In oncology, the agnostic model is increasingly affirmed, that is, that which provides for the treatment of a tumor based not so much on its anatomical site, but on the presence in its cells of a given genetic alteration, which can be attacked with a targeted drug (drug target) that specifically affects that alteration. Additional evidence confirming the value of this approach for precision medicine comes from the MyPathway study, a phase 2a basketball trial of which new results were recently presented in Paris, at the annual ESMO congress of the European Society for Medical Oncology (ESMO).
The agnostic model is increasingly affirmed in oncology, that is, the one that provides for the treatment of a tumor based not so much on its anatomical site, but on the presence in its cells of a given genetic alteration, which can be attacked with a targeted drug (drug target) that specifically affects that alteration. More evidence confirming the value of this approach for precision medicine comes from the study MyPathwaya phase 2a basketball trial of which new results were recently presented in Paris, at the annual (ESMO) congress of the European Society for Medical Oncology (ESMO).
In the study, the ALK inhibitor alectinib and the anti-PD-L1 atezolizumab in particular showed good response rates and long-lasting clinical activity in tumors with ALK rearrangements and elevated tumor mutational burden (TMB), respectively. , for which these drugs are not approved by regulatory authorities.
In addition to reinforcing the value of the agnostic approach in oncology, this study also demonstrates the value of basketball studies designed to evaluate the efficacy of biomarkers in different tumor types that otherwise could not be studied.
Lo studio MyPathway
Over the past decade, the landscape of target drugs, capable of targeting specific molecular targets, has evolved rapidly and steadily. However, data on the utility of these agents for the treatment of advanced solid tumors beyond their primary indication is still limited.
The MyPathway study (NCT02091141) was designed to fill this gap. It is a phase 2a, non-randomized, multi-arm, multi-center basketball study that uses an agnostic approach, evaluating the activity of targeted drugs in advanced solid tumors for which such drugs are not indicated by the FDA, but which they have ‘targetable’ alterations with these agents, such as alterations of HER2, BRAF, ALK, EGFR and the Hedgehog (Hh) pathway, as well as an elevated TMB. Alterations were identified prior to enrollment with routine testing.
The primary endpoint of the study is the objective response rate (ORR) and the authors also evaluated safety.
The data already known
Previously, researchers presented ORR data obtained in patients with tumors presenting with HER2 amplification and / or overexpression treated with the combination of the monoclonal antibodies trastuzumab and pertuzumab (23.3%), patients with tumors with high TMB treated with atezolizumab (38.1%) and patients with tumors with rearrangements or other alterations of ALK treated with alectinib (30% and 0%, respectively).
The updated results of these subgroups were reported in the ESMO presentation as well as the results of the BRAF mutation subgroup treated with vemurafenib ± cobimetinib, the Hh alteration subgroup treated with vismodegib and the EGFR alteration subgroup treated with erlotinib ( data cutoff March 24, 2022).
The characteristics of the patients
672 patients were enrolled in the study between April 2014 and July 2020.
Overall, 357 had HER2 alterations (overexpression, amplification, activating mutations those sought), 70 BRAF mutations, 21 ALK alterations, 13 EGFR mutations, 174 an elevated TMB and 37 alterations of the Hh pathway.
Median age was 64 years, gender distribution was well balanced, 80% of patients were white, over 90% had ECOG performance status of 0 or 1, and median number of systemic therapies already carried out was equal to two.
Enrolled patients had more than 20 different types of tumors and the most common were colorectal (22%), lung (15%) biliary (10%) and breast (7%) cancers.
The main findings
Among the biomarkers investigated, it was found that above all the presence of HER2-positivity, of ALK rearrangement, of a high TMB and of BRAF mutations, in patients treated with the relative target drug was associated with favorable ORR rates and a lasting clinical activity.
In particular, in the 109 HER2-positive patients (with IHC 3+ or ICH 2 + / ISH +) treated with trastuzumab plus pertuzumab the ORR was 32.1%, with a median confirmed response (DocR) of 7 months.
In patients with ALK rearrangements treated with alectinib the ORR was 30%, with a median DocR of 6.6 months, while in those with high TMB treated with atezolizumab the ORR and DocR were 39.5, respectively. % and 21 months and in those with BRAF mutations treated with vemurafenib ± cobimetinib by 24.3% and 7.4 months, respectively.
On the other hand, the presence of EGFR changes in patients treated with erlotinib was associated with a rather low ORR, about 8%, but the sample size in this analysis was limited (only 13 patients).
On the safety front, there were no surprises and new signs were observed with respect to the already known profiles of the drugs used.
In conclusion
The results of the study, the authors conclude, therefore highlight that genomic profiling has the potential to identify targeted therapies with significant antitumor activity for patients with tumors for whom there are currently few treatment options available and characterized by a high level of unmet medical need.
Other precision medicine basketball studies are already underway in Italy and in the world, for example the TAPISTRY study, which are enrolling patients assigned to different cohorts, some treated with target drugs and chemo-free based on the results of genomic profiling tests using next generation sequencing (NGS).
Bibliography
C.F. Friedman,, et al. MyPathway: A multiple target, multiple basket study of targeted treatments in tissue-agnostic cohorts of patients (pts) with advanced solid tumors. Annals of Oncology (2022) 33 (suppl_7): S27-S54. 10.1016/annonc/annonc1037; https://oncologypro.esmo.org/meeting-resources/esmo-congress/mypathway-a-multiple-target-multiple-basket-study-of-targeted-treatments-in-tissue-agnostic-cohorts-of-patients-pts-with-advanced-solid-tumors