Lorlatinib abstract

Abstract 9009 is a phase 1 dose escalation trial (dose levels ranged from 10-200 mg and the Recomended phas 2 dose was 100 mg once daily). There were 54 patients as of November 30, 2015. 41 are ALK positive and 12 are ROS1 positive. 29 patients remain on treatment.

The analysis of results was broken down into 3 sub groups (for simplicity sake I combine confirmed and unconfirmed results).

Group A had intracranial and extracranial mets. And had an Overall Response rate of 50% (6% complete responses and 44% partial response rate).

Group B had intracranial mets (target and non target mets). And had an Overall Response rate of 44% (28% complete responses and 17% partial response rate).

Group C had intracranial mets (target mets only). And had an Overall Response rate of 60% (30% complete responses and 30% partial response rate).

A phase 2 study is expected to enroll 240 patients across 6 cohorts.

Posted in 3922 - lorlatinib by Pfizer, Brain metastases, Lung cancer, Potential Treatments, Research, Resistance to treatment, Side Effects | Leave a comment

Britatinib abstract

Abstract 9007 covers the Phase 2 trial (ALTA) comparing two dosing schemes. There were 222 patients who had progressed on Crizotinib. Results where as of 12-7-15.

Arm A received 90 mg straight through.  Arm Breceived 90 mg for the first 7 days then received 180 mg from then on.

Arm A had ORR of 46% including 1 confirmed complete response, median PFS was 8.8 months. There were 3% discontinuations and 7% dose reductions.

Arm B had ORR of 54% including 5 confirmed complete responses, median PFS was 11.1 months. There were 6% discontinuations and 18% dose reductions.

While there were 6% (3% > or = grade 3 ) of early onset pulmonary events within the first 7 days after original dosing. However there were no such events during the first 7 days of increasing the dose to 180 mg.

the data will be updated at the oral presentation.

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Some Summaries of ASCO abstracts

So there are actually 128 different abstracts that use the term ALK in either the body or the title of the abstract. I can not look at all of them. If you want to look them over you can go to abstract.asco.org

I will be summarizing the ones that I find that appear to be of general interest.

To access the database containing the abstracts go to http://abstract.asco.org/176/IndexView_176.html

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Upcoming ASCO abstracts

There are 14 abstracts for the upcoming ASCO that have ALK in the title. But only 6 look like they are likely to be broadly applicable to people on this board. I will be posting summaries over the next week or so. They include updates on Brigatinib (2), HSP90 inhibitors combined with Crizotinib, Alectinib, brain metastases and ALK, and Lorlatinib.

Posted in 3922 - lorlatinib by Pfizer, alectinib - Alecensa from Chugai - Roche - GenenTech, AP26113 - brigatinib from Ariad, Brain metastases, crizotinib - Xalkori from Pfizer, Lung cancer | Leave a comment

Entrectinib phase 1-2 trial update

Entrectinib was tested in 119 patients with three kinds of mutations: NTRK+, ALK, and ROS1. Efficacy data was reported for 24 patients.

For ALK there appear to have been 5 patients, and 57% of them had a tumor response (presumably not all partial responses). The article said “‘This response is comparable to Crizotinib,’ Dr Gandhi said ‘With the next generation of ALK inhibitors likely to replace Crizotinib, the bar is set high for targeting ALK,’ she added.'”.

For ROS1 the overall response rate was 86% (12 of 14) (presumably not all partial responses).

For NTRK+ the overall response rate was 100% (5 of 5) (presumably not all partial responses).

There are plans to conduct a phase 2 trial now that the MTD has been defined.

http://www.medscape.com/viewarticle/862131

Posted in Lung cancer, Potential Treatments, Research, RXDX-101 - entrectinib - by Ignyta, Side Effects | Leave a comment

Ensartinib (X396) trial update

63 patients in trial but only 35 are ALK+, NSCLC, and treated at 200 to 250 mg daily.

Of those, 8 were ALK inhibitor naive, 7 (88%) had an objective response. 19 patients had received Crizotinib but not another ALK inhibitor, 16 ((84%) had demonstrated reductions in tumor size (unclear how many qualified as partial responses). That leaves 8 patients who presumably were treated with an ALK inhibitor other than or in addition to Crizotinib. No results were in the article for this last group. Responses have lasted as long as 30 months.

In patients with brain mets 63% (5 of 8) had some reduction in size.

http://www.businesswire.com/news/home/20160420005374/en/Xcovery-Presents-Data-Supporting-Potential-Efficacy-X-396

Posted in Brain metastases, Lung cancer, Potential Treatments, Research, Side Effects, X-396 - ensartinib from Xcovrery | Leave a comment

Additional Brigatinib info

Ariad has posted a new presentation from European Lung Cancer Conference on their website for a limited time.

