Brain mets

Abstract 9063 combines data from two trials on Alectinib. There were 225 patients. The conclusion reached was that “Alectinib is effective in patients with baseline CNS mets, regardless of prior radiation treatment. Based on the low incidence of CNS progressive disease in patients without CNS mets at baseline, Alectinib may also have a potential preventative effect on patients.”

Abstract e20527 looked at 291 patients in Canada. 141 with and 150 without brain mets. 12% had ALK mutations and 88% had EGFR mutations. They found that the patients without brain mets had a median survival about 2 years longer.

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HSP90 and Crizotinib

Abstract 9059 basically flung that administrating an HSP90 inhibitor at the same time as Crizotinib did not delay the development of resistance to Crizotinib.

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Alectinib, mutations, and liquid biopsy

Abstract 9061 pooled data from two clinical trials. 129 patients had biopsies done after Crizotinib but before Alectinib. Plasma samples were available for all 272 patients at baseline and for about 50% at progression.

At baseline 13 functional ALK mutations were identified (5 previously unreported). At progression 3 new mutations were seen. At least 7 baseline mutations had median PFS greater than 3 months suggesting Alectinib was active against them. Mutations I1171S/N ans G1202R may occur during treatment.

As for liquid biopsy, “Tumor DNA in plasma may be a non-invasive way to monitor resistance mutations”.

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Crizotinib and children

Abstract 11509 covers 107 pediatric patients and their tumors. ALK alterations were found in 18 of them (not all are fusion mutations). The ages ranged from 3-16 years. 7 patients were still being treated at the data cut off. At least 4 types of cancer were treated. To quote the abstract “Crz was well tolerated” and “children can benefit from crz therapy.” I am not a doctor so I can not compare these patients side effect profile with other similar studies. Among the 8 evaluable patients there was one complete response, 3 partial responses, and 1 stable disease (for a DCR of 5/8 (62.5%)).

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Ceritinib and mutations

Abstract 9064 covers 85 patients but only 8 patients has ALK mutations and baseline biopsies collected within 14 days of progression . L1196M was most common. The study indicated that Ceritinib was potent against several known ALK mutations.

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Info on Liquid biopsy

Abstract e20643 is only available online. In this trial, 10,000 solid cancer patients blood were tested by Guardian360 (a method that sequences compete exons (the part of the DNA that encodes for proteins)). Of those patients ALK fusions were detected in 6%. EML4 was the fusion partner in 81% of the patients and 4 other fusion partners made up the rest of the 19%. 24 patients has ALK+ NSCLC. Mutant alleles ranged from 0.06% to 12.5%. They found several Somatic mutations (SNV) of which 10% were known resistance mutations in ALK. They also found other occurring SNV in other genes that are rare or absent in untreated patients suggesting possible novel Crizotinib resistance mechanisms.

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X-396 update and info on liquid biopsy

Abstract 9056 is an update of info previously published on this site.

The study involved 60 patients of whom 30 were ALK+ NSCLC. Of that 30, 19 (60%) had partial responses (PR).

8 patients were Crizotinib naive and of them 7 (88%) had PRs.

12 patients had prior Crizotinib but no other ALK inhibitor, of them 10 (83%) had PRs.

CNS responses have been observed.

As for the liquid biopsy. ALK was detected in the blood plasma of 16 patients, all of whom responded to treatment. Serial sampling and sequencing demonstrated that a decrease in ALK in patients responding and a increase in ALK at the time of progression. These results do not appear to be robust enough to on their own justify routinely doing a liquid biopsy, but rather an area for more in depth research to be done.

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Alectinib Japan trial abstract

Abstract 9008 covers the J-ALEX phase 3 trial comparing Crizotinib (arm A) with Alectinib (arm B) in TKI naive patients. There were 207 patients at 41 centers in Japan randomized between the two arms.

Arm A had a median PFS of 10.2 months.

Arm B median PFS was not reached.

The trial was stopped early because an independent committee recommended the release of data because the superiority of PFS had been demonstrated.

there is another international trial ongoing.

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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 Brain metastases, lorlatinib - Lorbrena by Pfizer, 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.

Posted in brigatinib-Alunbrig from Takeda, Lung cancer, Potential Treatments, Research, Side Effects | Leave a comment