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Background: HIV testing remains an entry point into HIV care and treatment services. In 2007, Nigeria adopted and implemented a two-test rapid HIV testing algorithm of three HIV rapid test kits, following the sequence: Alere Determine (first test), UnigoldTM (second test), and STAT-PAK® as the tie-breaker. Sub-analysis of the 2018 Nigeria HIV/AIDS Indicator and Impact Survey data showed significant discordance between the first and second tests, necessitating an evaluation of the algorithm. This manuscript highlights lessons learnt from that evaluation. Intervention: A two-phased evaluation method was employed, including abstraction and analysis of retrospective HIV testing data from January 2017 to December 2019 from 24 selected sites supported by the United States President’s Emergency Plan for AIDS Relief programme. A prospective evaluation of HIV testing was done among 2895 consecutively enrolled and consented adults, aged 15–64 years, accessing HIV testing services from three selected sites per state across the six geopolitical zones of Nigeria between July 2020 and September 2020. The prospective evaluation was performed both in the field and at the National Reference Laboratory under controlled laboratory conditions. Stakeholder engagements, strategic selection and training of study personnel, and integrated supportive supervision were employed to assure the quality of evaluation procedures and outcomes. Lessons learnt: The algorithm showed higher sensitivity and specificity in the National Reference Laboratory compared with the field. The approaches to quality assurance were integral to the high-quality study outcomes. Recommendations: We recommend comparison of testing algorithms under evaluation against a gold standard. What this study adds: This study provides context-specific considerations in using World Health Organization recommendations to evaluate the Nigerian national HIV rapid testing algorithm.

BackgroundCervical cancer constitutes a huge burden among women in Nigeria, particularly HIV-infected women. However, the provision and uptake of cervical cancer screening and treatment is limited in Nigeria. Understanding implementation determinants is essential for the effective translation of such evidence-based interventions into practice, particularly in low-resource settings. COVID-19 pandemic necessitated online collaboration making implementation mapping challenging in some ways, while providing streamlining opportunities. In this study, we describe the use of a virtual online approach for implementation mapping (steps 1-3) to identify implementation determinants, mechanisms, and strategies to implement evidence-based cervical cancer screening and treatment in existing HIV infrastructure in Nigeria.MethodsThis study used a mixed methods study design with a virtual modified nominal group technique (NGT) process aligning with Implementation Mapping steps 1-3. Eleven stakeholders (six program staff and five healthcare providers and administrators) participated in a virtual NGT process which occurred in two phases. The first phase utilized online surveys, and the second phase utilized an NGT and implementation mapping process. The Exploration, Preparation, Implementation and Sustainment (EPIS) framework was used to elicit discussion around determinants and strategies from the outer context (i.e., country and regions), inner organizational context of existing HIV infrastructure, bridging factors that relate to bi-directional influences, and the health innovation to be implemented (in this case cervical cancer screening and treatment). During the NGT, the group ranked implementation barriers and voted on implementation strategies using Mentimeter.ResultsEighteen determinants to integrating cervical cancer screening and treatment into existing comprehensive HIV programs were related to human resources capacity, access to cervical cancer services, logistics management, clinic, and client-related factors. The top 3 determinants included gaps in human resources capacity, poor access to cervical cancer services, and lack of demand for services resulting from lack of awareness about the disease and servicesA set of six core implementation strategies and two enhanced implementation strategies were identified.ConclusionsRapid Implementation Mapping is a feasible and acceptable approach for identifying and articulating implementation determinants, mechanisms, and strategies for complex healthcare interventions in LMICs.

There is limited capacity and infrastructure in sub-Saharan Africa to conduct clinical trials for the identification of efficient and effective new prevention, diagnostic and treatment modalities to address the disproportionate burden of disease. This paper reports on the process to establish locally driven infrastructure for multicentre research and trials in Nigeria known as the Nigeria Implementation Science Alliance Model Innovation and Research Centres (NISA-MIRCs). We used a participatory approach to establish a research network of 21 high-volume health facilities selected from all 6 geopolitical zones in Nigeria capable of conducting clinical trials, implementation research using effectiveness-implementation hybrid designs and health system research. The NISA-MIRCs have a cumulative potential to recruit 60 000 women living with HIV and an age-matched cohort of HIV-uninfected women. We conducted a needs assessment, convened several stakeholder outreaches and engagement sessions, and established a governance structure. Additionally, we selected and trained a core research team, developed criteria for site selection, assessed site readiness for research and obtained ethical approval from a single national institutional review board. We used the Exploration, Preparation, Implementation, Sustainment framework to guide our reporting of the process in the development of this network. The NISA-MIRCs will provide a nationally representative infrastructure to initiate new studies, support collaborative research, inform policy decisions and thereby fill a significant research infrastructure gap in Africa's most populous country.

