Precision Oncology: a Clinical and Patient Perspective

Figures & data

Table 1. Select precision oncology targets or biomarkers with matched agents that are approved or in clinical development for solid tumors.

Target/biomarker	Cancer types	Investigational and approved agents	Development stage [2,3]†	Ref.
ALK	NSCLC, anaplastic large cell lymphoma	Repotrectinib, DS-6051b	Phase I	[4]
		Ensartinib	Phase III
		Crizotinib	Approved for locally advanced or metastatic ALK+ NSCLC: FDA (2011), EMA (2012) Approved for ALK-positive anaplastic large cell lymphoma in children and young adults: FDA (2021)
		Alectinib	Approved for advanced or metastatic ALK+ NSCLC after progression/intolerance to crizotinib: FDA (2015), EMA (2017) Approved for first-line metastatic ALK+ NSCLC: FDA (2017), EMA (2017)
		Brigatinib	Approved for metastatic ALK+ NSCLC after progression/intolerance to crizotinib: FDA (2017), EMA (2018) Approved for first-line metastatic ALK+ NSCLC: FDA (2020), EMA (2020)
		Ceritinib	Approved for second-line metastatic ALK+ NSCLC: FDA (2014), EMA (2015) Approved for first-line metastatic ALK+ NSCLC: FDA (2017), EMA (2017)
		Lorlatinib	Approved for second- or third-line metastatic ALK+ NSCLC: FDA (2018), EMA (2019) Approved for metastatic ALK+ NSCLC: FDA (2021)
EGFR	NSCLC	Gefitinib	Approved for metastatic NSCLC with EGFR exon 19 deletions or exon 21 substitution mutations: EMA (2009), FDA (2015)	[5]
		Erlotinib	Approved for metastatic NSCLC with EGFR exon 19 deletions or exon 21 substitution mutations: EMA (2011), FDA (2013)
		Afatinib	Approved for metastatic NSCLC with EGFR exon 19 deletions or exon 21 substitution mutations: FDA (2013), EMA (2013)
		Osimertinib	Approved for metastatic NSCLC with EGFR exon 19 deletions or exon 21 substitution mutations: EMA (2018), FDA (2020)
KRAS G12C	NSCLC	Sotarasib	Approved for KRAS G12C-mutated locally advanced or metastatic NSCLC after one prior systemic therapy: FDA (2021)
FGFR amplifications, mutation, rearrangements/fusion	Cholangiocarcinoma, breast cancer, NSCLC, CRC, GIST, squamous cell carcinoma, osteosarcoma, urothelial cancer	Debio 1347, AZD4547, futibatinib, infigratinib, rogaratinib	Phase I/II	[6,7]
		Erdafitinib	Approved for FGFR2/3-altered urothelial cancer: FDA (2019)
		Pemigatinib	Approved for patients with FGFR2-rearranged or FGFR2-fusion cholangiocarcinoma: FDA (2020)
RET alteration	NSCLC, papillary thyroid cancer, medullary thyroid cancers	Sitravantinib	Phase III	[8,9]
		Pralsetinib	Approved for adv RET fusion-positive NSCLC and RET-altered thyroid cancers: FDA (2020)
		Selpercatinib	Approved for metastatic RET fusion-positive NSCLC, medullary thyroid cancer and other types of thyroid cancers: FDA (2020)
ROS1	Glioblastoma, cholangiocarcinoma, CRC, sarcoma, NSCLC, ovarian carcinoma, angiocarcinoma, inflammatory myofibroblastic tumors, spitzoid melanocytic tumors	DS-6051b, repotrectinib	Phase I/II	[10,11]
		Brigatinib	Phase III
		Crizotinib	Approved for metastatic ROS1+ NSCLC: FDA (2016), EMA (2016)
		Entrectinib	Approved for metastatic ROS1+ NSCLC: FDA (2019), EMA (2020)
