The details of the Phase 3 study of K medicine + Lenva's failure are released!

Article source: Med

Author: Xixi

At present, for the first-line treatment of driver gene-negative advanced non-small cell lung cancer (NSCLC), immunotherapy represented by PD-(L)1 drugs has become the cornerstone of clinical treatment

Immune single drug, immune + chemotherapy, dual immunity ± chemotherapy, immune + anti-angiogenesis + chemotherapy.

Source: NextMed database research and analysis

In China, following O drugs and K drugs, carrelizumab, sintilizumab, tislelizumab, and atelizumab for NSCLC first-line indications have also been approved one after another, and immunotherapy has replaced them.

Source: Front Oncol.

A few days ago, the European Society of Medical Oncology (ESMO-IO) conference announced two first-line treatment studies for advanced NSCLC, and the results were mixed

The worry is that the K drug + lenvatinib (cola combination) and the K drug head failed the first phase III LAEP-007 study.

Fortunately, the exciting Phase 2 data of the Roche TIGHT+PD-L1 combination makes people look forward to the results of the Phase III study SKYSCRAPER-01

LEAP-007: Coke combination ushered in the first failure of Phase III study

In the past, in phase Ib/II, open-label, one-arm trials (study code 111/KEYNOTE-146, NCT02501096), drug K + lenvatinib showed encouraging results in patients with metastatic NSCLC (n=21) Anti-tumor activity (ORR 33%, median PFS 5.

The efficacy data of cola combination in different cohorts in the 111/KEYNOTE-146 study (Source: Future oncology)

Based on this, the researchers initiated a randomized, double-blind Phase III LEAP-007 study, aiming to further explore the first-line treatment of pembrolizumab ± lenvatinib in patients with PD-L1 positive (TPS≥1%) advanced NSCLC The clinical outcome

Source: ESMO-IO 2021, the same below

The study design is shown in the figure above.

The primary endpoints were progression-free survival (PFS) and overall survival (OS) assessed by the Independent Review Committee (BICR) according to RECIST v1.

It should be noted that the results announced this time are a pre-planned nonbinding futility analysis conducted by the Independent Data Monitoring Committee (DMC) in the fourth evaluation

Futility analysis corresponds to effectiveness analysis.

The results of this invalidity analysis show that the combination of pembro+lenva for mNSCLC with PD-L1TPS ≥1% is unlikely to achieve the expected effect

Let's take a closer look at the research results

At a median follow-up time of 15.

The median PFS of the combination treatment group and the control group were 6.
6 months and 4.
2 months, respectively.
On the basis of pembrolizumab combined with lenvatinib, the risk of disease progression or death was reduced by 22% (HR: 0.
78; 95% CI : 0.
64-0.
95; P=0.
00624)
.

Subgroup analysis showed that even in the population with PD-L1 TPS≥50%, the combination therapy group showed no benefit in PFS and OS
.
In addition, younger patient populations (<65), non-East Asian populations, and ECOG PS 0 patients seem to have a tendency to benefit from PFS in combination therapy, but this was not observed in the OS analysis
.
Compared with OS, histological classification has a greater impact on PFS, and smoking history has a smaller impact on PFS
.

Compared with the control group, the objective response rate (ORR) of the combination treatment group was higher (40.
5% vs 27.
7%).
At the cost of this, the proportion of grade 3-5 treatment-related adverse events (AE) was also higher (57.
9) % vs 24.
4%), the incidence of grade 5 treatment-related AEs in the two groups was 5.
2% and 1.
9%, respectively
.

The LEAP-007 study is the first failure of the cola combination in the confirmatory phase III study, and it is also a "high-profile but unsuccessful" clinical trial
.

In the expert discussion session of the ESMO-IO conference oral report, Professor HOSSEIN BORGHAEI from the Fox Chase Cancer Center in the United States said that it is too early to conclude that the first line of advanced NSCLC reaches the bottleneck stage, lenvatinib + pembrolizumab + chemotherapy The LEAP-006 study for the first-line treatment of advanced NSCLC is still underway, and we need to wait patiently for more data
.
It is hoped that the safety performance in the LEAP-006 study will not become a stumbling block, and it is also hoped that the therapeutic effect of the experimental group will be improved more significantly
.

On the other hand, Professor HOSSEIN BORGHAEI also pointedly pointed out that based on the anti-tumor activity (ORR 33%, median PFS 5.
9 months) demonstrated in the small sample size NSCLC cohort (n=21) in the phase Ib/II study, the phase III clinical trial was promoted.
, LEAP-007 research itself contains huge uncertainties
.

As the old saying goes, a well-designed combination therapy should be based on sufficient and solid Phase II data
.
In this regard, how many new immune combination therapies can stand the test of time? We will wait and see
.

CITISCAPE: Roche TIGHT+PD-L1 attracts attention

When LEAP-007 regretted its defeat, people turned their attention to the updated data of another exciting Phase II study, CITYSCAPE
.
The CITYSCAPE study mainly evaluated the difference in efficacy and safety of tiragolumab+atezizumab (TIGIT+PD-L1) compared with atezizumab in the first-line treatment of PD-L1-positive metastatic NSCLC
.

The results showed that after a median follow-up period of 2.
5 years, tiragolumab+atelizumab reduced the risk of disease progression or death in the intent-to-treat (ITT) population by 38%.
The median PFS in the two groups was 5.
6 vs 3.
9, respectively.
Month (HR=0.
62, 95% CI: 0.
42-0.
91)
.

Excitingly, the results of a scheduled exploratory analysis in a population with high PD-L1 expression showed that tiragolumab+atelizumab can reduce the risk of disease progression or death by 71%, compared with the control group (4.
1 months), The median PFS in the experimental group was 16.
6 months (HR=0.
29, 95% CI: 0.
15-0.
53)
.
You know, the control group is atelizumab monotherapy
.
This data is expected to give higher value in clinical screening of PD-L1 expression status
.

In terms of secondary endpoints, tiragolumab+atelizumab also improved the OS of the ITT population (23.
2 vs 14.
5 months, HR=0.
69, 95% CI: 0.
44-1.
07)
.

In a scheduled exploratory analysis of people with high PD-L1 expression, a clinically significant improvement was also observed in the OS of the tiragolumab+atelizumab group (immature vs 12.
8 months), which is expected to exceed 30.
3 months.
HR is as low as 0.
23
.
However, it should be noted that the OS of the atelizumab control group here is only 12.
8 months.
If the OS data of atelizumab in the PD-L1 high expression population in other studies is used as a historical control, it is not immune It is questionable whether the HR value as low as 0.
23 is trustworthy, and we look forward to more detailed data to be announced in the future
.

In terms of safety, tiragolumab+atilizumab is well tolerated, and the incidence of grade 3-4 treatment-related adverse events is similar to that of the control group (22.
4% vs 25%), and the most common (≥5%) infusion because of adverse side effects including, joint pain, dry skin, fatigue, rash
.
After a longer follow-up, no new safety incidents were found
.

On the whole, the latest data from the CITYSCAPE study supports the development of large-scale clinical trials in more tumor types and more populations
.
On January 5 this year, tiragolumab + atelizumab was certified as a breakthrough therapy by the FDA for the first-line treatment of metastatic NSCLC with PD-L1 positive and no EGFR or ALK gene mutations
.
Currently, Roche is conducting a confirmatory phase III SKYSCRAPER-01 study in this population
.

Judging from the ambition contained in the research code, CITYSCAPE is just an urban landscape, and SKYSCRAPER has risen to the height of a Ferris wheel
.
Looking forward to the "name" matching its "facts" and bringing new surprises to late NSCLC!

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