28 November: ROS1, single arm trials

For Lung Cancer Awareness Month #LCAM I’m going to summarize 30 important lung cancer trials over 30 days. These posts are directed at non-medical professionals, with descriptions of the results and of what makes a good trial. #lcsm 1/15
This month I have focused exclusively on randomized studies, because I believe strongly that they are our best tools for evaluating the benefits and harms of cancer therapies. Today will be my sole foray into non-randomized studies. I hope to illustrate some of their limitations.
In a single-arm study, every patient receives the study treatment. A common method of describing drug activity is the waterfall plot, below. Each bar on the plot is an individual patient. The height and direction of the bar show how the size of the tumours changed with treatment.
The horizontal bar at zero indicates the tumour neither grew nor decreased. Bars below the line indicate tumours that decreased in size by the percentage indicated on the vertical axis. Similarly, bars above the line indicate tumours that grew despite treatment.
4/15
The responses are arranged in order from worst to best, to give the “waterfall” appearance. In the example above, only two patients had their tumours grow after starting treatment. By convention, those who have had their tumour shrink by >30% are said to have had a response.
The other information often given is a KM curve (5, 16 Nov). Obviously, there is only one curve, not two like the others we’ve seen this month. In the example below the grey bars are 95% confidence intervals (10 Nov) around each point. 6/15
Both of the examples above are from a study of crizotinib in people with ROS1 mutated cancers. Below are the waterfall plot and KM curve for a study of entrectinib in the same cancer. Note FWIW not an intention-to-treat population, but people who got a certain amount of drug.7/15
And here are the same graphs from a study of lorlatinib, also in ROS1-mutated cancers. 8/15
On the basis of these graphs, do you feel confident in saying that these drugs are all comparable, or that one or the other is likely superior? I admit that I do not. We go back to the papers, trying to find differences in toxicity, or in patient selection between trials. 9/15
Even if one drug were obviously superior, would it be better to take it alone, or in sequence with another drug? Are any of these drugs better than standard chemotherapy? We look for answers in vain. These answers come from randomized studies. 10/15
Since 2013 the FDA has approved numerous drugs on the basis of such non-randomized data. This has the advantage of getting the drug to patients more quickly. The disadvantage is that once regular approval is granted, pharma has no more incentive to do trials of the drug. 11/15
To me, this seems a steep price to pay. Hundreds of patients today may access the drug sooner, but thousands of patients in the future will have to make decisions about these drugs with scant evidence about their relative effectiveness or survival outcomes. 12/15
I'm sensitive to the idea that it would be difficult to do a large randomized trial in rare cancer like ROS-1 lung cancer (~2% of lung cancers).
I would counter that initial randomized trials in ALK (~3% of lung ca) were feasible at a time when most hospitals didn’t test for ALK.
Many TKIs for driver-mutated lung cancer are excellent drugs: many people have long responses with manageable side effects. Other TKIs have lower response rates or worrying toxicity.
The absence of randomized data impairs our ability to rationally use these new drugs. 14/15
Though I’ve focused on ROS1, I could have written a similar thread about RET, NTRK, METex14, or any driver mutation with multiple available TKIs.

Tomorrow we’ll take a look at a study design somewhere between single-arm and full randomized trial, the randomized phase II trial.

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29 Nov
29 Nov: Chemo/gefitinib, randomized phase II

For Lung Cancer Awareness Month #LCAM I’m going to review 30 important lung cancer trials over 30 days. These posts are directed at non-medical professionals, with descriptions of the results and of what makes a good trial.#lcsm 1/11 Image
All of the randomized studies we’ve looked at to date have been phase III studies, meaning that they are randomized studies with sufficient statistical power to demonstrate a clinically meaningful difference. Today we’ll look at a randomized phase II study. 2/11
Traditionally, phase II studies were preliminary studies done to see if a treatment approach was promising enough to warrant a proper phase III trial. They were single arm, and considered “positive” if they met some pre-specified level of treatment activity. 3/11
Read 11 tweets
27 Nov
27 November:Temel, QoL outcomes

