ALK rearrangement + PIK3CA mutation

P2, N=72, Completed, German Cancer Research Center | Active, not recruiting --> Completed | N=175 --> 72 | Trial completion date: Jun 2025 --> Dec 2024 | Trial primary completion date: Jun 2025 --> Dec 2024

P2, N=175, Active, not recruiting, German Cancer Research Center | Recruiting --> Active, not recruiting

4 pts received TT at recurrence, within clinical trials: one with grade 3 meningioma and ALK rearrangement treated with alectinib, one with PTCH1 mutant medulloblastoma treated with vismodegib, and two with high TMB treated with nivolumab/ipilumumab. The incidence of targettable molecular alterations in adult CNS tumor patients was lower than in GBM. Nevertheless, in a few selected cases TT have the potential to increase treatment options at recurrence and improve outcomes.

Molecular hyperselection and comprehensive genomic profiling have a potential usefulness in elderly patients with RAS/BRAF wild-type, pMMR/MSS mCRC, eligible for upfront EGFR inhibition.

Conclusions Ipatasertib and atezolizumab were ineffective in this patient population with PI3K-AKT-altered tumors. More stringent molecular selection criteria and an addition trial arm were implemented (arm 5).

We identified pts with EGFR mutations or ALK rearrangements who developed PIK3CA/PTEN alterations in tissue biopsy and/or circulating tumor DNA upon progression to first-line osimertinib/alectinib. Activating PI3KCA mutations and molecular events leading to PTEN loss are frequent events at resistance to first-line EGFR/ALK TKIs, and can be detected concomitantly. Functional assays confirmed that these alterations act as resistance mechanisms. These observations are of interest as PI3KCA/mTOR inhibitors may have a role in overcoming resistance.

The present study illustrates the profile of the ALK fusion variants observed in this Indian cohort. The frequency of different fusion variants as well as the occurrence of co-mutations will help unravel the diverse mechanism of response to the ALK-directed therapy.

One patient with a BRAF-mutated MPNST was treated with BRAF/MEK inhibitors encorafenib and binimetinib, reaching partial response and a progression free survival of 7 months...Crizotinib was used in two heavily pretreated patients (one ROS1-rearranged liposarcoma and one ALK-rearranged liposarcoma), with disappointing outcomes... Nowadays, cytotoxic chemotherapy still remains the front-line therapy in most locally advanced and metastatic unresectable sarcomas. Considering the low response rates to standard treatment, the fact that effective therapeutic alternatives are scarce, and the young age of many of these patients, there is an urgent need for the development of novel therapies. A profound understanding of the molecular mechanisms of sarcomagenesis is essential to propel the era of personalized medicine in advanced sarcomas.

Of these, 52 received first-line alectinib treatment (1L) and 56 received alectinib after crizotinib resistance (2L). Also, NF2-mutant patients only had a median PFS of 4 months, significantly poorer than those without (HR 11.1, 95CI 2.17-50; p<0.001). Conclusions By analyzing different mutational profiles of ALK-rearranged patients after alectinib treatment, we proposed MET and NF2 as putative mechanisms that conferred resistance to early resistance of first-line alectinib, which shone light on future tailored treatment for ALK-positive NSCLCs.

A high positivity rate of detection of actionable and prognostic genomic alterations in the liquid biopsy has established the importance of blood as an important resource of detecting mutations in advanced NSCLC which directly impacts the clinical outcome in these patients. Furthermore, presence of co-positivity of mutations highlights the biologic mechanisms responsible for drug resistance in NSCLC patients.

CRAFT was activated in October 2021 and will recruit at 10 centers in Germany.