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.
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…