Heavy release of Professor Cheng Ying: Septinib Chinese data injects a "booster" into RET fusion-positive NSCLC patients

In recent years, a series of results based on the global phase I/II LIBRETTO-001 STUDY HAS BROUGHT HOPE
TO PATIENTS WITH RET FUSION.
Breakthrough therapy, accelerated approval, the world's first approval and other keywords have given cepitinib more therapeutic significance, and has been approved in many countries for the treatment of locally advanced or metastatic RET fusion-positive non-small cell lung cancer (NSCLC) and thyroid cancer, RET mutated medullary thyroid cancer (MTC).

In addition, based on its excellent performance in pan-tumor species, on September 21 this year, the FDA prioritized and accelerated the approval of ceplitinib as the first and only RET inhibitor, regardless of cancer species for adult patients with advanced or metastatic solid tumors with RET gene fusion [2]
。 In China, on September 30, cepitinib received accelerated approval from the National Medical Products Administration (NMPA) for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) who are transfection rearrangement (RET) gene fusion-positive, adults with advanced or metastatic RET mutant medullary thyroid cancer (MTC) requiring systemic therapy, and children aged 12 years and older, and adults
and children 12 years of age and older with advanced or metastatic RET fusion-positive thyroid cancer (TC) who require systemic therapy and are refractory to radioactive iodine (if radioiodine is appropriate).
It should be pointed out that cepitinib is currently the only RET inhibitor
approved for first-line treatment of lung cancer in China.

The three indications approved in China are mainly based on the data of the global study LIBRETTO-001 series and the Chinese population data
of the LIBRETTO-321 study.
The predecessor has the continuous iteration of a series of excellent research data of LIBRETTO-001, and then there are Professor Cheng Ying of Jilin Provincial Cancer Hospital, Professor Lu Shun of the Chest Hospital Affiliated to Shanghai Jiao Tong University, and Professor Gao Ming of Tianjin People's Hospital The co-led partial data of LIBRETTO-321 lung cancer specifically for Chinese groups was released, which further confirmed the consistency between the Chinese data and the global data, and the results fully demonstrated the good efficacy and safety of cepitinib in the Chinese RET fusion-positive NSCLC patient population, and injected a "booster"
into the treatment of Chinese RET fusion-positive NSCLC patients with ceptinib in China.

"Physician Daily" invited Professor Cheng Ying to walk into the LIBRETTO-321 study and the exploration of
the diagnosis and treatment of patients with non-small cell lung cancer RET fusion.

1

Hit the pain points and difficulties directly

Break the dilemma of RET fusion without precise targeted drugs

RET gene fusion is one of the important types of rare driver gene variants in NSCLC, although the incidence rate only accounts for about 1-2% of NSCLC patients [1], due to the large overall base of NSCLC patients, precision therapy for RET gene fusion NSCLC patients has great clinical needs and research value
。 Professor Cheng introduced that in clinical practice, chemotherapy and multi-target kinase inhibitors were the most commonly used therapeutic drugs for patients with RET gene fusion, but the median survival (mPFS) of first-line chemotherapy was 5.
2~9.
2 months, and the mPFS of second-line chemotherapy was only 2.
8~4.
9 months[3]; However, multi-target kinase inhibitors (such as cabozantinib, sunitinib, sorafenib, and vandetanib) have low targeting of RET, which not only has limited efficacy, but also leads to serious toxicity due to off-targeting; In addition, the benefits of immune checkpoint inhibitors in patients with RET modification are also unsatisfactory
.

Therefore, the lack of RET-specific targeted drugs has been a pain point and difficulty in the clinical treatment process, and it will not turn around
until 2020.
With the advent of the specific RET inhibitors ceptinib and platinib, it has brought a ray
of hope to patients with RET fusion NSCLC.
Seplitinib and platinib were successively approved by the FDA in 2020, completely breaking the dilemma
of RET fusion NSCLC without precision targeted drugs.

2

The world's first highly selective RET inhibitor approved

Four consecutive years of continuous data iteration

LIBRETTO-001 is the first clinical study
of a specific RET inhibitor to publish results.
At the 2018 ASCO Annual Meeting, preliminary safety and efficacy data
of a Phase 1 study of ceplinib in the treatment of RET genetically modified solid tumors were presented for the first time.
In the study, 38 patients with NSCLC have an objective response rate (ORR) of 77%, showing strong antitumor activity [4].

In September of the same year, it was granted breakthrough therapy designation by the FDA for the treatment of NSCLC and medullary thyroid cancer (MTC)
with RET gene mutations.