PIK3CA	Breast, CRC, gastric, cervical, prostate, lung	PI3K-targeted agents and dual PI3K/mTOR inhibitors	Phase I/II	[12]
		Alpelisib	Approved for HR^+, HER2^−, PIK3CA^+ breast cancer: FDA (2019), EMA (2020)
BRAF V600E	Melanoma, thyroid, CRC, NSCLC	Vemurafenib	Approved for unresectable/metastatic BRAF V600E melanoma: FDA (2011), EMA (2012)	[13]
		Dabrafenib	Approved for unresectable or metastatic BRAF V600E melanoma: FDA (2013), EMA (2013) Approved in combination with trametinib in unresectable or metastatic BRAF V600E or V600K melanoma: FDA (2014), EMA (2015) Approved in combination with trametinib for BRAF V600E NSCLC: FDA (2017), EMA (2017) Approved in combination with trametinib for adjuvant treatment of stage III BRAF V600E or V600K melanoma involving lymph nodes following complete resection: FDA (2018), EMA (2018) Approved in combination with trametinib for metastatic BRAF V600E anaplastic thyroid cancer with no locoregional treatment options: FDA (2018)
		Encorafenib	Approved in combination with binimetinib for unresectable/metastatic BRAF V600E or V600K melanoma: FDA (2018), EMA (2018) Approved in combination with cetuximab for metastatic BRAF V600E CRC: FDA (2020), EMA (2020)
KIT/PDGFR	GIST	Imatinib	Approved for KIT-positive malignant metastatic or unresectable GIST: FDA (2001), EMA (2001) Approved for adjuvant treatment of KIT-positive GIST at substantial risk of relapse following resection: FDA (2008), EMA (2009)	[14]
		Avapritinib	Approved for unresectable or metastatic GIST harboring a PDGFRA exon 18 mutation: FDA (2020), EMA (2020)
		Ripretinib	Approved as fourth-line treatment of advanced GIST: FDA (2020)
HER2	Breast, gastric cancers	Trastuzumab^‡	Approved for HER2-overexpressing breast cancer: FDA (1998), EMA (2000) Approved for HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma: FDA (2010), EMA (in combination with capecitabine/5-fluorouracil and cisplatin; 2009) Approved in combination with adjuvant chemotherapy consisting of docetaxel and carboplatin for HER2^+ early breast cancer: EMA (2011)	[15]
		Pertuzumab	Approved in combination with trastuzumab and docetaxel for HER2^+ metastatic breast cancer in patients without prior anti-HER2 therapy or chemotherapy for metastatic disease: FDA (2012), EMA (2012) Approved in combination with trastuzumab and chemotherapy as neoadjuvant treatment of HER2^+, locally advanced inflammatory, or early stage breast cancer: FDA (2013), EMA (2015) Approved as adjuvant treatment of HER2^+ early breast cancer at high risk of recurrence: FDA (2017), EMA (2018)
		Lapatinib	Approved in combination with capecitabine for HER2-overexpressing advanced or metastatic breast cancer after prior anthracycline, taxane and trastuzumab: FDA (2007), EMA (2008) Approved in combination with letrozole (aromatase inhibitor) in postmenopausal women for HER2-overexpressing, HR^+ metastatic breast cancer: FDA (2010), EMA (2010) Approved in combination with trastuzumab for relapsed HER2-overexpressing, HR^− metastatic breast cancer after progression: EMA (2013)