Abstract Background In 2015, the World Health Organization recommended that all people living with HIV begin antiretroviral treatment (ART) regardless of immune status, a policy known as ‘Treat-All to end AIDS’, commonly referred to as Treat-All. Almost all low- and middle-income countries adopted this policy by 2019. This study describes how linkage to treatment of newly diagnosed persons changed between 2015 and 2018 and how complementary policies may have similarly increased linkage for 13 African countries. These countries adopted and implemented Treat-All policies between 2015 and 2018 and were supported by the U.S. Government’s President’s Emergency Plan for AIDS Relief (PEPFAR). The focuses of this research were to understand 1) linkage rates to ART initiation before and after the adoption of Treat-All in each country; 2) how Treat-All implementation differed across these countries; and 3) whether complementary policies (including same-day treatment initiation, task-shifting, reduced ART visits, and reduced ART pickups) implemented around the same time may have increased ART linkage. Methods HIV testing and treatment data were collected by PEPFAR country programs in 13 African countries from 2015 to 2018. These countries were chosen based on the completeness of policy data and availability of program data during the study period. Program data were used to calculate proxy linkage rates. These rates were compared relative to the Treat All adoption period and the adoption of complementary policies. Results The 13 countries experienced an average increase in ART linkage of 29.3% over the entire study period. In examining individual countries, all but two showed increases in linkage to treatment immediately after Treat All adoption. Across all countries, those that had adopted four or more complementary policies showed an average increased linkage of 39.8% compared to 13.9% in countries with fewer than four complementary policies. Conclusions Eleven of 13 country programs examined in this study demonstrated an increase in ART linkage after Treat-All policy adoption. Increases in linkage were associated with complementary policies. When exploring new public health policies, policymakers may consider which complementary policies might also help achieve the desired outcome of the public health policy.

KRAS is the most commonly mutated oncogene in NSCLC and development of direct KRAS inhibitors has renewed interest in this molecular variant. Different KRAS mutations may represent a unique biologic context with different prognostic and therapeutic impact. We sought to characterize genomic landscapes of advanced, KRAS-mutated non-small cell lung cancer (NSCLC) in a large national cohort to help guide future therapeutic development.Molecular profiles of 17,095 NSCLC specimens were obtained using DNA next-generation sequencing of 592 genes (Caris Life Sciences) and classified on the basis of presence and subtype of KRAS mutations. Co-occurring genomic alterations, tumor mutational burden (TMB), and PD-L1 expression [22C3, tumor proportion score (TPS) score] were analyzed by KRAS mutation type.Across the cohort, 4,706 (27.5%) samples harbored a KRAS mutation. The most common subtype was G12C (40%), followed by G12V (19%) and G12D (15%). The prevalence of KRAS mutations was 37.2% among adenocarcinomas and 4.4% in squamous cell carcinomas. Rates of high TMB (≥10 mutations/Mb) and PD-L1 expression varied across KRAS mutation subtypes. KRAS G12C was the most likely to be PD-L1 positive (65.5% TPS ≥ 1%) and PD-L1 high (41.3% TPS ≥ 50%). STK11 was mutated in 8.6% of KRAS wild-type NSCLC but more frequent in KRAS-mutant NSCLC, with the highest rate in G13 (36.2%). TP53 mutations were more frequent in KRAS wild-type NSCLC (73.6%).KRAS mutation subtypes have different co-occurring mutations and a distinct genomic landscape. The clinical relevance of these differences in the context of specific therapeutic interventions warrants investigation.

