FDA conditionally approves Loralatinib

As of 11-2-2018 the FDA conditionally approved Loralatinib.

The approval is for Loralatinib treatment for patients who have already received either: 1) crizotinib and one other ALK inhibitor, or 2) as first line treatment only either: A) Alectinib, or B) Ceritinib.

At this time Brigatinib as a first line treatment has not been approved by The FDA. Although a positive Phase 3 trial results were recently published.

The FDA approval is conditioned on a Phase 3 trial being completed.

https://www.pfizer.com/news/press-release/press-release-detail/u_s_fda_approves_lorbrena_lorlatinib_for_previously_treated_alk_positive_metastatic_nsclc

 

Posted in 3922 - lorlatinib by Pfizer, alectinib - Alecensa from Chugai - Roche - GenenTech, AP26113 - brigatinib from Ariad, Brain metastases, ceritinib - Zykadia from Novartis, crizotinib - Xalkori from Pfizer, Lung cancer, Potential Treatments, Regulatory applications & approvals | Leave a comment

Impact of EML4-ALK Variants on resistance

As of April 20, 2018

Study of 2 groups of patients. Group A = 129 patients, Group B = 577 patients.

The most frequent variants were Variant 1 (43%) and Variant 3 (40%).

“ALK resistance mutations were significantly more common in variant 3 than in variant 1 (57% v 30%).”

“In particular, ALK 1202R was more common in variant 3 than in variant 1 (32% v 0%).”

“Among patients treated with the third-generation ALK TKI lorlatinib, variant 3 was associated with a significantly longer progression-free survival than variant 1.”

https://www.ncbi.nlm.nih.gov/pubmed/29373100

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

Pfizer files for FDA approval of lorlatinib

As of February 12, 2018

Pfizer filed a new drug application (NDA) for lorlatinib with the FDA, Japan, and Europe for use in patients with ALK-positive lung cancer. FDA’s decision is expected by the end of August.

In support of the 3 applications, Pfizer submitted data from the phase II part of a phase I/II trial in which the overall response rate (ORR) was 69% in ALK-positive patients previously treated with crizotinib (Xalkori) with or without chemotherapy, and the Intracranial ORR was 68%. See previous posts for more detail.

https://www.onclive.com/web-exclusives/fda-grants-priority-review-to-lorlatinib-for-alk-nsclc

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Liquid Biopsy can be used to track evolution of resistance

As of January 23, 2018 and March 29, 2018:

Plasma genotyping by Next Generation Sequencing (Liquid Biopsy) can be used to track evolution of resistance to various ALK inhibitors.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5785105/

https://www.ncbi.nlm.nih.gov/pubmed/29599410

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FDA approves alectinib (Alecensa) as 1st line treatment

As of November 6, 2017

FDA approves alectinib (Alecensa) as 1st line treatment based on Phase 3 results.

The estimated median Progression Free Survival (PFS) for patients taking alectinib was 25.7 months, compared with 10.4 months for those taking crizotinib.

The Objective Response Rate (ORR) was 79% and 72%  in the alectinib and crizotinib arms, respectively.

Among the 120 responders in the alectinib arm and the 109 responders in the crizotinib arm, the proportion of patients with response duration of ≥12 months was 64% and 36%, respectively.

The Central Nervous System (CNS) ORR was 81% among patients taking alectinib and 50% among patients taking crizotinib.

Among patients with measurable CNS lesions and a CNS response, the proportion of patients with a CNS response duration of ≥12 months was 59% in the alectinib arm and 36% in the crizotinib arm.

https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm584082.htm

Posted in alectinib - Alecensa from Chugai - Roche - GenenTech, Brain metastases, Lung cancer, Potential Treatments, Regulatory applications & approvals | Leave a comment

Phase 1 & 2 full results for Lorlatinib

As of Oct. 16, 2017 Pfizer presented a Press release associated with a presentation at IASLC on Phase 2 results for 275 patients.

