate under the Japanese government scholarship. His areas of clinical and research interests include evidence-based oncology practice, global oncology, cancer policy, cancer management in resource-limited settings, financial toxicities of cancer treatment, clinical trial methods and supportive treatment of cancer. He has no conflicts of interest to declare. Dr Gyawali tweets at @oncology_bg. Read his previous blog posts here. Dr Gyawali is an independent blogger and his views are not representative of ecancer.