Pages 7-13 are most relevant. Page 8 shows a breakdown of how patients  responded by dose. 90 mg had a ORR of 77%; 90->180 mg had an ORR 79%; 180 mg had an ORR of 65%.

Page 9 has a PFS survival curve graph and a regular survival curve graph. Both show Crizotinib naive patients doing better than Crizotinib pretreated patients. Importantly both charts show a fair degree of plateauing in the curves after about 12 to 18 months and the plateaus are at relatively high levels. For example, a plateau for Crizotinib pretreated patients of over 70% surviving after 2 years. The plateaus look impressive, but I think each tick mark indicates a patient who left the study for unknown reasons (but probably many were moving on to other treatments). But the graphs do look better than graphs I have seen for other ALK inhibitors. If anyone knows more than I do about survival curves please correct me.

Page 10 looks at brain Mets and finds that the median brain PFS is 15.6 months. Pages 11-13 look at side effects of the drug.

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Ariad announces start of Phase 3 trial

Ariad today announced the initiation of a first line phase 3 trial comparing Brigatinib with Crizotinib. Patients must be ALK inhibitor naive. They are planning to enroll around 270 patients. They expect to complete enrollment in 2018.

Of interest, the Brigatinib arm of the trial will be 90 mg once daily for 7 days followed by a escalation to 180 mg once daily. This suggests that the risk reward analysis from the phase 2 trial between 90 mg daily permanently and 90 mg for 7 days followed by 180 mg daily permanently, must have favored the higher dose (the side effects must have only increased a bit and the benefit in terms of tumor shrinkage or duration or both must have been significant as well). As far as I know this result has not been previously announced.

Separately, Ariad has posted a phase 2 trial on Clinicaltrials.gov but not posted a related press release yet. This is a trial of only about 40 patients and is looking at Brigatinib in the third line setting after patients have relapsed on Ceritinib or Alectinib.

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Brigatinib update

Thanks to Dave for pointing this out.

This info can be found on Ariad’s site under Investors, presentations. It’s from the Cowan Healthcare presentation which may only be available for a few weeks. The relevant info is on pages 15-16. Similar info can be found in a press release from 4/15/2016.

Page 15 is a Waterfall graph with 70 patients from the Phase 1-2 trial. It shows a disease control rate of 92.9% and an objective response rate of 82.9% and a complete response rate of 10%. It appears that over 85% of these patients are Crizotinib resistant.

Of note, there are 25 patients who achieved either 100% shrinkage of tumors or a complete response (35.7%). Not sure why these are not all labeled as complete responses.

Page 16 shows a different kind of graph, which shows how long patients are on the drug before they progress. The median PFS for Crizotinib resistant patients is 13.4 months (which I think is the longest yet reported but I am not sure about Alectinib). For 8 patients who are Crizotinib naive as of 24 months the Median PFS has not been reached and is not known but the line is trending better than the Crizotinib resistant patients.

Comparing Brigatinib to Ceritinib and Alectinib. The Objective response rate for ALK inhibitor pretreated patients was 56% for Ceritinib, 48% for Alectinib, and 80.6% for Brigatinib. For ALK naive patients the objective response rate for Ceritinib was 72%, for Britatinib was 100% (8 of 8), and unknown for Alectinib.

 

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Article on latest develpments

In January 2016 an article was published that reviewed the current status of nine 2nd generation and 3rd generation ALK inhibitors, some HSP 90 inhibitors and briefly 2 immunotherapies for lung cancer. Much of that research has been described in this blog.

There appears to be updated data on Entrectinib (RXDX-101) and TSR -011. Specifically for RXDX-101, 67  patients have been tested, and among 17 inhibitor (not just ALK) naive patients (10/11) 91% treated at or above 400 mg/m2 achieved an objective response rate with durable responses up to 16 cycles (a cycle appears to be 4 weeks so that would be a durable response up to 64 weeks).

Specifically for TSR-011, 69 patients were tested and 46 ALK+ NSCLC patients were reported. For total daily doses at or above 120 mg, 3/5 (60%) ALK inhibitor naive patients responded and 3/6 (50%) patients who had progressed on Crizotinib responded. Unclear if a “response” is an objective response only or includes stable responses.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4699265/

Posted in 3922 - lorlatinib by Pfizer, alectinib - Alecensa from Chugai - Roche - GenenTech, AP26113 - brigatinib from Ariad, ASP3026 from Astellas, CEP-37440, ceritinib - Zykadia from Novartis, Imunotherapies, Lung cancer, NMS-E628, Potential Treatments, Research, Resistance to treatment, RXDX-101 - entrectinib - by Ignyta, Side Effects, TSR-011 from Tesaro, X-396 - ensartinib from Xcovrery | Leave a comment