All following are for ALK+ patients except where Ros1 is indicated

Treatment Naive:  ORR 90%; IC-ORR 75%

Prior treatment with Crizotinib: ORR 69%; IC-ORR 68%

Prior treatment with ALK Inhibitor other than Crizotinib: ORR 33%; IC-ORR 42%

Prior treatment with 2+ ALK Inhibitors: ORR 39%; IC-ORR 48%

ROS1 + regardless of prior treatments: ORR 36%; IC-ORR 56%

ORR = Objective Response Rate

IC-ORR = Intracranial ORR

for more details from press release see: https://www.pfizer.com/news/press-release/press-release-detail/pfizer_presents_full_results_from_phase_2_study_of_next_generation_investigational_alk_inhibitor_lorlatinib_in_alk_positive_and_ros1_positive_advanced_non_small_cell_lung_cancer

 

As of Dec. 2017 an article was published of Phase 1 results for 54 patients

For all 41 ALK+ patients the ORR was 46%

For 26 ALK+ patients that received 2+ ALK Inhibitors the ORR was 42%

For 12 ROS1 +patients the ORR was 50%

For published article see also https://www.thelancet.com/pdfs/journals/lanonc/PIIS1470-2045(17)30680-0.pdf

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

Great page with very high quality info on AlK & AlK inhibitors

Below is a link to a page that provides comprehensive regularly updated info written by two ALK research oncologists Dr. Alice Shaw and Ben Solomon, Phd (then edited by three people). It is written for an audience of doctors and other professionals so it can get technical, but generally I believe most people will be able to understand the key ideas.

https://www.uptodate.com/contents/anaplastic-lymphoma-kinase-alk-fusion-oncogene-positive-non-small-cell-lung-cancer

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

Roche at ASCO with Alectinib findings

Roche (Genentech) announced on June 6, 2017 at the 2017 ASCO conference that the have results from their first line Phase 3 Global Trial that Alectinib had a median PFS of 25.7 months vs 10.4 months for Crizotinib (over a year longer). The trial also found that Alectinib reduced the risk of cancer progression or death by 53% vs. Crizotinib. Furthermore, at 12 months the incidence of brain metastases was 9% for Alectinib and 41% for Crizotinib. Serious side effects were marginally better with Alectinib.

These results compliment earlier results from a Japan only trial and are likely to be the basis of FDA Application to move Alectinib to the first line setting.

I strongly recommend reading the New England Journal of Medicine (NEJM) article. The charts on page 6 are particularly persuasive.

http://www.nejm.org/doi/pdf/10.1056/NEJMoa1704795

http://www.onclive.com/web-exclusives/alectinib-beats-crizotinib-in-frontline-alk-nsclc-alex-trial

 

Posted in alectinib - Alecensa from Chugai - Roche - GenenTech, Brain metastases, crizotinib - Xalkori from Pfizer, Lung cancer, Potential Treatments, Research | Leave a comment

Zykadia (ceritinib) by Novartis is approved for first line use in US

As of May 26, 2017 the FDA approved ceritinib for first line use. So it will go head to head with crizotinib. One article said a similar EU approval was likely “in coming weeks”.

The results are based on the phase 3 ASCEND-4 trial which found that in the first line setting that patients who took  ceritinib had a median progression-free survival of 16.6 months vs. 8.1 months on Pemetrexed platinum chemotherapy.

https://www.novartis.com/news/media-releases/novartis-receives-fda-approval-expanded-use-zykadiar-first-line-alk-positive

 

Posted in Brain metastases, ceritinib - Zykadia from Novartis, Lung cancer, Potential Treatments, Regulatory applications & approvals, Research | Leave a comment

FDA approves brigatinib

On April 28, 2017 the FDA granted Takeda (formerly Ariad) approval for Alunbrig (brigatinib) to be sold in the US to patients who are resistant to Crizotinib.

Posted in AP26113 - brigatinib from Ariad, Lung cancer, Potential Treatments, Regulatory applications & approvals | Leave a comment