"The Lancet-Oncology": What about PD-(L)1 resistance in NSCLC patients?

▎WuXi AppTec Content Team Editor Lung cancer is one of the malignant tumors with high morbidity and mortality in China and the world.
Among them, non-small cell lung cancer (NSCLC) is the most common type, and most patients are diagnosed in the middle and advanced stages
.

 In recent years, with the breakthrough progress of immune checkpoint inhibitors (ICIs) such as PD-1/PD-L1 inhibitors and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) inhibitors, tumor immunotherapy has opened a milestone.
development
.

Previous studies have confirmed that the combination of PD(L)-1 inhibitors and CTLA-4 inhibitors shows synergy and has been used for first-line treatment of metastatic non-small cell lung cancer (NSCLC)
.

However, NSCLC patients resistant to PD(L)-1 immunotherapy have a poor prognosis
.

 Radiotherapy is one of the main treatment methods, and it has also been confirmed that it can play an important role in the regulation of anti-tumor immunity and enhance the anti-tumor effect
.

So, what are the potential clinical benefits of combined use of PD(L)-1 inhibitors and CTLA-4 inhibitors, or immunocombination therapy further combined with radiotherapy? A study led by researchers at Dana-Farber Cancer Center was published today in The Lancet Oncology
.

The study was designed to evaluate the effect of a combination of PD-L1 inhibitor (durvalumab) and CTLA-4 inhibitor (tremelimumab) alone or in combination with radiotherapy
.

The results showed that: 1) in patients resistant to a single immunotherapy drug, the combination of the two drugs inhibited tumor growth in some NSCLC patients; 2) the addition of radiotherapy to the two-drug regimen did not improve outcomes
.

Screenshot source: The Lancet Oncology This open-label, multicenter, randomized Phase 2 trial was conducted at 18 clinical centers in the United States
.

The primary endpoint of the study was overall response rate (ORR, the proportion of patients achieving partial or complete response after best local assessment), and a safety analysis was performed in patients who had received at least one dose of treatment
.

 Eligible patients were: age ≥18 years; diagnosed with metastatic NSCLC; Eastern Cooperative Oncology Group (ECOG) performance status (PS) score of 0 or 1; disease progression during prior PD(L)-1 therapy
.

 Between August 24, 2017, and March 29, 2019, a total of 90 patients were enrolled and randomly assigned in a 1:1:1 ratio to receive durvalumab (1500 mg IV every 4 weeks for up to 13 cycles) ) plus tremelimumab (75 mg IV every 4 weeks for up to 4 cycles); or the immune combination in combination with low-dose fractionated RT (0.
5 Gy twice daily, repeated 2 days each for the first 4 cycles); or The immune combination was combined with hypofractionated radiotherapy (24 Gy total, delivered in 3 fractions, delivered in the first cycle only, 8 Gy each)
.

Radiotherapy was performed 1 week after the first durvalumab + tremelimumab
.

Of these, 78 patients (26 in each group) actually received treatment
.

Treatment continued for 1 year or until disease progression
.

 At the time of the final analysis on April 12, 2021, at a median follow-up of 12.
4 months (IQR 7.
8–15.
1), durvalumab-tremelimumab alone (3 of 26 patients [11.
5%, 90% CI 1] .
2-21.
8]) versus the low-dose RT group (2 of 26 patients [7.
7%, 0.
0-16.
3]; p=0.
64) and the hypofractionated RT group (3 of 26 patients [11.
5%, 1.
2] –21.
8]; p=0.
99), the overall response rate was not statistically different
.

The disease control rate (DCR) was 30.
8% in the durvalumab-tremelimumab arm, 23.
1% in the low-dose radiotherapy arm, and 34.
6% in the hypofractionated radiotherapy arm
.

 In terms of safety, treatment-related adverse events occurred in 59 of 78 patients (76%), including 19 (73%) in the durvalumab-tremelimumab monotherapy group; the low-dose radiotherapy group and the hypofractionated radiotherapy group Each had 20 cases (77%)
.

Serious treatment-related adverse events occurred in 1 patient (4%) in the durvalumab-tremelimumab alone group (maculopapular rash) and in 5 (19%) patients in the low-dose RT group (abdominal pain, diarrhea, dyspnea, hypokalemia and respiratory failure) and 4 (15%) patients in the hypofractionated radiotherapy group (adrenal insufficiency, colitis, diarrhea, and hyponatremia)
.

In the low-dose radiotherapy group, one death from respiratory failure may have been related to study treatment
.

 Studies have shown that in patients with NSCLC resistant to PD(L)-1 therapy, further combined radiotherapy did not increase the patient's response to PD-L1 combined with CTLA-4 inhibitors
.

However, PD-L1 inhibitors plus CTLA-4 inhibitors may be a treatment option for some patients
.

Future studies should refine predictive biomarkers
.

 Image credit: 123RF Researchers also analyzed tumor tissue samples from patients
.

They found that those patients with a large number of immune system T cells in their tumors were more likely to respond to treatment than those with fewer T cells in their tumor tissue
.

 The study's lead author, Dr.
Jonathan Schoenfeld of Dana-Farber Cancer Center, "should further explore the clinical benefit of the durvalumab/tremelimumab dual regimen in patients with NSCLC who have progressed on prior PD(L)-1 therapy
.

" He further "In future trials of these and similar drugs, analysis of T-cell infiltration in tumor tissue may identify which patients may benefit from this treatment
.

"Related reading Five types of strategies, ten blockbuster studies! Yale Cancer Center: Driver gene-negative NSCLC, how to choose first-line immunotherapy? Yale Cancer Center team: These strategies are expected to cure non-small cell lung cancer in the next ten years, led by Wu Yilong and Zhou Caicun! Benefiting Chinese patients with non-small cell lung cancer, two new immunotherapy drugs published in "The Lancet-Oncology"! JAMA Sub-Journal: Whether metformin can "assist" lung cancer treatment, the key may be this indicator! Immunotherapy prolongs "cancer-free survival" , Breakthrough in adjuvant therapy for non-small cell lung cancer! The Lancet published a landmark study reference [1] Jonathan D Schoenfeld et al.
, (2022).
Durvalumab plus tremelimumab alone or in combination with low-dose orhypofractionated radiotherapy in metastatic non- small-cell lung cancer refractory to previous PD(L)-1 therapy: an open-label, multicentre, randomised, phase 2 trial, The Lancet Oncology.
DOI: 10.
1016/S1470-2045(21)00658-6[2] Immunotherapycombination may benefit patients with non-small cell lung cancer resistant tosingle immunotherapy.
Retrieved JANUARY 17, 2022 from https://medicalxpress.
com/news/2022-01-immunotherapy-combination-benefit-patients-non-small.
htmlDisclaimer: Medication The content team of Mingkant focuses on introducing the progress of global biomedical health research
.

This article is for information exchange purposes only, and the views expressed in this article do not represent WuXi AppTec's position, nor do they represent WuXi AppTec's support or opposition to the views expressed in this article
.

This article is also not a treatment plan recommendation
.

For guidance on treatment options, please visit a regular hospital
.