The early period of the COVID-19 pandemic limited access to HIV services for children and adolescents living with HIV (C/ALHIV). To determine progress in providing care and treatment services, we describe viral load coverage (VLC) and suppression (VLS) (

Abstract Background The continuous supply of affordable and quality HIV self-test (HIVST) is a key pillar toward achieving the global HIV 95–95-95 target in Nigeria. This was a descriptive qualitative study that explored private sector stakeholders’ perceptions of the enablers and barriers of the HIVST market in Nigeria. Methods A total of 29 In-depth interviews (IDIs) were conducted with HIVST supply chain stakeholders and private sector providers (PPMVs and Community Pharmacies). Responses were analyzed using Nvivo software and we systematically developed a total market approach analysis for supply chain stakeholders and archetypes for community Pharmacies and PPMVs based on insights gathered from their journey map. Results Challenges to the supply side dynamics include forecasting, point of care service delivery, the availability of free and subsidized HIVST kits in the market, neglect of private sector providers (Community Pharmacists and PPMVs) in the healthcare delivery system, limited demand for HIVST, and regulatory bottlenecks influences the overall market dynamics. High cost of the HIVST kit, which triggers low availability, accessibility and affordability from the demand side, depicts the need to understand the market dynamics. Addressing the barriers and optimizing the enablers of the three-model pharmacist and PPMV’s will change the market dynamic and service delivery to generate demand. Conclusion To address challenges which already exist, the government need to revise the process guidelines for introducing new HIVST products in the Nigerian market, developing contingency plans to ensure the supply of HIVST remains sufficient when experiencing economic shocks, and create a sustainable roadmap toward optimizing the market for HIVST kits.

BackgroundCervical cancer constitutes a huge burden among women in Nigeria, particularly HIV-infected women. However, the provision and uptake of cervical cancer screening and treatment is limited in Nigeria. Understanding implementation determinants is essential for the effective translation of such evidence-based interventions into practice, particularly in low-resource settings. COVID-19 pandemic necessitated online collaboration making implementation mapping challenging in some ways, while providing streamlining opportunities. In this study, we describe the use of a virtual online approach for implementation mapping (steps 1–3) to identify implementation determinants, mechanisms, and strategies to implement evidence-based cervical cancer screening and treatment in existing HIV infrastructure in Nigeria.MethodsThis study used a mixed methods study design with a virtual modified nominal group technique (NGT) process aligning with Implementation Mapping steps 1–3. Eleven stakeholders (six program staff and five healthcare providers and administrators) participated in a virtual NGT process which occurred in two phases. The first phase utilized online surveys, and the second phase utilized an NGT and implementation mapping process. The Exploration, Preparation, Implementation and Sustainment (EPIS) framework was used to elicit discussion around determinants and strategies from the outer context (i.e., country and regions), inner organizational context of existing HIV infrastructure, bridging factors that relate to bi-directional influences, and the health innovation to be implemented (in this case cervical cancer screening and treatment). During the NGT, the group ranked implementation barriers and voted on implementation strategies using Mentimeter.ResultsEighteen determinants to integrating cervical cancer screening and treatment into existing comprehensive HIV programs were related to human resources capacity, access to cervical cancer services, logistics management, clinic, and client-related factors. The top 3 determinants included gaps in human resources capacity, poor access to cervical cancer services, and lack of demand for services resulting from lack of awareness about the disease and servicesA set of six core implementation strategies and two enhanced implementation strategies were identified.ConclusionsRapid Implementation Mapping is a feasible and acceptable approach for identifying and articulating implementation determinants, mechanisms, and strategies for complex healthcare interventions in LMICs.

The number of children newly infected with HIV dropped by 50%, from 320 000 in 2010 to 160 000 in 2021. Despite progress, ongoing gaps persist in diagnosis, continuity of care, and treatment optimization. In response, the United States President's Emergency Plan for AIDS Relief created the Faith-based Action for Scaling-Up Testing and Treatment for Epidemic Response (FASTER). Faith-based Action for Scaling-Up Testing and Treatment for Epidemic Response addressed gaps in countries with the highest unmet need by working with government to operationalize innovative interventions and ensure alignment with national priorities and with communities living with HIV to ensure the change was community-led. Between 2019 and 2021, FASTER's interventions were incorporated into national policies, absorbed by Ministries of Health, and taken up in subsequent awards and country operating plans. Continued effort is needed to sustain gains made during the FASTER initiative and to continue scaling evidence-based interventions to ensure that children and adolescents are not left behind in the global HIV response.

