Keynote speech on the JAVELIN not going far enough to improve survival
The treatment landscape for metastatic renal-cell carcinoma has changed dramatically with the introduction of immunotherapies. Unfortunately though, we are promoting combinations over single agents without having much idea of added benefit of each drug. This is an important issue because when we combine two drugs, the only thing we are certain of are the added toxicities. PD-1 inhibitor nivolumab had improved OS when given in second line, however nivolumab was tested in combination with ipilimumab (not as a nivolumab monotherapy) in the first line trial. Now, pembrolizumab and avelumab have followed suit, although their combination partner was axitinib – a VEGF inhibitor. The control arm was sunitinib for both of the trials of pembrolizumab plus axitinib (KEYNOTE 426) and avelumab plus axitinib (Javelin 101). This is a little surprising because we are testing A B versus C, where both A and B haven’t been approved for the given setting – axitinib was approved for RCC in second line. Both these combinations improved PFS versus sunitinib but only the pembrolizumab combination has shown improved OS. However, I have doubts about the contribution of axitinib to these results. What would the outcome be if pembrolizumab alone is followed by sunitinib in second line? It is important to note that only one third of patients who discontinued sunitinib received PD-1 inhibitor subsequently in the KEYNOTE 426 trial. The important question for patients and clinicians would be to consider a survival difference had most of these patients received a PD-1 inhibitor subsequently. As for avelumab, the JAVELIN trial hasn’t reached as far as pembrolizumab and nivolumab have reached: The OS benchmark – so let’s reserve this combination until we see that benefit.
Have we successfully landed on the COMET?
We should remember that this combo-mania with PD-1/PD-L1 inhibitors may also backfire. Previously, the RCTs of nivolumab and pembrolizumab combos were halted in multiple myeloma for higher deaths in the combo arms. Another RCT IMblaze 370 also reports that atezolizumab, alone or in combination with cobimetinib, failed to improve survival versus regorafenib in patients with metastatic colorectal cancer. This time again A B failed versus C although C in itself is a drug with very marginal benefits in this setting. Also, I don’t understand testing A plus B combo when both A and B are unapproved for the disease.
In this episode of Radiology Firing Line Podcast, I speak with Bishal Gyawali MD, PhD. Dr. Gyawali obtained his medical degree from Kathmandu. He received a scholarship to pursue a PhD in Japan. Dr. Gyawali’s work focuses on getting cheap and effective treatment to under developed parts of the world. Dr. Gyawali is an advocate for evidence-based medicine. He has published extensively in many high impact journals. He coined the term “cancer groundshot.” He was a research fellow at PORTAL. He is currently a scientist at the Queen’s University Cancer Research Institute in Kingston, Ontario.
As news of Tom Brokaw’s cancer diagnosis spreads, so does his revelation that his cancer treatments cost nearly $10,000 per day. In spite of this devastating diagnosis, Mr. Brokaw is not taking his financial privilege for granted. He is using his voice to bring attention to the millions of Americans who are unable to afford their cancer treatments.
My patient Phil is among them. At a recent appointment, Phil
mentioned that his wife has asked for divorce. When I inquired, he revealed a
situation so common in oncology, we have a name for it: Financial
Toxicity. This occurs when the burden of medical costs becomes so high,
it worsens health and increases distress.
Phil, at the age of 53, suffers with the same type of bone
cancer as Mr. Brokaw. Phil had to stop working because of treatments and
increasing pain. His wife’s full time job was barely enough to support
them. Even with health insurance, the medical bills were mounting. Many
plans require co-pays of 20 percent or more of total costs, leading to insurmountable
patient debt. Phil’s wife began to panic about their future and her debt
inheritance. In spite of loving her husband, divorce has felt like the only
solution to avoiding financial devastation.
Well, you might not have noticed that my blogs were missing for the last three months but anyways, its good to be back. I was having a little time off blogs and social media as I was transitioning in my career but now I am back. Sometimes, it is very difficult to manage time for things that you must do versus things you enjoy doing, especially when these two don’t intersect. For me, these last few months the things I had to do were all bureaucratic while I couldn’t find the time for things I enjoy doing like writing these blogs. But now that we are back, let’s recap what has happened in the oncology world in the year 2019 so far. I can’t cover all of them, but will try to summarise the major events in oncology.