		Neratinib	Approved for extended adjuvant treatment of early stage HER2^+ breast cancer following adjuvant trastuzumab: FDA (2017), EMA (2018) Approved in combination with capecitabine for advanced or metastatic HER2^+ breast cancer after two or more prior anti-HER2-based regimens in metastatic setting: FDA (2020)
		Tucatinib	Approved in combination with trastuzumab and capecitabine for treatment with advanced unresectable or metastatic HER2^+ breast cancer after one or more prior anti-HER2-based regimens in metastatic setting: FDA (2020), EMA (2020)
Homologous recombination repair (HRR)	Ovarian, breast, prostate cancers	Olaparib	Approved as maintenance treatment of deleterious or suspected deleterious germline BRCA-mutated advanced ovarian cancer after three or more prior lines of chemotherapy: FDA (2014) Approved as maintenance treatment of relapsed, platinum-sensitive, high-grade ovarian, fallopian tube or primary peritoneal cancer with germline or somatic BRCA mutations: EMA (2014) Approved for deleterious or suspected deleterious germline BRCA-mutated, HER2^− metastatic breast cancer: FDA (2018), EMA (2019) Approved for maintenance treatment of deleterious or suspected deleterious germline BRCA-mutated metastatic pancreatic adenocarcinoma: FDA (2019), EMA (2020) Approved for mCRPC with deleterious or suspected deleterious germline or somatic HRR gene mutation after progression on a new hormonal agent (e.g., enzalutamide or abiraterone): FDA (2020), EMA (2020)	[16]
		Rucaparib	Approved for maintenance treatment of deleterious germline or somatic BRCA mutation-associated ovarian, fallopian tube or peritoneal cancer after two or more chemotherapies: FDA (2016), EMA (2018) Approved for mCRPC with deleterious BRCA mutation after previous treatment with androgen receptor-directed therapy and a taxane-based therapy: FDA (2020)
		Talazoparib	Approved for deleterious or suspected deleterious germline BRCA-mutated, HER2^− locally advanced or metastatic breast cancer: FDA (2018)
Targets with approved tumor-agnostic therapies
MSI-H/dMMR	Lynch syndrome, CRC, gastric, breast, prostate, cholangiocarcinoma, leukemia, bladder, ovarian, endometrial, pancreatic, follicular thyroid, adrenocortical	Nivolumab+ipilimumab, Other checkpoint inhibitors	Phase II	[17]
		Pembrolizumab	Approved for unresectable or metastatic MSI-H/dMMR CRC or MSI-HdMMR solid tumors: FDA (2017)
NTRK gene fusion	Infantile fibrosarcoma, congenital mesoblastic nephroma, secretory breast carcinoma, mammary analogue secretory carcinoma, papillary thyroid carcinoma, CRC, appendiceal adenocarcinoma, NSCLC, GBM, spitzoid tumors/melanoma	Repotrectinib, selitrectinib, DS-6051b, milciclib	Phase I/II	[18,19]
		Sitravantinib	Phase III
		Larotrectinib	Approved for TRK fusion-positive solid tumors: FDA (2018), EMA (2019)
		Entrectinib	Approved for TRK fusion-positive solid tumors: FDA (2019), EMA (2020)
TMB-H	SCLC, neuroendocrine, cervical, anal, vulvar, salivary, endometrial	Nivolumab+ipilimumab, other ICI	Phase II	[20]
		Pembrolizumab	Approved for unresectable or metastatic TMB-H solid tumors: FDA (2020)

