ROS1 targeted therapy drug resistance mechanism revealed; new targeted drugs have considerable efficacy in the treatment of indolent lymphoma | Cancer Information

*Only for medical professionals to read for reference, 1 minute a day, to give you professional "talking information" in the tumor circle! (If you need the original text of the literature, you can add the editor WeChat yxj_oncology to obtain) Key points: JCO: Nivolumab + Ipilimumab maintenance treatment of ED-SCLC, OS has not been significantly improved JCO: Umbralisib treatment of relapsed/refractory indolence Lymphoma with good curative effect and controllable safety.
CCR: Compared with other NSCLC, patients with EGFR ex20ins have a better prognosis for platinum-based chemotherapy.
CCR: ROS1 fusion patients undergo targeted therapy, and the main cause of resistance is ROS1 mutation 01JCO: Nano Wuliyuumab + ipilimumab maintenance treatment of ED-SCLC, OS has not been significantly improved A few days ago, Journal of Clinical Oncology (JCO) published a double-blind phase III study online, showing that nivolumab combined with ipilimumab The monoclonal antibody is used for the maintenance treatment of extensive-stage small cell lung cancer (ED-SCLC), and does not significantly prolong the overall survival (OS).

The screenshot of the article was released.
The study included 834 patients with ED-SCLC who did not progress after receiving ≤ 4 cycles of first-line chemotherapy.
They were randomly divided into 3 groups (1:1:1): (1) Nivolumab 1 mg/kg + Iraq Pimimumab 3 mg/kg, once every 3 weeks for 12 weeks, then nivolumab 240 mg once every 2 weeks; (2) nivolumab 240 mg, once every 2 weeks; (3) Placebo treatment.

The primary endpoint is OS.

The results showed that the minimum follow-up time was 8.
9 months.

Compared with placebo, the OS of nivolumab + ipilimumab did not significantly extend [hazard ratio (HR) 0.
92; 95% CI 0.
75-1.
12; P=0.
37; median value of 9.
2 vs 9.
6 months ].

Compared with placebo, the HR for OS in the nivolumab group was 0.
84 (95% CI 0.
69-1.
02), and the median OS was 10.
4 months. Compared with placebo, the median progression-free survival (PFS) HR of nivoliumab + ipilimumab was 0.
72 (95% CI 0.
60-0.
87), and that of the nivoliumab group was 0.
67 (95% CI 0.
60-0.
87).
%CI 0.
56-0.
81).

In patients with tumor mutation burden (TMB) ≥13 muts/mb, a trend of nivolumab+ipilimumab OS benefit was observed.

The incidence of grade 3-4 treatment-related adverse events in the nivolumumab+ipilimumab group, nivolumumab group, and placebo group were 52.
2%, 11.
5%, and 8.
4%, respectively.

The above results indicate that nivolumab combined with ipilimumab maintenance therapy did not significantly prolong the OS of ED-SCLC patients, but it may be worth exploring further research based on TMB screening in the future.

02JCO: Umbralisib in the treatment of relapsed/refractory indolent lymphoma with good efficacy and controllable safety.
Recently, JCO released an open-label, phase IIb study online, showing that PI3Kδ and CK1-ε inhibitor umbralisib are effective in indolent non-Hodgkin lymphoma.
In patients with tumor (iNHL), the curative effect is good and the safety is controllable.

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The study included 208 patients with relapsed or refractory marginal zone lymphoma (MZL), follicular lymphoma (FLSLL) or small lymphocytic lymphoma (SLL), and umbralisib (800 mg) was taken orally once a day until Disease progression, unacceptable toxicity, or withdrawal from the study.

The primary endpoint is the overall response rate (ORR), and the secondary endpoints include time to response (TTR), duration of response (DOR), PFS, and safety.

The results showed that the median follow-up time was 27.
7 months (effectiveness) and 21.
4 months (safety).

The ORR was 47.
1%, 86.
4% of patients had tumor remission, and the median TTR was 2.
7-4.
6 months.

MZL did not reach the median DOR, FL was 11.
1 months, and SLL was 18.
3 months.

MZL did not reach the median PFS, FL was 10.
6 months, and SLL was 20.
9 months. In 53.
4% ​​of patients, at least one adverse event (TEAE) ≥ grade 3 during treatment was reported, and 32 patients (15.
4%) discontinued the drug due to TEAE.

More than 10% of patients reported ≥ grade 3 TEAEs including neutropenia (11.
5%) and diarrhea (10.
1%), and 6.
7%/7.
2% of patients had an increase in ALT/AST (≥ grade 3).

The above results indicate that in iNHL patients, Umbralisib has a good curative effect and controllable safety, and the incidence of drug withdrawal due to immune-mediated toxicity and adverse events is relatively low.

