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.
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…