This year for Lung Cancer Awareness Month #LCAM I’m going to summarize 30 important lung cancer trials over 30 days. These posts are directed at non-medical professionals, with descriptions of the results and of what makes a good trial.#lcsm 1/19 Image
Today’s trial is one of the most thought-provoking of the month, and it has been discussed widely since its publication in 2010. It is a trial looking at the timing of referral to palliative care for people with advanced, incurable lung cancer. 2/19
Many people hold the view that palliative care is care at the end of life. While this is a component of it, palliative care physicians are experts in controlling symptoms, which is valuable in a highly-symptomatic disease like metastatic lung cancer. 3/19
Read 19 tweets
24 Nov
24 November: And now a word from our sponsor

For Lung Cancer Awareness Month #LCAM I’m going to review 30 important lung cancer trials over 30 days. These posts are directed at non-medical professionals, with descriptions of the results and of what makes a good trial. #lcsm 1/16
To date we have reviewed at a couple of trials looking at the role of surgery in multidisciplinary management (Nov 6 & 8). Today we’ll look at a proper randomized trial of two surgical procedures for staging the mediastinum (the middle of the chest, between the lungs). 2/16
Knowing whether cancer has spread to mediastinal nodes is essential for staging a tumour. As we have seen, staging is required for any treatment decisions. Mediastinal nodes have numbers corresponding to the locations in the diagram below. 3/16
Read 16 tweets
23 Nov
23 November: ALEX and clarity

This year for Lung Cancer Awareness Month #LCAM I’m going to summarize 30 important lung cancer trials over 30 days. These posts are directed at non-medical professionals, with descriptions of the results and of what makes a good trial. 1/11 #lcsm
Today we’re returning to ALK-positive lung cancer. Way back on 5 November we looked at the PROFILE study that established crizotinib rather than chemotherapy as the second-line standard of care.
Today’s study compares crizotinib to a newer generation of ALK drug, alectinib. 2/11
This trial enrolled 303 previously untreated people between 2014 and 2016. Primary outcome was progression-free survival, with an 80% power to detect an increase in median PFS form 10.9 to 16.8 months. Particular attention was paid to brain metastases. 3/11
Read 11 tweets
22 Nov
22 November: PACIFIC, intention to treat

For Lung Cancer Awareness Month #LCAM I’m going to summarize 30 important lung cancer trials over 30 days. These posts are directed at non-medical professionals, with descriptions of the results and of what makes a good trial. #lcsm 1/13 Image
We previously looked at locally-advanced lung cancer on 4, 6, and 9 November. We have established standard treatment as ~60 Gy radiotherapy with concurrent chemotherapy for those that are not resectable by lobectomy. Today’s trial looked at adding immunotherapy. 2/13 Image
The antibody in this trial is durvalumab. Like the previously mentioned pembrolizumab (Nov 13, 16) and nivolumab (Nov 19), durvalumab inhibits the interaction of PD-1 and PD-L1. Unlike the other two, durvalumab binds to PD-L1. Clinically, the difference seems negligible. 3/13
Read 13 tweets
21 Nov
21 November: Screening part 2

This year for Lung Cancer Awareness Month #LCAM I’m going to summarize 30 important lung cancer trials over 30 days. These posts are directed at non-medical professionals, with descriptions of the results and of what makes a good trial. #lcsm 1/17 Image
Yesterday we went over the major results of the NLST. We discussed screening in general and the concept of overdiagnosis in particular. Today we’ll look at the Dutch-Belgian NELSON study, the next largest randomized study in this field. 2/17
NELSON enrolled 13 195 people between 2000 and 2004. They were randomly assigned to no screening, or to CT scans at baseline, 1 year, 3 years, and 5.5 years later. The trial was powered to detect a 25% reduction in lung cancer mortality over the 10 years from enrollment. 3/17
Read 17 tweets

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