03CCR: Compared with other NSCLC, patients with EGFR ex20ins have a better prognosis for platinum-based chemotherapy.
A few days ago, Clinical Cancer Research (CCR) published an online study showing that it is compared with patients with other gene mutation types of non-small cell lung cancer (NSCLC) , NSCLC patients with EGFR exon 20 insertion (ex20ins) have a better prognosis for platinum-based chemotherapy.

The screenshot of the article was released.
The study included 6290 NSCLC patients, of which 106 (2%) were EGFR ex20ins patients, and their clinical results and pathological characteristics were compared with other NSCLC patients.

The results showed that compared with other NSCLC patients, patients with EGFR ex20ins were more likely to be black (14% vs 6%, p<0.
001) or Asian (22% vs 10%, p<0.
001), with a median tumor mutation burden ( TMB) (3.
5 vs 5.
9 muts/mb, p<0.
001) and the proportion of tumors expressing PD-L1 (22% vs 60%, p<0.
001) was lower. Compared with patients with metastatic NSCLC without targeted genetic changes (n = 192), platinum-based chemotherapy for EGFR ex20ins patients had longer overall survival (OS) (median OS: 20 vs 12 months, HR 0.
56, p = 0.
007), and longer withdrawal time (TTD) (median TTD: 7 vs 4 months, HR 0.
6, p=0.
02); while immune checkpoint inhibitor (ICI) treatment of patients with TTD did not improve (HR 1.
75, p=0.
05).

The above results indicate that compared with NSCLC patients without targeted genetic changes, EGFR ex20ins NSCLC patients receive platinum-based chemotherapy have a better prognosis, and PD-L1 expression and TMB are reduced, and they are less benefited from ICI.

In addition, molecular targeted therapy can benefit patients with EGFR ex20ins more, and there are already a variety of new drugs targeted at this target are being developed.

04CCR: ROS1 fusion patients undergo targeted therapy, and the main reason for resistance is ROS1 mutation.
Recently, CCR published a study online showing that ROS1 mutation can mediate ROS1 fusion-positive NSCLC patients to develop resistance to crizotinib and loratinib treatment medicine.

The screenshot of the article was released.
A total of 55 patients with ROS1 fusion NSCLC who progressed after treatment were included in the study.
Among them, 47 were treated with crizotinib and 32 were treated with loratinib.
Biopsies of the patients were analyzed by gene sequencing to evaluate crizoline.
The resistance mechanism of tinib and loratinib.

The results showed that the mutation rates of ROS1 were 38% and 46%, respectively.
ROS1 G2032R was the most common, accounting for about one-third.

Other ROS1 mutations include: D2033N (2.
4%) and S1986F (2.
4%) after crizotinib treatment; L2086F (3.
6%), G2032R/L2086F (3.
6%), G2032R/S1986F/L2086F after loratinib treatment (3.
6%) and S1986F/L2000V (3.
6%). In the biopsy of patients with loratinib resistance, the researchers also found MET amplification (4%), KRAS G12C (4%), KRAS amplification (4%), NRAS mutation (4%), and MAP2K1 mutation ( 4%).

The above results indicate that in more than one-third of NSCLC patients, ROS1 mutations mediate resistance to crizotinib and loratinib, and it is necessary to develop potentials to resist these mutations (including G2032R and L2086F) The next generation of ROS1 inhibitors, and the resistance mechanism independent of ROS1 remains to be elucidated.

Reference: [1]Taofeek K.
Owonikoko, Keunchil Park, Ramaswamy Govindan, et al.
Nivolumab and Ipilimumab as Maintenance Therapy in Extensive-Disease Small-Cell Lung Cancer: CheckMate 451.
published on March 08, 2021.
DOI: 10.
1200/ JCO.
20.
02212 Journal of Clinical Oncology.
[2]Nathan H.
Fowler, Felipe Samaniego, Wojciech Jurczak, et al.
Umbralisib, a Dual PI3Kδ/CK1ε Inhibitor in Patients With Relapsed or Refractory Indolent Lymphoma.
published on March 08, 2021.
DOI : 10.
1200/JCO.
20.
03433 Journal of Clinical Oncology[3]Noura J.
Choudhury, Adam J Schoenfeld, Jessica Flynn, et al.
Response to standard therapies and comprehensive genomic analysis for patients with lung adenocarcinoma with EGFR exon 20 insertions.
published on March 08, 2021.
doi: 10.
1158/1078-0432.
CCR-20-4650[4]Jessica J.
Lin, Noura J.
Choudhury, Satoshi Yoda, et al.
Spectrum of Mechanisms of Resistance to Crizotinib and Lorlatinib in ROS1 Fusion-Positive Lung Cancer.
published on March 08, 2021.
doi: 10.
1158/1078-0432.
CCR-21-0032