Tanstrive (Selpercatinib) enters India, Bringing New Hope for RET-Targeted Cancer Care

The phase III data from the LIBRETTO clinical trial have confirmed the importance of selective RET (REarranged during Transfection) inhibition as a new standard of care in RET-driven malignancies, with a significant increase in progression-free survival (PFS) and response rates when compared to conventional therapies ^(1,2). Despite advances in precision oncology, RET-altered cancers remain an uncommon but clinically important molecular subgroup in which delayed molecular testing ⁽³⁾, limited historical efficacy of non-selective multi-kinase inhibitors ⁽⁴⁾, and CNS disease in NSCLC have contributed to persistent treatment gaps ⁽¹⁾.

Eli Lilly has expanded access for patients with RET-altered malignancies by introducing Tanstrive^® (Selpercatinib) in India supported by this evolving evidence ⁽⁵⁾.

RET Alterations: A Rare but Actionable Oncogenic Driver

RET (REarranged during Transfection) is a receptor tyrosine kinase that regulates cell proliferation, differentiation, and survival. Oncogenic activation occurs through gene fusion or point mutation, resulting in constitutive signalling that promotes cancer ⁽⁶⁾. RET fusions are found in 1-2% of NSCLC and lower fractions of other solid tumours, while RET mutations play a key role in medullary thyroid carcinoma (MTC) - both hereditary and spontaneous cases ^(5,6). Despite their low incidence ⁽⁷⁾, RET mutations are a clinically significant subset due to their high targetability ^(2,7) and limited reactivity to conventional immunotherapy ⁽⁸⁾, emphasizing the necessity of complete molecular profiling ⁽³⁾.

Moving Beyond Multi-Kinase Therapy: Selective RET Inhibition

Historically, multi-kinase inhibitors such as Cabozantinib and Vandetanib were utilized in RET-driven malignancies, but they lack selectivity and are associated with considerable off-target side effects ⁽⁹⁾. Selpercatinib is a highly selective RET inhibitor that targets both RET fusions and mutations while sparing other kinases ⁽²⁾, resulting in better safety and tolerability ⁽¹⁰⁾.

The LIBRETTO-001 phase I/II trial first established its activity. In RET fusion-positive NSCLC, objective response rates (ORR) reached 83–84% in treatment-naïve patients and ~60% in previously treated patients, with durable responses exceeding 20–30 months ⁽¹⁰⁾. Long-term follow-up has confirmed sustained clinical benefit and manageable safety, with median overall survival approaching 47.6 months in pretreated patients ⁽¹⁰⁾.

Selpercatinib's capacity to cross the blood–brain barrier is evidenced by its strong intracranial activity, which is a significant advantage in non-small cell lung cancer (NSCLC) where brain metastases are common ^(2,11).

Selpercatinib - Phase III Data Establish New Standards in NSCLC and MTC

In RET fusion-positive advanced non-small cell lung cancer (NSCLC), the phase III LIBRETTO-431 study demonstrated first-line evidence that Selpercatinib significantly extended median progression-free survival (PFS) when compared to platinum-based treatment with or without pembrolizumab (24.8 vs. 11.2 months; HR 0.46; 95% CI, 0.31–0.70; P<0.001). Selpercatinib's advantage as an initial targeted therapy in this patient population is further supported by the higher objective response (84% vs. 65%) ⁽¹⁾.

Selective RET inhibition is the recommended first line of treatment when a RET fusion is detected, as checkpoint inhibitors seem to have little additional effectiveness in RET fusion-positive NSCLC ⁽¹¹⁾.

It is noteworthy that the phase III LIBRETTO-531 trial demonstrated superiority of Selpercatinib over Cabozantinib or Vandetanib in advanced RET-mutant MTC. Median PFS was not reached with Selpercatinib versus 16.8 months with standard therapy (HR 0.28), with a higher ORR of 69.4% versus 38.8% ^(2,12). These findings have major clinical implications, establishing selective RET inhibition as not just an option, but also a recommended therapeutic strategy for a variety of RET-driven cancers.

A Tumour-Agnostic Approach: Expanding Beyond Tumour Type

With an objective response rate of about 44% and durable responses observed in a heavily pretreated population, Selpercatinib has shown activity across RET fusion-positive solid tumours, including pancreatic, colorectal, salivary, and sarcoma subtypes, in addition to lung and thyroid cancers ⁽⁵⁾. This is consistent with more general developments in oncology, as treatment choices for various tumour types are increasingly influenced by genomic changes.

Selpercatinib- Clinical Considerations and Safety Profile

Selpercatinib provides a focused strategy, but close observation is still necessary. Hypertension, hepatotoxicity, QT interval prolongation, diarrhoea, exhaustion, and hypothyroidism are common side effects ⁽⁵⁾. One of the most common test abnormalities is elevated liver enzymes, which call for regular monitoring. Although they are comparatively rare, interstitial lung disease/pneumonitis and haemorrhagic episodes are additional significant hazards ⁽⁵⁾. Selpercatinib has a better tolerability profile than previous multi-kinase inhibitors like Cabozantinib and Vandetanib, with less severe side effects such as diarrhoea and stomatitis. However, thorough monitoring for cardiovascular and metabolic consequences is still needed in clinical practice ⁽²⁾.