BackgroundIn Nigeria, results from the pilot of the Test and Treat strategy showed higher loss to follow up (LTFU) among people living with HIV compared to before its implementation. The aim of this evaluation was to assess the effects of antiretroviral therapy (ART) initiation within 14 days on LTFU at 12 months and viral suppression.MethodsWe conducted a retrospective cohort study using routinely collected de-identified patient-level data hosted on the Nigeria National Data Repository from 1,007 facilities. The study population included people living with HIV age ≥15. We used multivariable Cox proportional frailty hazard models to assess time to LTFU comparing ART initiation strategy and multivariable log-binomial regression for viral suppression.ResultsOverall, 26,937 (38.13%) were LTFU at 12 months. Among individuals initiated within 14 days, 38.4% were LTFU by 12 months compared to 35.4% for individuals initiated >14 days (p14 days was not statistically significant.ConclusionLTFU was higher among individuals who were initiated within 14 days compared to greater than 14 days after HIV diagnosis. There was no difference for viral suppression. The provision of early tailored interventions to support newly diagnosed people living may contribute to reducing LTFU.

BackgroundHIV is a public health burden in Nigeria. HIV self-testing is one of the approaches to testing, which is the first of the 95:95:95 cascade of a coherent response to the epidemic. The ability to self-test HIV is influenced by various factors that can either serve as enablers or barriers. Exploring these enablers and barriers to the uptake of HIVST will help achieve optimal HIV self-testing and provide a deeper understanding of the HIVST kits users' journey.ObjectiveThe purpose of the study was to identify enablers and barriers to the uptake of HIV self-testing among sexually active youth in Nigeria using journey map methodology.MethodsWe conducted a qualitative exploratory study between January 2021 to October 2021 to understand the journey map for taking up and using HIVST in the private health delivery systems which include the pharmacies and PPMVs. 80 youths in Lagos, Anambra and Kano states were interviewed using IDIs and in-person FGDs. Their responses were audio-recorded, transcribed and analyzed using a qualitative software package (Nvivo software).ResultsA journey map for taking up and effectively using HIVST using the private sector among sexually active youths using key enablers and barriers at the attract, purchase, use, confirmation, linkage, and reporting stage was developed. The major enablers among participants were privacy and confidentiality, bundling purchases with other health products, easy-to-use instructions, and past experience with other self-testing kits. The major barriers were fear of discrimination, big packaging, high price, lack of confidence from user error and fear of status disclosure.ConclusionsSexually active young people's perspectives enhance our understanding of the barriers and enablers of using HIVST through the private sector. Optimizing the enablers such as improved confidentiality that may be seen in e-pharmacy, reducing barriers and factoring sexually young people's perspectives will enhance the market and the uptake of HIVST towards ensuring sustainability and accelerating progress towards the 95-95-95 targets.

The percentage of Human Immunodeficiency Virus (HIV) positive pregnant women that receive anti-retroviral treatment in Nigeria is low and has been declining. Consequently, 14% of all new infections among children in 2020 occurred in Nigeria. A detailed analysis of available data was undertaken to generate evidence to inform remedial actions. Data from routine service delivery, national surveys and models were analyzed for the six-year period from 2015 to 2020. Numbers and percentages were calculated for antenatal registrations, HIV testing, HIV positive pregnant women and HIV positive pregnant women on antiretroviral treatment. The Mann-Kendall Trend Test was used to determine the presence of time trends when the p-value was less than 0.05. In 2020, only 35% of an estimated 7.8 million pregnant women received antenatal care at a health facility that provided and reported PMTCT services. Within these facilities, the percentage of HIV-positive pregnant women on anti-retroviral treatment from 71% in 2015 to 88% in 2020. However, declining HIV positivity rates at these antenatal clinics and an absence of expansion of PMTCT services to other pregnant women due to cost-efficiency considerations contributed to a progressive decline in national PMTCT coverage rates. To achieve elimination of mother-to-child transmission of HIV, all pregnant women should be offered a HIV test, all who are HIV positive should be given anti-retroviral treatment, and all PMTCT services should be reported.

