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| LETTER TO EDITOR |
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| Year : 2022 | Volume
: 5
| Issue : 1 | Page : 175-176 |
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Are we there RET?
Ashutosh Jaiswal, Raajit Chanana
Department of Medical Oncology, Dharamshila Narayana Superspecialty Hospital, New Delhi, India
| Date of Submission | 17-Jan-2022 |
| Date of Decision | 26-Jan-2022 |
| Date of Acceptance | 26-Jan-2022 |
| Date of Web Publication | 31-Mar-2022 |
Correspondence Address:
Raajit Chanana
(DM Medical Oncology) Consultant, Department of Medical Oncology, Dharamshila Narayana Superspeciality Hospital Vasundhara Enclave, New Delhi
India
 Source of Support: None, Conflict of Interest: None
DOI: 10.4103/crst.crst_28_22
How to cite this article:
Jaiswal A, Chanana R. Are we there RET?. Cancer Res Stat Treat 2022;5:175-6 |
Rearranged during transfection (RET) is a proto-oncogene found to be rearranged in 1%–2% of patients with non-small-cell lung cancer (NSCLC). RET fusion is most commonly seen in younger, female, non- or light-smoker patients with adenocarcinoma histology.[1],[2] In the previous issue of the journal, Nathany et al. have comprehensively discussed the basic biology of RET, its role in tumorigenesis, and the clinical significance of RET mutation in the treatment of NSCLC, including the relevant trials.[3]
Many fusion partners have been described in the literature for RET, of which KIF5B and CCDC6 are the most common. RET alteration can be detected by fluorescence in situ hybridization (FISH) and reverse transcriptase polymerase chain reaction. However, these techniques are unable to detect de novo or new mutations in RET. This lacuna can be overcome by the use of next-generation sequencing which, although less sensitive than FISH, is more specific. RET rearranged NSCLC is likely to show a good response to pemetrexed and platinum-based chemotherapy and is less likely to respond to immunotherapy. RET alteration is a well-recognized mechanism of EGFR resistance, and it is imperative to test for RET in patients progressing on EGFR TKIs. Multi-kinase inhibitors such as vandetanib, cabozantinib, and lenvatinib have shown objective response rates (ORRs) ranging from 16% to 47% in various trials.[4] However, limited RET selectivity and off-target kinase inhibition lead to poor tolerability and adverse events. Recent approval of two highly selective RET inhibitors, i.e., selpercatinib and pralsetinib, on the basis of the phase 1/2 data from the LIBRETTO-001 and ARROW trials, respectively, have expanded the treatment options in RET-rearranged NSCLC. The ORR of selpercatinib was 64% including an intracranial response of 91% in the LIBRETTO-001 trial. Pralsetinib showed an ORR of 61%, irrespective of CNS involvement in the ARROW trial.[5] Both these trials enrolled heavily pre-treated patients, and the optimal sequencing of these agents in RET-altered NSCLC is still not clear.
These data are very promising, however, many questions remain unanswered. Since the survival data of both the drugs are still not mature, it is as yet unknown which of the two, selpercatinib or pralsetinib, results in better survival. Apart from this, the question of whether to use these agents alone or in combination with chemotherapy also remains to be ascertained. I request the authors to comment on this. Few of these questions will be answered after the completion of the ongoing Phase III trials, LIBRETTO-431 for selpercatinib and AcceleRET Lung study for pralsetinib. Another issue with the use of these drugs is the emergence of resistance after their use. A recent study found MET amplification, KRAS amplification, and solvent-front G810C/S mutations in patients treated with selpercatinib and pralsetinib as possible mechanisms of acquired resistance.[6]
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
| References | |  |
| 1. | Drusbosky LM, Rodriguez E, Dawar R, Ikpeazu CV. Therapeutic strategies in RET gene rearranged non-small cell lung cancer. J Hematol Oncol 2021;14:50.  |
| 2. | Batra U, Sharma M, Nathany S, Soni S, Bansal A, Jain P, et al. Biomarker testing in non-small cell lung carcinoma – More is better: A case series. Cancer Res Stat Treat 2020;3:742-7. [Full text] |
| 3. | Nathany S, Diwan H, Batra U. RET in non-small cell lung carcinoma: A narrative review. Cancer Res Stat Treat 2021;4:702-8. [Full text] |
| 4. | Cascetta P, Sforza V, Manzo A, Carillio G, Palumbo G, Esposito G, et al. RET inhibitors in non-small-cell lung cancer. Cancers (Basel) 2021;13:4415. |
| 5. | Fancelli S, Caliman E, Mazzoni F, Brugia M, Castiglione F, Voltolini L, et al. Chasing the target: New phenomena of resistance to novel selective RET inhibitors in lung cancer. Updated evidence and future perspectives. Cancers (Basel) 2021;13:1091. |
| 6. | Lin JJ, Liu SV, McCoach CE, Zhu VW, Tan AC, Yoda S, et al. Mechanisms of resistance to selective RET tyrosine kinase inhibitors in RET fusion-positive non-small-cell lung cancer. Ann Oncol 2020;31:1725-33. |
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