† Clinicaltrials.gov was used to identify stage of clinical testing for investigational agents.

‡ Variants of anti-HER2 antibodies not included in the table.

CRC: Colorectal carcinoma; dMMR: Deficient mismatch repair; GBM: Glioblastoma multiforme: GIST: Gastrointestinal stromal tumor; HR: Hormone receptor; HRR: Homologous recombination repair; ICI: Immune checkpoint inhibitor; mCRPC: Metastatic castration-resistant prostate cancer; MSI-H: Microsatellite instability high; NSCLC: Non-small-cell lung cancer; SCLC: Small-cell lung cancer; TMB-H: Tumor mutational burden high.

Figure 1. Schematic of BRAF V600E-mediated resistance to EGFR inhibition in cancers with EGFR-activating mutations.

Table 2. Summary of quality of life findings for agents approved in tumor-agnostic indications.

Agent	Target	Approved Indication	Key efficacy and safety data	Quality of life data	Ref.
Pembrolizumab	MSI-H or dMMR	Indication: • Adult and pediatric patients with unresectable or metastatic, MSI-H or dMMR solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options; or CRC that has progressed following treatment with a fluoropyrimidine, oxaliplatin and irinotecan • First-line treatment of patients with unresectable or metastatic MSI-H or dMMR CRC	KEYNOTE-158 (n = 149; non-CRC): • 40% ORR (7% CR) • Safety profile consistent with other pembrolizumab studies KEYNOTE-177 (n = 307; metastatic CRC): • mPFS: 16.5 vs 8.2 months for pembrolizumab vs chemotherapy, respectively (HR: 0.60, 95% CI: 0.45–0.80; p = 0.0002) • mOS: 13.7 vs 10.8 months • ORR: 43.8 vs 33.1% • Treatment-related grade ≥3 AEs: 22 vs 66%	KEYNOTE-177 • EORTC QLQ-C30, -CR29 and EQ-5D-3L • Clinically meaningful improvements in QLQ-C30 global health status/QoL and EQ-5D VAS for pembro vs SOC • Prolonged time to deterioration was also observed with pembrolizumab for global health status/QoL, physical functioning, social functioning and fatigue	[66–69]
Pembrolizumab	TMB-H	Indication: • Adult and pediatric patients with unresectable or metastatic TMB-H (≥10 mutations/Mb) solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options FoundationOneCDx assay was also approved as companion diagnostic	KEYNOTE-158 (n = 102): • 29% ORR (4% CR, 25% PR) • Safety profile consistent with other pembrolizumab studies	No QoL data available	[67,70]
Larotrectinib	NTRK gene fusions	Indication: • Adult and pediatric patients with solid tumors that have an NTRK gene fusion without a known acquired resistance mutation, are metastatic or where surgical resection is likely to result in severe morbidity, and have no satisfactory alternative treatments or that have progressed following treatment	Pooled data (LOXO-TRK-14001, SCOUT, NAVIGATE; n = 55): • 75% ORR (22% CR, 53% PR) • AEs predominantly grade 1, including fatigue, nausea, dizziness, vomiting, increased transaminases, constipation and diarrhea Expanded analysis (n = 159): • 79% ORR (16% CR, 63% PR) • No new safety signals	• Clinically meaningful QoL improvements that reached or exceeded the minimally important difference for most patients • Sustained QoL improvements occurred by 2 months of treatment for 68% of adults and 71% of children • PedsQL (PRO): improvements across all functional domains (physical, emotional, social and school) • EORTC QLQ-C30: improvements in physical, role, cognitive, emotional and social domains • EORTC QLQ-C30 global health score: most patients (adult and pediatric) either maintained at normal range or showed improvement • Median duration of sustained improvement was 12 months for EORTC QLQ-C30 global health score and NE for PedsQL total score	[71–76]
Entrectinib	NTRK gene fusions^†	Indication: • Adult and pediatric patients 12 years of age and older with solid tumors that have a NTRK gene fusion without a known acquired resistance mutation, are metastatic or where surgical resection is likely to result in severe morbidity, and have progressed following treatment or have no satisfactory alternative therapy	Pooled data (ALK, STARTRK-1, STARTRK-2; n = 54): • 57% ORR • Most common grade 3/4 AEs: increased weight and anemia	• EORTC/QLQ-C30 scores showed either no change or trended toward improvement • Clinically meaningful improvements were seen in domains of role functioning and pain • Patients with moderate lung cancer-related symptom burden at baseline: trend toward improvement in symptom severity during treatment, including a clinically meaningful improvement (>10 points) in cough • CRC patients: CRC-related symptoms (e.g., bloating) either unchanged or improved with time • Symptoms associated with treatment (nausea) were absent or of low severity	[77–79]

† Also approved for adult patients with metastatic non-small-cell lung cancer whose tumors are ROS1-positive.

AE: Adverse event; CR: Complete response; CRC: Colorectal carcinoma; dMMR: Deficient mismatch repair; mOS: Median overall survival; mPFS: Median progression-free survival; MSI-H: Microsatellite instability high; NE: Not evaluable; ORR: Overall response rate; PR: Partial response; QoL: Quality of life; SOC: Standard of care; TMB-H: Tumor mutational burden high.

US Food & Drug Administration . Drug approvals and databases. www.fda.gov/drugs/development-approval-process-drugs/drug-approvals-and-databases

 Google Scholar

European Medicines Agency . Medicines. www.ema.europa.eu/en/medicines

 Google Scholar

Sabir SR , YeohS, JacksonG, BaylissR. EML4-ALK variants: biological and molecular properties, and the implications for patients. Cancers9(9), 118 (2017).

 PubMed Web of Science ®Google Scholar

Riely GJ , YuHA. EGFR: the paradigm of an oncogene-driven lung cancer. Clin. Cancer Res.21(10), 2221–2226 (2015).

