Long list of news in lung cancer

Last month 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.

When the PACIFIC trial was presented at ESMO 2017, the DFS benefits with durvalumab among patients with stage III NSCLC who were treated with definitive concurrent chemoradiotherapy were so impressive that many thought OS results would turn positive. This time, we were not wrong. The OS results were presented at the conference and showed a significant improvement in OS with nearly an 11% increase in 2 year OS rates with durvalumab versus placebo. These are practice changing results; however, again, only 23% of patients in the placebo cohort received immunotherapy at progression, so the outcomes when immunotherapy has now become the standard first-line treatment at progression remains unknown. So rapid have been the changes in treatment landscape of NSCLC that even new trial results look outdated. In this median follow up of 2 years, 144 of 237 patients in the placebo group experienced a second progression or death, which means 39% of patients did well without any treatment at all. All these patients will now be getting durvalumab for a year. So, I think it is important to know whether all stage III patients receiving durvalumab confers any extra benefit to receiving pembrolizumab (plus chemotherapy) upon progression which is-the current standard of care.

We also finally saw some positive results in patients with small cell lung cancer. Addition of atezolizumab to chemotherapy improved OS significantly in extensive stage SCLC. However, the margin of benefit was small (median OS 12.3 v 10.3 months) and we have miles to go in the treatment of this lethal disease.

Finally, as a reminder that not all immunotherapies are necessarily better, avelumab failed to improve survival versus docetaxel in the second line treatment of patients with NSCLC. The JAVELIN trial didn’t reach very far.

Although not presented at the conference, an interesting analysis shows that for NSCLC patients age >70 years, addition of cisplatin to gemcitabine/pemetrexed didn’t add any survival or quality of life benefits.

Breast cancer treatment: Still stuck on bevacizumab?

Adding bevacizumab to chemotherapy failed to improve survival in breast cancer leading to withdrawal of its accelerated approval by the FDA. A drug that has failed in metastatic setting, to my knowledge, has never been proven to work in adjuvant setting. This sounds logical, because a drug that can’t delay progression is also unlikely to improve cure rates. However, last month we saw a huge trial of bevacizumab plus chemotherapy as adjuvant treatment in HER2 negative breast cancer. Nearly five thousand (yes, five thousand!) patients were randomised to chemotherapy plus placebo, chemotherapy plus bevacizumab or chemotherapy plus bevacizumab followed by bevacizumab maintenance. Patients randomised to bevacizumab arms experienced no improvement in invasive disease-free survival rates or overall survival rates, but suffered greater rates of toxicities.

Another important question in the adjuvant treatment of breast cancer is the duration of adjuvant trastuzumab for HER2 positive disease. Lately, some trials have tested non-inferiority of shorter course of adjuvant trastuzumab to one-year duration. A meta-analysis has now shown that one-year duration of adjuvant trastuzumab remains superior to shorter durations although for node negative and hormone positive disease, there was no significant difference. This information will be useful especially for treatment decisions in settings with more limited resources, where node negative and hormone positive patients may be counselled for a shorter course of trastuzumab.

Undertreatment-overtreatment paradox

While many patients in the US can’t afford curative cancer treatments, a recent report has shown that the Medicare is spending a median of $14,453 per patient within 3 years after the diagnosis of localised prostate cancer in elderly men. Localised prostate cancer is a condition that is rarely fatal, especially in elderly men because localised prostate cancer grows slowly such that there are higher chances of the patient dying of something else. That means we are spending a big amount of taxpayers’ money to prevent…nothing. 

Dr. Gyawali is a research fellow at Program On Regulation, Therapeutics And Law (PORTAL) at Brigham and Women’s Hospital/Harvard Medical School. The opinions expressed herein are his own. You can read his previous blogs here.