Tackling RET driven Cancers in India: Another Step Forward with Selpercatinib

The launch of Tanstrive underscores the growing importance of targeted treatment approaches in India.

• Next-generation sequencing enables detection of rare but actionable mutations, such as RET fusions ⁽³⁾.

• Early genetic profiling at diagnosis is crucial for effective therapy selection, especially in advanced NSCLC and thyroid malignancies ^(2,11).

• As data evolves, selective RET inhibition offers a paradigm shift—from empiric chemotherapy to biomarker-driven, highly targeted therapy; offering better results and personalized care for patients with RET-driven malignancies ^(1,2,4).

Abbreviations

RET- REarranged during Transfection; PFS- Progression-Free Survival; MTC- Medullary Thyroid Carcinoma; NSCLC- Non-Small Cell Lung Cancer

References

1. Zhou C, Solomon B, Loong HH, Park K, Pérol M, Arriola E, Novello S, Han B, Zhou J, Ardizzoni A, Mak MP, Santini FC, Elamin YY, Drilon A, Wolf J, Payakachat N, Uh MK, Rajakumar D, Han H, Puri T, Soldatenkova V, Lin AB, Lin BK, Goto K; LIBRETTO-431 Trial Investigators. First-Line Selpercatinib or Chemotherapy and Pembrolizumab in RET Fusion-Positive NSCLC. N Engl J Med. 2023 Nov 16;389(20):1839-1850. doi: 10.1056/NEJMoa2309457. Epub 2023 Oct 21. PMID: 37870973; PMCID: PMC10698285.

2. Hadoux J, Elisei R, Brose MS, et al. Phase 3 trial of selpercatinib in advanced RET-mutant medullary thyroid cancer. N Engl J Med. 2023;389:1851-1861

3. Passiglia F, et al. RET Fusion Testing in Patients With NSCLC: The RETING Study. JTO Clinical and Research Reports. 2024.

Link: https://www.sciencedirect.com/science/article/pii/S2666364324000237

4. Subbiah V, Hu MI, Wirth LJ, Schuler M, Mansfield AS, Curigliano G, et al. Precision therapy for RET-altered cancers with RET inhibitors. Trends Cancer. 2021;7(5):385–397. doi:10.1016/j.trecan.2021.02.003

5. Eli Lilly and Company. Tanstrive® (selpercatinib) – Product Information / Clinical Document. https://image.mc.lilly.com/lib/fe9312747462077971/m/1/cde34d81-7770-45bc-8a34-09a983be3ce9.pdf

6. Drilon A, Hu ZI, Lai GGY, et al. Targeting RET-driven cancers: lessons from evolving preclinical and clinical landscapes. Nat Rev Clin Oncol. 2018;15:151-167.

7. Stinchcombe TE. Selpercatinib in RET fusion-positive NSCLC: updated analysis. Transl Lung Cancer Res. 2023;12:1655-1657.

8. Peng Z, Ding K, Xie M, Xu Y. Efficacy of immunotherapy in RET fusion-positive NSCLC: A meta-analysis. Heliyon. 2024;10:e34626. https://pmc.ncbi.nlm.nih.gov/articles/PMC11324980/

9. Vodopivec DM, Hu MI. RET kinase inhibitors for RET-altered thyroid cancers. Ther Adv Med Oncol. 2022 Jun 21;14:17588359221101691. doi: 10.1177/17588359221101691. PMID: 35756966; PMCID: PMC9218446.

10. Gautschi O, Park K, Solomon BJ, et al. Final results of LIBRETTO-001 selpercatinib trial. J Clin Oncol. 2025. https://ascopost.com/issues/april-25-2025/final-results-of-libretto-001-selpercatinib-in-ret-fusion-positive-nsclc/?utm

11. National Cancer Institute. Selpercatinib improves outcomes in RET-altered cancers. 2023. https://www.cancer.gov/news-events/cancer-currents-blog/2023/selpercatinib-ret-lung-medullary-thyroid?utm

12. Lilly. LIBRETTO-431 and LIBRETTO-531 phase III results. 2023. Lilly's Retevmo^® (selpercatinib) Phase 3 Results in RET Fusion-Positive Non-Small Cell Lung Cancer and RET-Mutant Medullary Thyroid Cancer Both Published in The New England Journal of Medicine and Presented in a Presidential Symposium at ESMO Congress 2023

CMAT- 27409  | Exp- 28 Apr 2028

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Tanstrive PI: https://image.mc.lilly.com/lib/fe9312747462077971/m/1/cde34d81-7770-45bc-8a34-09a983be3ce9.pdf

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