Point mutations in TRK inhibitor-resistant cancer and methods relating to the same

A method of treating a subject having a Trk-associated cancer, the method comprising:

• (a) administering one or more doses of a first Trk inhibitor to the subject for a period of time, wherein the first Trk inhibitor is entrectinib (N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methylpiperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide);
• and
• (b) after (a), administering a treatment comprising one or more doses of the first Trk inhibitor and a second Trk inhibitor to the subject, wherein the second Trk inhibitor is (6R,15R)-9-fluoro-15-methyl-2,11,16,20,21,24-hexaazapentacyclo[16.5.2.02,6.07,12.021,25]pentacosa-1(24),7,9,11,18(25), 19,22-heptaen-17-one;
• wherein the subject is identified as having (i) at least one point mutation in a NTRK1 gene that results in the expression of a TrkA kinase polypeptide comprising a mutation at one or more amino acid position(s) selected from the group consisting of:
• 517, 542, 568, 573, 589, 595, 599, 600, 602, 646, 656, 657, 667, and 676, and/or (ii) at least one point mutation in a NTRK2 gene that results in the expression of a TrkB kinase polypeptide comprising a mutation at one or more amino acid position(s) selected from the group consisting of:
• 545, 570, 596, 601, 617, 623, 624, 628, 630, 672, 682, 683, 693, and 702, and/or (iii) at least one point mutation in a NTRK3 gene that results in the expression of a TrkC kinase polypeptide comprising a mutation at one or more amino acid position(s) selected from the group consisting of:
• 545, 570, 596, 601, 617, 623, 624, 628, 630, 675, 685, 686, 696, and 705.

A method of treating a subject having a Trk-associated cancer, the method comprising administering to the subject one or more doses of entrectinib (N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methylpiperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide) and (6R,15R)-9-fluoro-15-methyl-2,11,16,20,21,24-hexaazapentacyclo[16.5.2.02,6.07,12.021,25]pentacosa-1(24),7,9,11,18(25), 19,22-heptaen-17-one;

• wherein the subject is identified as having (i) at least one point mutation in a NTRK1 gene that results in the expression of a TrkA kinase polypeptide comprising a mutation at one or more amino acid position(s) selected from the group consisting of:
• 517, 542, 568, 573, 589, 595, 599, 600, 602, 646, 656, 657, 667, and 676, and/or (ii) at least one point mutation in a NTRK2 gene that results in the expression of a TrkB kinase polypeptide comprising a mutation at one or more amino acid position(s) selected from the group consisting of:
• 545, 570, 596, 601, 617, 623, 624, 628, 630, 672, 682, 683, 693, and 702, and/or (iii) at least one point mutation in a NTRK3 gene that results in the expression of a TrkC kinase polypeptide comprising a mutation at one or more amino acid position(s) selected from the group consisting of:
• 545, 570, 596, 601, 617, 623, 624, 628, 630, 675, 685, 686, 696, and 705.