 PubMed Web of Science ®Google Scholar

Chae YK , RanganathK, HammermanPSet al. Inhibition of the fibroblast growth factor receptor (FGFR) pathway: the current landscape and barriers to clinical application. Oncotarget8(9), 16052–16074 (2017).

 PubMedGoogle Scholar

Zhou Y , WuC, LuG, HuZ, ChenQ, DuX. FGF/FGFR signaling pathway involved resistance in various cancer types. J. Cancer.11(8), 2000–2007 (2020).

 PubMed Web of Science ®Google Scholar

Li AY , McCuskerMG, RussoAet al. RET fusions in solid tumors. Cancer Treat. Rev.81, 101911 (2019).

 PubMed Web of Science ®Google Scholar

Subbiah V , CoteGJ. Advances in targeting RET-dependent cancers. Cancer Discov.10(4), 498–505 (2020).

 PubMed Web of Science ®Google Scholar

Giustini NP , BazhenovaL. ROS1-rearranged non-small cell lung cancer. Thorac. Surg. Clin.30(2), 147–156 (2020).

 PubMed Web of Science ®Google Scholar

Patil T , SimonsE, MushtaqR, PachecoJM, DoebeleRC, BowlesDW. Targeted therapies for ROS1-rearranged non-small cell lung cancer. Drugs Today55(10), 641–652 (2019).

 PubMed Web of Science ®Google Scholar

Yang J , NieJ, MaX, WeiY, PengY, WeiX. Targeting PI3K in cancer: mechanisms and advances in clinical trials. Mol. Cancer18(1), 26 (2019).

 PubMed Web of Science ®Google Scholar

Croce L , CoperchiniF, MagriF, ChiovatoL, RotondiM. The multifaceted anti-cancer effects of BRAF-inhibitors. Oncotarget10(61), 6623–6640 (2019).

 PubMedGoogle Scholar

Kelly CM , GutierrezSainz L, ChiP. The management of metastatic GIST: current standard and investigational therapeutics. J. Hematol. Oncol.14(1), 2 (2021).

 PubMed Web of Science ®Google Scholar

File D , CuriglianoG, CareyLA. Escalating and de-escalating therapy for early-stage HER2-positive breast cancer. Am. Soc. Clin. Oncol. Educ. Book40, 1–11 (2020).

 PubMedGoogle Scholar

Jang A , SartorO, BarataPC, PallerCJ. Therapeutic potential of PARP inhibitors in the treatment of metastatic castration-resistant prostate cancer. Cancers12(11), 3467 (2020).

 PubMed Web of Science ®Google Scholar

Li K , LuoH, HuangL, LuoH, ZhuX. Microsatellite instability: a review of what the oncologist should know. Cancer Cell Int.20, 16 (2020).

 PubMed Web of Science ®Google Scholar

Amatu A , Sartore-BianchiA, BencardinoK, PizzutiloEG, TosiF, SienaS. Tropomyosin receptor kinase (TRK) biology and the role of NTRK gene fusions in cancer. Ann. Oncol.30(Suppl. 8), VIII5–VIII15 (2019).

 PubMedGoogle Scholar

Marino FZ , PagliucaF, RonchiAet al. NTRK fusions, from the diagnostic algorithm to innovative treatment in the era of precision medicine. Int. J. Mol. Sci.21(10), 1–15 (2020).

 Web of Science ®Google Scholar

Shao C , LiG, HuangLet al. Prevalence of high tumor mutational burden and association with survival in patients with less common solid tumors. JAMA Netw. Open.3(10), e2025109 (2020).

 PubMed Web of Science ®Google Scholar

KEYTRUDA® [package insert]. Merck & Co., Inc, NJ, USA (2020). www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_pi.pdf

 Google Scholar

Marabelle A , FakihM, LopezJet al. Association of tumour mutational burden with outcomes in patients with advanced solid tumours treated with pembrolizumab: prospective biomarker analysis of the multicohort, open-label, Phase 2 KEYNOTE-158 study. Lancet Oncol.21(10), 1353–1365 (2020).

 PubMed Web of Science ®Google Scholar