Letter to the Editor
Vol. 4, Issue 1, 2024 · P1-5
Precision Oncology in Solid Tumors: Key learning points from the 2023 Precision Oncology Summit.
Abdul Moiz Khan, MD,Inas Abuali, MD,Hannah Abrams, MD,Ivy Riano, MD,Pauline Funchain, MD
Submission received: 2023-12-04 / Accepted: 2024-02-08 / Published: 2024-03-03
Abstract
The 2023 Precision Oncology Summit was organized by Binaytara foundation in San Francisco on October 7th and 8th. The theme of the conference was to discuss the recent advances in precision oncology and future directions to move away from a one-size-fits-all model in order to improve patient outcomes. This manuscript reviews the session on precision oncology in solid tumors. The first lecture during this session was on tumor-agnostic FDA approvals delivered by Peter J. O'Dwyer, M.D., whereas the second lecture by Pauline Funchain, M.D., discussed melanoma as a paradigm for precision immuno-oncology.
The drugs with tumor agnostic FDA approvals include pembrolizumab and dostarlimab (2017, 2021) for deficient mismatch repair (MMRd)/microsatellite instability high (MSI-H) tumors; pembrolizumab (2020) for high tumor mutation burden (TMB-H); larotrectinib and entrectinib (2018, 2019) for NTRK-fusions; Dabrafenib plus Trametinib (2022) for BRAF V600E mutation; and selpercatinib (2022) for RET Fusions.
The NCI-MATCH (Molecular Analysis for Therapy Choice) trial (NCT02465060) launched in 2015 was a genomically driven, precision oncology platform trial which largely encompassed patients with treatment-refractory, solid malignancies.2 It was completed in 2023 and remains one of the largest tissue-agnostic trials to date. About 6,000 patients underwent screening and molecular testing, and subsequently, a total of 1,593 patients were assigned to one of 38 sub-studies, each of which was a phase 2 trial of a therapy matched to a genomic alteration, with the primary endpoint being objective tumor response (OR). The secondary endpoints included progression-free survival (PFS), PFS at 6 months (PFS6), time to progression/death, toxicity, and exploration of potential predictive biomarkers. NCI-MATCH trial was not only a major step in drug development in oncology, but also taught many lessons for the future. It highlighted that proactive outreach should be ensured to achieve optimal patient and physician diversity. While rare tumors are an area of unmet need, this need can be met to a degree with genomic trials but novel trial designs and regulatory approaches are essential. Furthermore, intervention earlier in the disease course may also help circumvent resistance mechanisms. Finally, the trial design should include as many therapeutic options for as many molecular abnormalities, to have an impact commensurate with the collective effort.
Take Home Messages
1. Since 2017, tumor agnostic drugs have been approved for deficient mismatch repair/microsatellite instability high, high tumor mutation burden, NTRK-fusions, BRAF V600E mutation, and RET Fusions.
2. The issues encountered in the development of tumor agnostic drugs are unique and can be dealt by novel trial designs such as basket trials.
3. Tumor mutational burden (TMB), neo-antigen load, Human leukocyte antigen (HLA) type, germline mutations, and family history of cancer can be helpful markers of response to immunotherapy.
4. The biology of newer therapies such as tebentafusp-tebn may necessitate markers of response other than RECIST criteria, such as circulating tumor DNA.
I) Tumor-Agnostic FDA Approvals
Tissue or tumor agnostic drug refers to any drug that targets a specific molecular alteration across multiple cancer types.1 While tumor agnostic drug approvals expedite the development of new therapies especially in rare cancers, this should be backed by a strong scientific rationale. The issues encountered in the development of these drugs are unique and novel trial designs such as basket trials may provide optimal setting of testing these drugs.
Real world evidence/data (RWE/RWD) may also be helpful in rare diseases where there are scant treatment options.3 Alpelisib, which is an FDA approved therapy for hormone-positive, HER2-negative, PIK3CA-mutated breast cancer based on a phase III study, was approved in for patients with severe manifestations of PIK3CA-related overgrowth spectrum (PROS) based on RWE/RWD. RWD/RWE also led to approval of abatacept for the prophylaxis of acute graft versus host disease.4
In conclusion, FDA has taken a pragmatic approach to evaluation and approval of tissue-agnostic drug applications and more drugs may get approved in the coming years through this pathway. Both the molecular profile and tissue of origin have their significance in defining the behavior of the tumor and response to treatment, therefore we should account for both. The basket trial design is a useful way of drug development and affirmed in that there are four NCI-sponsored trials in development using this model. Finally, formal integration of RWE/RWD criteria is desirable and we should benefit from RWE/RWD despite acknowledging its limitations.
II) Melanoma as a Paradigm For Precision Immuno-Oncology
Despite ongoing advances in precision medicine, there is still a long way to go when it comes to optimum patient selection to derive maximum benefits of our therapies. As an example, pembrolizumab was FDA approved for the adjuvant treatment of patients with stage IIB or IIC melanoma following complete resection.5 The absolute recurrence free survival (RFS) benefit at 12 months in this trial was 7.4%, while grade 3–4 treatment-related adverse events occurred in 16% of the patients in pembrolizumab groups versus 4% in the placebo group. This calls for better identification of patient who could potentially benefit more. However, no predictor of RFS with adjuvant pembrolizumab in stage II melanoma could be identified based on the traditional subgroup analysis (based on factors such as age, sex, T-category, race, and performance status).
This is where genomic markers such as tumor mutational burden (TMB) and neo-antigen load have a value as they correlate with the response to immunotherapy.6,7 Certain Human leukocyte antigen (HLA) types and family history of cancer also serve as predictors of efficacy of immunotherapy.8,9 Evidence is mounting on the value of germline testing in immuno-oncology. Germline mutations in genes such as BAP1, BRCA1/2 and CDKN2A have a well-known association with melanoma and extended genetic testing may enable recognition of more genes of interest.
This knowledge is starting to form the basis of clinical studies exemplified by the phase II NCT04187833 trial which is aimed at studying nivolumab in combination with talazoparib in unresectable or metastatic melanoma patients with homologous recombination deficiency (HRD) (mutations in BRCA or BRCAness).10
Another example of precision medicine in melanoma is tebentafusp-tebn, a bispecific gp100 peptide-HLA-directed CD3 T cell engager, approved for HLA-A*02:01-positive unresectable or metastatic uveal melanoma.11 Treatment with tebentafusp resulted in longer overall survival than the investigator's choice of therapy with single agent pembrolizumab, ipilimumab, or dacarbazine. Interestingly, circulating tumor DNA (ctDNA) reduction as early as 9 weeks on tebentafusp was strongly associated with improved OS, even in patients with progressive or stable disease based on the RECIST criteria.12 This postulates that the biology of newer immunotherapies may necessitate markers of response other than RECIST.
Conflict(s) of Interest
The authors declare no conflicts of interest.
Funding Information
N/A
Ethical Statements
N/A
Informed Consent
N/A
Data Availability Statement
N/A
Acknowledgements
Peter J. O'Dwyer, MD, Professor of Medicine, University of Pennsylvania
Declaration of AI Use in Scientific Writing
N/A
Author Contributions
Concept and design: AMK, HA, IR, IAA, PF
Data acquisition: AMK
Data analysis and interpretation: AMK
Drafting of the manuscript: AMK
Critical revision of the manuscript: HA, IR, IAA, PF
All authors (AMK, HA, IR, IAA, PF) approved the final version of the manuscript and agree to be accountable for all aspects of the work, in accordance with the International Committee of Medical Journal Editors criteria.
References
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