At the 2020 ASCO meeting, the study updated the results of 105 treated and 39 treatment-new-cure RET-fused NSCLC patients and published in the New England Journal of Medicine in August 2020, showing that 105 patients with RET confluent NSCLC who had previously received platinum-based chemotherapy had an ORR of 64%, mPFS of 16.
5 months, a median response rate (mDoR) of 17.
5 months, and an 81% proportion of patients with mDOR over 6 months.

。 The ORR of 39 treatment-naïve patients was 85 percent, and the proportion of patients with mDoR older than six months was 90 percent [5].

Based on the results of this study, the FDA accelerated its marketing approval on May 8, 2020 for the treatment of RET fusion-positive NSCLC and thyroid cancer, as well as RET mutant MTC, becoming the world's first approved highly selective RET inhibitor.

In September 2022, the Journal of Clinical Oncology again published updated data on a larger sample size of the study, with an ORR of 61 percent, mPFS of 24.
9 months, and mDoR of 28.
6 months in 247 platinum-treated patients, and an ORR of 84%, mPFS of 22.
0 months, and mDoR of 20.
2 months in 69 treatment-novice patients [6].

3

Data highlights

Sustained patient benefit and efficient brain metastasis control rates

In the LIBRETTO-001 trial, patients were allowed to continue seplitinib
after disease progression (PD) if the patient had sustained benefit as assessed by the investigator (INV) and approved by the sponsor 。 At this year's ESMO meeting, the LIBRETTO-001 study presented post-hoc exploratory analysis data on the safety and efficacy of continued use of cepitinib in NSCLC patients after PD, showing that of the 169 RET-fused NSCLC patients assessed as progressive in INV, 120 (71%) continued to use ceplinib after PD (including 86 platinum treatment and 22 initial treatment).

The median duration of treatment before and after PD was 10.
9 months and 5.
0 months
, respectively.
At 6 and 9 months after PD, 45% and 34.
3% of patients were still treated; Of the 120 post-PD patients, 40 (33 percent) received topical therapy, of which 36 received radiation therapy (12 received radiation to the brain) [7].

The median time of treatment for these 40 patients after PD was 5.
4 months, and the safety profile was basically the same as that of the
general population.
This updated data suggests that patients with RET fused NSCLC appear to derive sustained clinical benefit
from continued treatment with cepitinib after PD.
Professor Cheng Ying said that although it is only an exploratory post-hoc analysis, it has certain reference significance for clinicians to make treatment decisions, and further data analysis is still needed in the future to provide more evidence-based medical basis
for clinical choices.

In addition, ceplitinib showed good blood-brain barrier penetration in preclinical models, and in the published LIBRETTO-001 study brain metastases population data, 80 patients had brain metastases at baseline, of which 56% received ≥ 1 course of intracranial radiation therapy (14% whole brain radiation therapy, 45% stereotactic radiation therapy).

Among the 22 patients with measurable intracranial lesions at baseline, intracranial ORR was 82%, 23% achieved CR, 59% obtained PR, and 18% had SD.

Among them, patients who had not previously received central nervous system radiotherapy (n=14) had an ORR of 86%, 29% achieved CR, 57% had PR, and 14% had SD; Patients who had received CNS radiotherapy had an ORR of 75%, CR of 13%, PR of 63%, and SD of 25%.

The median intracranial PFS for all 80 patients was 13.
7 months [8].

LATEST DATA FROM LIBRETTO-001 SHOWED THAT OF THE 106 PATIENTS WITH BRAIN METASTASES AT BASELINE, THE MEDIAN FOLLOW-UP WAS 22.
1 MONTHS AND THE MEDIAN INTRACRANIAL PFS WAS 19.
4 MONTHS
.
In patients with measurable intracranial lesions at baseline (n = 26), the intracranial ORR was 85% and CR was 27%.

Objective responses
were observed regardless of whether patients had previously received systemic therapy or radiation therapy.
In addition, among 22 responders with measurable CNS metastasis, the median DOR was 9.
4 months [6].

In the LIBRETTO-321 study, five patients with measurable brain metastases at baseline, four achieved CR or PR, demonstrating efficient cepitinib control [8].

The above research data suggest that cepitinib can be used as a new choice for the treatment of patients with RET fusion-positive NSCLC brain metastases, and also increase confidence in the clinical treatment of patients with brain metastases, and it is expected that cepitinib will be included in the medical insurance directory as soon as possible, so as to increase the drug accessibility of RET fusion-positive patients in China and benefit more patients
.

