16 November: The right side of the curve

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 1/14 Image
In our previous discussion of immunotherapy (13 Nov) we talked about the expression of PD-L1 on tumour cells. At the time of this study (2014) there was some evidence that tumours with more cells expressing PD-L1 were more likely to benefit from immunotherapy. 2/14 Image
This trial enrolled people with metastatic lung cancer (non-EGFR, non-ALK) where >50% of tumour cells expressed PD-L1. About one third of NSCLC meet this criterion. They were randomized to either standard chemotherapy, or to pembrolizumab immunotherapy for up to two years. 3/14
Primary outcome was time to cancer worsening (PFS). There was a very complex interim analysis scheme that ultimately stopped the trial due to evidence of a survival advantage with pembrolizumab. Here are the initial KM curves showing PFS. 4/14 Image
The overall survival results have been updated in a subsequent paper.  I think it's striking that the median PFS is around 9 months, yet the median OS is 30 months! 5/14 Image
Considering the previous trials we’ve looked at, we know that chemo-immuno is better than chemo in first line regardless of PD-L1 expression.
We know from today’s trial that immuno is better than chemo if PD-L1>50%. Of course it’s a different story if EGFR or ALK positive. 6/14
It remains unknown if there are subgroups of PD-L1>50% where chemo-immuno is better than immuno alone.
It is also unknown if there are groups of PD-L1<50% where immuno alone might be better than chemo/immuno. 7/14
Let’s take a look at the KM curve here. We previously looked at these in detail on 5 November. There are aspects of these curves we have not considered. Take a look at the numbers along the bottom. 8/14 Image
“No. at Risk” is the number of participants followed to that time point. There are only 5 people in each arm who’ve been followed to 30 months. Look at all the censored people between 21-30 months: they were enrolled in the last 9 months of the trial and are still in follow-up. Image
Look at the big drop in the pembro arm right around 30 months. This large steps happens because there are only 6 people followed to that time. When one of them dies, the curve drops down one sixth of the distance to zero. (in this case from 52% to about 43%)
10/14 Image
All of this is pertinent, because people tend to focus on the part of the KM curve furthest to the right. This gives us information about long-term survivors, and if the curve is flat for a long period of time, we speculate about people being “cured”. 11/14
But this is the least certain part of the curve. Its shape is determined by the smallest number of people, and events in a few drastically alter how this part of the curve looks. 12/14
We can’t help but look with interest at the right-most part of the curve. We can be cautious, though, about over-reading it. 13/14
Tomorrow we’ll be back to adjuvant chemo for NSCLC, and we will wrestle again with the question of which analyses you can take to the bank, and which ones are not so sure... 14/14 Image

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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 Image
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 Image
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
15 Nov
15 November: Vitamins, a note to trainees

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 1/14
To date we have looked at trials that compared different treatments. Today, we’re going to look at something a little different: a trial of the schedule of supportive medications that are given along with chemotherapy, in this case vitamin B12 and folic acid with pemetrexed. 2/14
We have seen how pemetrexed has become one of the most commonly used chemotherapy drugs in non-squamous NSCLC (11, 13 November). Compared to other chemo drugs we think that it has a relatively good safety profile, but it was not always so. 3/14
Read 14 tweets
14 Nov
November 14: Controversy, hierarchy
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
This is the most recent study we’ve looked at so far, from 2020. You may recall that adjuvant chemotherapy (after surgery) increases the chances of cure for early stage lung cancer (Nov 2), and also that we have good oral medications for lung cancer with EGFR mutation (Nov 7, 12)
This trial enrolled people who had resected lung cancer with EGFR mutation. They were allowed to have adjuvant chemotherapy. They were then randomized to three years of the EGFR TKI osimertinib, or three years of placebo. 3/17
Read 17 tweets
13 Nov
13 November: Our 1st Keynote, HR

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
The uptake of immunotherapy in lung cancer has been rapid and widespread. In 2014 it was research only: in 2021 it is used in all types of lung malignancies, in almost all stages of disease. We will discuss at least six immunotherapy studies in the remainder of the month. 2/17
Lymphocytes are white blood cells that should lead an immune response to tumours. In some cases, tumour cells have a protein on the surface called PD-L1 that binds to a protein called PD-1 on lymphocytes, and serves to “turn off” that part of the immune response. 3/17
Read 17 tweets

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