Hundred Foxes’ Howl versus One LION’s Roar
In my country, there is a saying that goes somewhat like the roar of one lion will scare hundreds of howling foxes away. In medicine, I guess, it translates as one good RCT trumps the results from hundreds of observational studies. For patients with advanced ovarian cancer, primary surgery to achieve complete resection is the most important treatment and prognostic factor. However, what to do with the lymph nodes is a question that has troubled the oncology community for a long time. Logically, it makes sense to remove the lymph nodes too because they are the sanctuary sites for cancer cells. However, lymph node dissection carries high morbidity. Although multiple observational studies suggested a survival benefit with lymph node dissection, the LION trial, now published in the NEJM, shows that for women with macroscopic complete resection of primary tumour, lymph node dissection increases morbidity (postoperative complications) and post-operative mortality rates but doesn’t improve survival. I am glad that this trial was carried out and these results will now save many women with ovarian cancer worldwide from unnecessary harmful procedures, but I am also sad that we didn’t answer this question until now and thus, many patients suffered unnecessarily. I hope this LION’s roar scares us from jumping to conclusions based on logic or observational data alone and without RCT evidence in future. Another lesson here is the importance of public funds in supporting RCTs like these.
September was an important month in oncology—especially for lung cancer. The World Conference in Lung Cancer (WCLC) 2018 gave us some important practice-changing results, also leading to four NEJM publications. The trial with most public health impact is unfortunately not published yet. It’s the NELSON trial that randomised more than 15000 asymptomatic people at high risk of lung cancer to either CT-based screening for lung cancer or to no screening and found a significant reduction in lung cancer mortality rates among the screened cohort compared with the control cohort. This reduction was more pronounced among women, although they constituted only 16% of the trial population. I am looking forward to reading the full publication and am particularly interested in knowing if there were any differences in all-cause mortality rates and the rates of overdiagnoses.
A new ALK-inhibitor on the block—brigatinib—has significantly improved PFS versus crizotinib when used as first-line therapy in ALK-positive non-small cell lung cancer (NSCLC) patients. However, I assume that it will be difficult for brigatinib to replace alectinib in this setting, since the latter has already been tested in two different RCTs and has more mature data.
With Keynote 407, pembrolizumab has entered into the treatment arsenal for squamous NSCLC by improving overall survival in combination with chemotherapy versus chemotherapy alone as a first-line regimen. However, when A B is compared with A, it is important to know whether A B is better than A followed by B. In this trial, 32% of patients who were in the control arm received a PD-1 inhibitor upon progression. Nivolumab is already approved as a second-line option in this setting after first-line chemo; so how much benefit in Keynote 407 is due to more than half of control arm patients not getting PD-1 inhibitor at all versus the benefit of combining pembrolizumab with chemo upfront is an important question.
In this episode of Firing Line, Saurabh Jha (aka @RogueRad), has a conversation with Chadi Nabhan, MD MBA FACP, who is a preeminent oncologist, speaker and the Chief Medical Officer of Cardinal Health Specialty Solutions.
At the great heights of his career, and a secure American citizen, Chadi recalls the struggle and effort it took to get from Syria to Boston. He credits his journey to good luck and a tenacious drive and uncompromising desire to work in the U.S. Chadi speaks for thousands of international medical graduates to fight odds to get here.
Some books draw you in based on a catchy title, a provocative book jacket, or familiarity with the author. For me, recollections of medical school primers written by the renowned lymphoma pioneer Vincent DeVita Jr. and my own path as an oncologist immediately attracted me to “The Death of Cancer.” I felt a connection to this book before even reading it and prepped myself for an optimistic message about how the cancer field is moving forward. Did I get what I bargained for?
Co-authored with his daughter, Elizabeth DeVita-Raeburn, DeVita brings us back decades ago to when he had just started at the National Cancer Institute (NCI) under the wings of Jay Freireich and Tom Frei. At the time, he was a clinical associate and a “chemotherapist”; the field was ultimately renamed and defined as medical oncology. (Note to self: I am ecstatic the field was renamed; I would prefer to be called a medical oncologist anytime than a chemotherapist, but that’s just me). He recounts how chemotherapy was frowned upon in favor of the two preferable ways to treat cancer at the time: surgery and radiotherapy. DeVita eloquently describes how his mentors were ridiculed when they announced their pursuit to cure childhood leukemia using combination chemotherapy; their approach and determination provided him with inspiration to push his research further. He goes on to describe in a fascinating manner the way he designed the MOPP regimen, which cured many patients with Hodgkin lymphoma. He recounts events when he presented his own MOPP data, and how he was verbally attacked by radiotherapists who claimed his data were insufficient and attempts to drive them “out of business”. Even in 2018, my radiation oncology colleagues protest when medical oncologists challenge the role of radiation therapy in Hodgkin lymphoma. I have actually grown tired of attending debates between any two prominent lymphoma figures discussing whether to use radiation or not in such setting; there are better topics to argue about, like who might win the Super Bowl.
There was a very sobering piece in NEJM by the FDA last month in which the authors try to explore what went wrong with the Keynote-183, Keynote-185 and checkmate 602 trials testing PD-1 inhibitors combinations with pomalidomide or lenalidomide and dexamethasone in multiple myeloma. Interim analysis of Keynote 183 and 185 revealed detrimental effects on overall survival (OS) with hazard ratios of 1.61 and 2.06, not explained by differences in toxicities alone. The checkmate 602 trial was also halted in light of these findings and also showed higher mortality in the nivolumab combination arm.