4

China's data is highly consistent with global data

The LIBRETTO-321 study is an open-label, multicenter phase 2 study in patients with advanced RET mutant solid tumors in China, enrolling a total of 77 patients, of which 47 were RET fusion NSCLC, and Jilin Provincial Cancer Hospital successfully enrolled the first patient
as CO-PI in March 2020.
Professor Ying Cheng was pleased to point out that the results of the study showed that the data of the Chinese cohort were similar to the global data, and 26 patients with NSCLC in cohort 1 were confirmed positive for RET fusion by the central laboratory and included in the main analysis set (PAS).

。 The results of the study showed that the ORR assessed by IRC at a median follow-up of 9.
7 months was 69.
2%, of which the ORR of novice and treated patients was 87.
5% and 61.
1%, respectively, the median DoR was not achieved, 94.
4% of patients were still in continuous remission, and the median PFS and OS were not achieved.
The ORR for all NSCLC patients (n=47) was 66.
0%, and the ORR for naïve and treated patients was 90.
9% and 58.
3%, respectively; Common AEs associated with ≥ grade 3 therapy are hypertension, elevated AST, and elevated ALT [8].

Prof.
Ying Cheng concluded: Overall, ceplinib has excellent anti-tumor activity and is well tolerated in Chinese patients with advanced RET fusion-positive NSCLC, which is consistent
with the previously reported results of LIBRETTO-001 。 Based on the excellent performance of cepitinib in the global LIBRETTO-001 study and the Chinese LIBRETTO-321 study, it was approved by the NMPA on September 30, 2022 for the treatment of locally advanced or metastatic NSCLC patients with RET gene fusion, which is the first highly selective RET inhibitor in China to obtain first-line NSCLC indications, which will further increase the clinical accessibility of RET inhibitors in China.
It also brings more treatment options to clinicians and patients when making treatment decisions, and will also bring more survival benefits
to Chinese patients.

In the process of clinical practical application, accurately screening out NSCLC patients with RET fusion is an important prerequisite for precision treatment, because RET inhibitors have just been listed in China, and the start of RET testing is late, there are problems such as lack of unified normative standards, testing items are not included in medical insurance, clinicians lack detection awareness, and many medical institutions cannot carry out independently due to lack of instruments and equipment and technicians.
In addition, because drugs are expensive and not included in the medical insurance list, their popularity in clinical application is limited to a certain extent, and more RET inhibitors need to be promoted into the clinic
.
In addition to drug accessibility, the resistance of RET inhibitors is also a difficult problem that currently plagues clinical practice, and common drug resistance mechanisms include RET G810 mutation, MET amplification, KRAS amplification, etc.
, and there is still a lack of effective countermeasures
to overcome drug resistance.

References

[1] Sung H, Ferlay J, Siegel R L, et al.
Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries[J].
CA Cancer J Clin, 2021,71(3):209-249.

[2] FDA approves selpercatinib for locally advanced or metastatic RET fusion-positive solid tumors.
News release.
FDA.
September 21, 2022.
Accessed September 21, 2022.
https://bit.
ly/3f8Wzr7

[3] Cascetta P, Sforza V, Manzo A, et al.
RET Inhibitors in Non-Small-Cell Lung Cancer.
Cancers (Basel).
2021; 13(17):4415

[4] Drilon A et al.
, Durability of efficacy and safety with selpercatinib in patients with RET fusion+ non-small-cell lung cancer: LIBRETTO-001.
ELCC 2022, abstract 27P

[5] Corrao G, et al.
Lung Cancer.
2020 Apr; 142:70-79.
2.
Yu J, et al.
Nat Med.
2021 Jan; 27(1):152-164.

[6] Bronte G, Ulivi P, Verlicchi A, et al.
Targeting RET-rearranged non-small-cell lung cancer: future prospects[J].
Lung Cancer: Targets and Therapy, 2019,10.

[7] Gainor J F, Curigliano G, Kim D W, et al.
Pralsetinib for RET fusion-positive non-small-cell lung cancer (ARROW): a multi-cohort, open-label, phase 1/2 study[J].
Lancet Oncol, 2021,22(7):959-969.

[8] Drilon A, Subbiah V, Gautschi O, et al.
27P Durability of efficacy and safety with selpercatinib in patients (pts) with RET fusion+ non-small cell lung cancer (NSCLC)[J].
Annals of Oncology, 2022,33:S43.

[9]] Lilly Presents Updated Data on Retevmo® (selpercatinib) in Advanced RET Fusion-Positive Non-Small-Cell Lung Cancer (NSCLC) at the 2022 European Lung Cancer Congress | Eli Lilly and Company

Typesetting: Qin Miao

Editor: Wang Lina

Reviewed: Song Zhen

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