Abstract Background World Health Organization (WHO) reports that people who indulge in risky behaviours such as penile-anal sex, unprotected intercourse, multiple sex partners, and alcohol and illicit drugs are at risk of HIV/AIDS and classified as Key Populations (KPs). Since the introduction of PrEP and HIVST for the key population groups in Nigeria, government entities and implementing partners have used a range of channels in messaging these essential services across to the target groups—ranging from in-person, social media, television, and radio adverts. Yet, few successes have been documented, thereby necessitating the need to understand the enabling facilitators, barriers to, and communication needs of the KP groups in messaging PrEP and HIVST services in Nigeria. Communicating PrEP and HIVST services will empower the key populations to seek available HIV prevention services and help to increase access to HIV testing services in Nigeria. Methods This study was a mixed-method cross-sectional design; involving 1169 participants from the key populations in Nigeria. The study used a survey and qualitative exploratory methods (interviews and focus group discussion), to collect data from the participants—MSM, FSWs, and key influencers of the KP groups (health providers, peer educators, HIV program officers). In August 2020, data collection was conducted using an open data kit (ODK). Quantitative data were analyzed using SPSS version 20 for descriptive statistics, while qualitative data were analyzed using deductive and thematic analysis based on the codebook. Results The KPs were mainly urban dwellers (77.7%), and the majority of the participants were between 18 to 28 years (89.3%). However, the MSM group was of a younger population compared to the FSWs. A majority completed secondary education (56.1% FSWs and 43.5% MSM). The MSM group showed more tendency to acquire higher education compared to the FSWs. For example, about 51.3% of the MSM group were undergraduates compared to 9.5% of the FSWs. The majority of the KPs were self-employed (56.4% FSWs and 40% MSM). Only about 51% of the KPs were aware of PrEP, with typological variations (39.9% FSWs and 62.3% MSM). MSM group in Lagos (82.5%) were more aware of PrEP services, than 53.1% and 54.5% in A/Ibom (53.1%) and C/River (54.5%). Among the enablers to acquiring PrEP information was the ability of the KPs to network within their communities and on personal relationships. Evidence shows that no single approach influenced the acquisition and use of PrEP information by KPs. Although this proportion varied across the geographic locations, only about 50% of the KPs were aware of HIVST services (40% FSWs and 60% MSM). The factors that enabled the acquisition and use of the prevention commodities were cross-cutting, including a previous or current role as a peer educator, integration of the messages, peer networking, multi-lingual and multi-channel presentation, job aids, and reminders. KPs expressed the need for information on how to take PrEP, eligibility, clarification on differences between PrEP and PEP, clarification on any side effects, for PrEP, price, efficacy, sales point, dosage, available brands. A scale-up of the research across all geopolitical zones and a survey to quantify the prevalence would help understand the dynamics and prioritization of interventions for scaling up PrEP and HIVST services in Nigeria. Conclusions The study documented barriers and facilitators to the uptake of PrEP and HIVST among key populations in Nigeria. It highlighted that KPs are willing to receive PrEP and HIVST messages. The policy actors should consider the preferences of the KPs and the key influencers in reducing barriers to communication and increasing the uptake of PrEP and HIVST services; ensure it reflects in a tailored communication strategy. Since multi-linguistics and multi-channels of presentation were enablers to acquiring PrEP and HIVST messages, the communications strategy for HIV prevention should incorporate these recommendations and adapt to context-specific approaches for effective messaging.

Abstract Introduction The potential disruption in antiretroviral therapy (ART) services in Africa at the start of the COVID‐19 pandemic raised concern for increased morbidity and mortality among people living with HIV (PLHIV). We describe HIV treatment trends before and during the pandemic and interventions implemented to mitigate COVID‐19 impact among countries supported by the US Centers for Disease Control and Prevention (CDC) through the President's Emergency Plan for AIDS Relief (PEPFAR). Methods We analysed quantitative and qualitative data reported by 10,387 PEPFAR‐CDC‐supported ART sites in 19 African countries between October 2019 and March 2021. Trends in PLHIV on ART, new ART initiations and treatment interruptions were assessed. Viral load coverage (testing of eligible PLHIV) and viral suppression were calculated at select time points. Qualitative data were analysed to summarize facility‐ and community‐based interventions implemented to mitigate COVID‐19. Results The total number of PLHIV on ART increased quarterly from October 2019 (n = 7,540,592) to March 2021 (n = 8,513,572). The adult population (≥15 years) on ART increased by 14.0% (7,005,959–7,983,793), while the paediatric population (

