AP26113 Trial - 1257896

Rather than try to summarize all the prior discussions, if you run a search for AP26113 in the search box at the upper right you will see many results. It's an inhibitor of both ALK and EGFR do it may be effective.

JimC
Forum moderator

I'm sorry about your mother's progression. We don't have many results with AP26113 yet, but as Jim notes, it inhibits both ALK and EGFR. However, it's a far more potent ALK inhibitor than EGFR inhibitor, and I don't know of any evidence that speaks to its activity in the setting of acquired resistance to a prior EGFR tyrosine kinase inhibitor.

-Dr. West

My very non-medical hearsay opinion-
I heard that the dose of AP26113 needed to inhibit EGFR is much higher than that needed for ALK, and the toxicity would probably limit its use for EGFR, as Dr.West mentions. But again, it's early and that's what trials are for.

Maybe look around and try for something with more data?

Best of luck,
Jazz

Don't sell yourself short, Jazz. That's the medical hearsay I might have offered as well.

-Dr. West

First-in-human dose-finding study of the ALK/EGFR inhibitor AP26113 in patients with advanced malignancies: Updated results.
http://meetinglibrary.asco.org/content/114967-132
ackground: AP26113 is a novel tyrosine kinase inhibitor (TKI) that potently inhibits mutant activated forms of anaplastic lymphoma kinase (ALK+) and epidermal growth factor receptor (EGFRm), and TKI-resistant forms including L1196M (ALK) and T790M (EGFR). AP26113 does not inhibit native EGFR. Methods: The dose finding phase (3+3 design) of this phase I/II open-label, multicenter study is ongoing in pts with advanced malignancies (except leukemia) refractory to available therapies or for whom no standard treatment exists. Initial dosing is orally once daily. Results: As of 14 Jan 2013, 44 pts were enrolled: 30 mg n=3, 60 mg n=3, 90 mg n=8, 120 mg n=8, 180 mg n=11, 240 mg n=9, 300 mg n=2; 64% female, median age 60 yrs; diagnoses: non-small cell lung cancer (NSCLC, n=37), other (n=7). 26 pts discontinued: 18 disease progression, 6 adverse event (AE), 2 deaths (sudden death, hypoxia; both possibly related). Most common AEs: nausea (45%), fatigue (39%), diarrhea (27%); most common grade 3/4 treatment-related AE: diarrhea (5%). 2 dose limiting toxicities observed: grade 3 ALT increase, 240 mg; grade 4 dyspnea, 300 mg. Doses <300 mg are being explored further. 21 pts had ALK+ history (18 NSCLC, 3 other). Among 18 evaluable ALK+ pts, 10 responded. 15 ALK+ pts had 0 (n=3) or 1 (n=12) prior ALK TKI (crizotinib); of these, 2/3 and 8/12 pts (67%) responded, including 2 complete responses. The longest response is 40 wks (ongoing). 4 of 5 ALK+ pts with untreated or progressing CNS lesions at baseline and with follow-up scans had evidence of radiographic improvement in CNS, including 1 pt resistant to crizotinib and LDK378 (overall response = stable disease).

16 pts had EGFRm history (15 NSCLC, 1 SCLC); 14 pts had ≥1 prior EGFR TKI. Of 12 EGFRm pts with a follow-up scan, 1 pt (prior erlotinib) responded at 120 mg (duration 21 wks, ongoing), 6 pts had stable disease (2 ongoing, duration 7-31 wks). Conclusions: AP26113 has promising anti-tumor activity in ALK+ pts, with initial evidence of activity in EGFRm pts, and is generally well tolerated. Phase II will begin after the recommended phase II dose is determined, with 4 cohorts: crizotinib-naïve NSCLC; crizotinib-resistant NSCLC; EGFR TKI-resistant NSCLC; other tumors. NCT01449461. Clinical trial information: NCT01449461.

SUMMARY
Initial evidence of activity (PR) was observed in a patient with a history of exon 19 deletion and unknown T790M status. Cohort 3 in the phase 2 portion of the study will provide an opportunity to test AP26113 activity in a rigorously defned patient population with T790M-mediated resistance to 1 prior EGFR TKI (documented EGFR T790M following disease progression on the most recent EGFR TKI therapy.
Further phase 1 testing at 240 mg will occur in patients with documented EGFR T790M (same enrollment criteria as phase 2 cohort 3)

1 response, 6 stable EGFR patients. That makes me sad. The data doesn't specifically outline the response dose(s) for the ALK patients vs. the stable EGFR patients, although we can infer the EGFR group must have needed the higher doses. The language is "promising" for ALK, and "initial evidence of activity" for the 1 EGFR pt. But, even promising trials have taken downturns at later phases. One never knows, I guess.

I once enrolled in a trial whose data was abysmal (and I hear the company isn't going forward with the drug now), but it was the only thing around at the time. Worked for a few months, so I was grateful. Being pulled off the edge counts for quite a lot!

Thanks for sharing the abstract.

Jazz

Thinking out loud.. perhaps AP26113 and some other EGFR Inhibitors that show modest efficacy or don't quite make it to the finish line could still be used in combination strategy methods to address resistance. I know that compounding factors including the researching company trying to see the financial advantage of such, as well as deciding to pursue adequate quantity and distribution for a no-guarantee "plan B". I just hope that the EGFR Inhibitor-acquired resistance population is big enough to explore such. It sounds quite likely that AP26113 will be approved for ALK+ populations. Then, like Nexavar and Ceetuximab, it is out there to explore combination strategies. Dr. West, tell me when I need to take my "get real" pill.

Dave, I don't know specifics of the drugs in question but I think it makes perfect sense to have hope for a finding of a drug combo if the drugs are already approved. As the science stands now it seems a combo is less likely to be found if the drugs fail to get approved as a stand alone.

HOPEFORLIFE

did your mom ever start the ap26113 trial for EGFR?

Thanks for the update, and I hope she can get back on it. It's really helpful to know more about the tolerability of the different second generation ALK inhibitors as we may have more of an opportunity to choose among them over time.

Good luck.

-Dr. West

Thanks for the update hopeforlife. I wish your Mom all the best, and hope that her docs come up with a really good game plan for her. . . Please keep us posted.

Laya