TKI Retreatment

Treatment with tyrosine kinease inhibitors (or other targeted drugs) can be beneficial even after a patient has progressed on this treatment earlier. After a break from this treatment (usually on chemotherapy) tumors can resensitize to the drug and TKI inhibitors can show beneficial effect when used again. This way a patient can get tumor control and some more time on the same drug or a different TKI inhibitor.  

The effect here can be explained by the evolution and clonal competition in the tumor. Progression on EGFR inhibitors is caused by clones of cells that are resistant to the treatment. When EGFR inhibition is stopped, then the original EGFR sensitive clones can prevail again and the tumor (as a whole) becomes more sensitive to EGFR treatment again. Stopping the TKI or using other therapies can change the share of those TKI sensititive and insensitive clones and sensitize the tumor.                The longer the break from a TKI, the higher the chance for success of rechallenge.                                                                          In some countries, after a patient has progressed on 1st line TKI, the only option that is offered to them is chemotherapy (especially when they are T790M negative). Getting back on TKI treatment can help them get more time on the same or other TKI inhibitor.

However, this should also come with a warning: With stopping a TKI there is risk of fast progression in a certain number of patients (20% ). This effect of fast progression after stopping TKI inhibition is called "flare". It is described in studies that can be googled up:                                                                                                                    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3756539/         Disease flare after tyrosine kinase inhibitor discontinuation in patients with EGFR-mutant lung cancer and acquired resistance to erlotinib or gefitinib - implications for clinical trial design.  The study suggests that the flare can happen quite quickly (median time to disease flare was 8 days). Therefore when TKI inhibition is stopped the tumor should be watched closely. (markers, CT scan soon ...).                                                              Fast progression was also the case for my mother when she stopped 1st line Afatinib and was just on pemetrexed monotherapy. After stopping TKI inhibition a stronger chemotherapy combination should be used or chemotherapy+imunotherapy combination.

The following studies analyze records of patients who underwent TKI retreatment. Disease control rate in the studies is quite high (60-85%) . Since these are retrospective studies only with patients for whom the retreatment was probably a suitable option, in random studies of all patients who progressed on a previous TKI the success rates would be somewhat lower.

Re-administration of osimertinib in osimertinib-acquired resistant non-small-cell lung cancer  https://www.sciencedirect.com/science/article/abs/pii/S016950021930337X     We reviewed the medical records of consecutive patients with advanced NSCLC harboring EGFR-activating mutations and secondary T790M, who had undergone osimertinib re-administration to treat acquired resistance. Seventeen patients were re-administered osimertinib after acquiring resistance to osimertinib. The objective response and disease control rates were 33% and 73%, respectively. The median progression-free survival (PFS) time of all 17 patients was 4.1 months

P2.14-11 Retreatment with EGFR-TKI for 541 NSCLC Patients with EGFR Mutation                                      https://www.jto.org/article/S1556-0864(19)32479-7/fulltext                                                                                                        Conclusion:     Retreatment with EGFR-TKI was shown to be effective for both patients who discontinued prior EGFR-TKI because of disease progression as well as adverse events.

https://www.practiceupdate.com/content/predictive-factors-for-egfr-tki-retreatment-in-patients-with-egfr-mutated-non-small-cell-lung-cancer/47615/7/1/1        Retreatment with EGFR-TKI led to 7.3% PR and 37.1% SD. Following retreatment, the PFS was 4.1 months and the OS was 12.8 months. Outcomes were significantly improved by a treatment break of more than 7 months (HR, 0.62) and by mutations in exon 21 of female patients (HR, 0.51).

https://pubmed.ncbi.nlm.nih.gov/21784628/   Retreatment with erlotinib: Regain of TKI sensitivity following a drug holiday for patients with NSCLC who initially responded to EGFR-TKI treatment

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4296083/    Effect of EGFR-TKI retreatment following chemotherapy for advanced non-small cell lung cancer patients who underwent EGFR-TKI                                                                                             Of the 27 patients who received EGFR-TKI retreatment, 1 (3.7%) patient was observed in complete response (CR), 8 (29.6%) patients in partial response (PR), 14 (51.9%) patients in stable disease (SD), and 4 (14.8%) patients in progressive disease (PD). The disease control rate (DCR) was 85.2% (95% CI: 62%-94%). The median progression-free survival (mPFS) was 6 months (95% CI: 1-29). Of the 13 patients who received the same EGFR-TKI, 1 patient in CR, 3 patients in PR, 8 patients in SD, and 2 patients in PD were observed. The DCR was 84.6%, and the mPFS was 5 months. Of the 14 patients who received another EGFR-TKI, no patient in CR, 6 patients in PR, 6 patients in SD, and 2 patients in PD were observed. The DCR was 85.7%, and the mPFS was 9.5 months.

Studies providing theoretical background :

Tracking and tackling the tumor dynamics clonal evolution: osimertinib rechallenge after interval therapy might be an effective treatment approach in epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC)               https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9096286/                                                                                                                  Study says that in theory, re-administration of osimertinib could be reasonable: while cytotoxic chemotherapy eradicates the cancer clones, responsible for resistance to the EGFR-TKI, new clones that may still be sensitive to the same target therapy could arise

Tumor clonality and resistance mechanisms in EGFR mutation-positive non-small-cell lung cancer: implications for therapeutic sequencing          https://www.futuremedicine.com/doi/full/10.2217/fon-2018-0736

Case reports:

Retreatment with Erlotinib of a Patient with Metastatic NSCLC Harboring EGFR Mutation: A Case Report    https://journals.sagepub.com/doi/abs/10.1700/1578.17234

Hu XY, Fei YC, Zhou WC, Zhu JM, Lv DL. Triple administration of osimertinib followed by chemotherapy for advanced lung adenocarcinoma: A case report. World J Clin Cases 2021; 9(11): 2627-2633 [PMID: 33889629 DOI: 10.12998/wjcc.v9.i11.2627]  https://www.wjgnet.com/2307-8960/full/v9/i11/2627.htm?fbclid=IwAR3SAGGuMqellmdagh9yVQNx6QyGfC2v_trRNFmTsfxNwYyg4RmE7JKPGEw

Effective tyrosine kinase inhibitor re-treatment in epidermal growth factor receptor-mutated non-small-cell lung cancer patient: a case report   https://pcm.amegroups.com/article/view/5926/html