Abstract Background To accelerate progress toward the UNAIDS 90-90-90 targets, US Centers for Disease Control and Prevention Nigeria country office (CDC Nigeria) initiated an Antiretroviral Treatment (ART) Surge in 2019 to identify and link 340,000 people living with HIV/AIDS (PLHIV) to ART. Coronavirus disease 2019 (COVID-19) threatened to interrupt ART Surge progress following the detection of the first case in Nigeria in February 2020. To overcome this disruption, CDC Nigeria designed and implemented adapted ART Surge strategies during February–September 2020. Methods Adapted ART Surge strategies focused on continuing expansion of HIV services while mitigating COVID-19 transmission. Key strategies included an intensified focus on community-based, rather than facility-based, HIV case-finding; immediate initiation of newly-diagnosed PLHIV on 3-month ART starter packs (first ART dispense of 3 months of ART); expansion of ART distribution through community refill sites; and broadened access to multi-month dispensing (MMD) (3–6 months ART) among PLHIV established in care. State-level weekly data reporting through an Excel-based dashboard and individual PLHIV-level data from the Nigeria National Data Repository facilitated program monitoring. Results During February–September 2020, the reported number of PLHIV initiating ART per month increased from 11,407 to 25,560, with the proportion found in the community increasing from 59 to 75%. The percentage of newly-identified PLHIV initiating ART with a 3-month ART starter pack increased from 60 to 98%. The percentage of on-time ART refill pick-ups increased from 89 to 100%. The percentage of PLHIV established in care receiving at least 3-month MMD increased from 77 to 93%. Among PLHIV initiating ART, 6-month retention increased from 74 to 92%. Conclusions A rapid and flexible HIV program response, focused on reducing facility-based interactions while ensuring delivery of lifesaving ART, was critical in overcoming COVID-19-related service disruptions to expand access to HIV services in Nigeria during the first eight months of the pandemic. High retention on ART among PLHIV initiating treatment indicates immediate MMD in this population may be a sustainable practice. HIV program infrastructure can be leveraged and adapted to respond to the COVID-19 pandemic.

Abstract METex14 skipping mutations occur in about 3–4% of lung adenocarcinoma patients and 1–2% of patients with other lung cancer histology. The MET receptor tyrosine kinase and its ligand hepatocyte growth factor (HGF) are established oncogenic drivers of NSCLC. A mutation that results in loss of exon 14 in the MET gene leads to dysregulation and inappropriate signaling that is associated with increased responsiveness to MET TKIs. Results from GEOMETRY mono-1 and VISION Phase I/II clinical trials demonstrated significant clinical activity in patients treated with the MET Exon 14 skipping mutation inhibitors capmatinib and tepotinib with tolerable toxicity profile. In the GEOMETRY mono-1 trial, capmatinib was especially active in treatment-naïve patients supporting the upfront testing of this oncogenic driver. Tepotinib demonstrated superior activity in the pretreated patients in the VISION trial. Savolitinib is another MET TKI that has shown efficacy in the first- and second-line settings, including patients with aggressive pulmonary sarcomatoid carcinoma. These studies have demonstrated that these TKIs can cross the blood brain barrier and demonstrated some activity toward CNS metastases. MET Exon 14 skipping mutation is detected by NGS-based testing of liquid or tissue biopsies, with preference for RNA-based NGS. The activity of capmatinib and tepotinib is limited by the development of acquired resistance. Current research is focused on strategies to overcome resistance and improve the effectiveness of these agents. Our aim is to review the current status of MET Exon 14 skipping mutation as it pertains NSCLC.

Abstract The recent approvals by the Food and Drug Administration several tumor-agnostic drugs have resulted in a paradigm shift in cancer treatment from an organ/histology-specific strategy to biomarker-guided approaches. RET gene fusions are oncogenic drivers in multiple tumor types and are known to occur in 1–2% of non-squamous NSCLC patients. RET gene fusions give rise to chimeric, cytosolic proteins with constitutively active RET kinase domain. Standard therapeutic regimens provide limited benefit for NSCLC patients with RET fusion-positive tumors, and the outcomes with immunotherapy in the these patients are generally poor. Selpercatinib (LOXO-292) and pralsetinib (BLU-667) are potent and selective inhibitors that target RET alterations, including fusions and mutations, irrespective of the tissue of origin. Recently, the results from the LIBRETTO-001 and ARROW clinical trials demonstrated significant clinical benefits with selpercatinib and pralsetinib respectively, in NSCLC patients with RET gene fusions, with tolerable toxicity profiles. These studies also demonstrated that these RET-TKIs crossed the blood brain barrier with significant activity. As has been observed with other TKIs, the emergence of acquired resistance may limit long-term efficacy of these agents. Therefore, understanding the mechanisms of resistance is necessary for the development of strategies to overcome them.