In the thoughtful NEJM piece, the authors make at least three important points. First, they question why these PD-1 inhibitors were tested in combination despite their having limited single-agent activity. In fact, a couple of years ago, Vinay Prasad and I asked the same question: why are novel cancer drugs being tested in combination despite having limited activity as a single agent? We found that these drugs, even when ultimately approved, provide relatively low value and recommended that drugs with poor single agent activity not be tested in combinations unless there are specific reasons to expect synergy.
The second important point in the article is that many cancer drug approvals are lately based on durable response rates in single arm trials without a control group, a situation in which it is difficult to evaluate the safety and efficacy of drug combinations. Indeed, without an RCT, the oncology community would never have known these signals of detrimental effect. If the FDA had approved these PD-1 inhibitors in multiple myeloma on the basis of non-randomized trials, which it often does in other oncology contexts, who knows how long it would have taken to recognize the increased mortality in patients—and at what cost. This is another reason why we need RCTs more now than ever. Finally, the authors point out that these PD-1 inhibitors in multiple myeloma were directly advanced to phase 3 trials after phase 1 trials were completed, without phase 2 information. Indeed, in a recent paper, Alfredo Addeo and I showed that a substantial percentage of drugs that fail in phase 3 trials do not have supporting phase 2 data. Continue reading…
I read the report of a phase 3 RCT of a “new” breast cancer drug but I had the feeling that I had already read this before. Later I realized that this was indeed a new trial of a new drug, but that I had read a very similar report of a very similar drug with very similar results and conclusions. This new drug is a PARP inhibitor called talazoparib and the deja vu was related to another PARP inhibitor drug called olaparib tested in the same patient population of advanced breast cancer patients with a BRCA mutation. The control arms were the same: physician choice of drug, except that physicians couldn’t choose the one drug that is probably most effective in this patient population (carboplatin). The results were nearly the same: these drugs improved progression-free survival, but didn’t improve overall survival. In another commentary, I had raised some questions on the choice of control arm, endpoint and quality of data about the olaparib trial when it was published last year. This current talazoparib trial is so similar to the olaparib trial that you can literally replace the word “olaparib” with “talazoparib” in that commentary and all statements will stay valid.
The oncology version of half-full, half-empty glass
The PARP inhibitors olaparib and niraparib are also approved in ovarian cancer based on improvement in progression-free survival (PFS), without improving overall survival (OS). If a drug doesn’t improve OS but improves only PFS, it should also improve quality of life to justify its use. According to two new reports, these drugs do not appear to improve quality of life. The niraparibtrial reported that the patients were able to “maintain” their quality of life during treatment while the olaparib trial reported that olaparib did not have a “significant detrimental effect” on quality of life. I find it remarkable that a drug that isn’t proven to improve survival is lauded for not significantly worsening quality of life … at $10,000 a month!
It is also important to recognize that these drugs were tested as maintenance therapy against placebos. For “maintenance therapies,” as explained in this paper, improving PFS alone is not an important endpoint. That’s why I am also not excited about this new trial of sorafenib maintenance in ovarian cancer. A drug has to be very ineffective to fail to improve even PFS as a maintenance therapy against placebo. Continue reading…
WTF Health – ‘What’s the Future’ Health? is a new interview series about the future of the health industry and how we love to hate WTF is wrong with it right now. Can’t get enough? Check out more interviews at www.wtf.health.
Central to the ‘WTF Health’ ethos is the idea that around the world, there is a shared passion for creating a new future for healthcare — and that the less-positive ‘WTF moment’ is a shared experience, regardless of which country’s health system one is standing in.
So, I’m going around the world this year — to 17 different health innovation conferences in 11 different countries — to find out what innovators abroad are doing to tackle the problems in their health systems and what we can learn from one another.
Driving down the cost of care, managing chronic conditions, helping people achieve better health, improving care delivery and patient experience — these goals know no borders. What’s different is the framework around them. So, what if the payment model were different? What if there was a single electronic patient record? What if certain laws and regulations didn’t exist?
Different constraints breed different solutions. What a hopeful and inspiring idea. And, with any luck, food for your thoughts and innovative thinking.
So here is the first interview I’d like to share from abroad! Everyone meet Finnish startup Kaiku Health, fresh off closing a €4.4M Euro series A. Their patient monitoring monitoring platform lets cancer patients (and others with chronic diseases) self-report on how they’re doing, using their hospital’s existing patient portal. Stick around until the end: Bonus insight on the strengths of the health tech startup scene in the Nordics for those who want to go explore.
Filmed at Upgraded Life Festival in Helsinki, early June.