Summary: An exploration of immunotherapy strategies for stage III non-small cell lung cancer

Stage III non-small cell lung cancer (NSCLC) accounts for about one-third
of newly diagnosed NSCLC cases.
Stage III NSCLC is a heterogeneous group of diseases that must be managed
by an experienced multidisciplinary team.
According to the CheckMate-816 findings, chemotherapy + immunity is currently the neoadjuvant therapy
of choice for patients with resectable stage III-N2 NSCLC if the drug is available.

Most patients with stage III are "unresectable.
"
In the case of good physical status (PS), the standard regimen for these patients is concurrent chemoradiotherapy (CCRT) sequential 1-year vallimumab consolidation therapy
.
In the PACIFIC trial, post-CCRT sequentical valizumab consolidation therapy significantly improved median overall survival (OS) (47.
5 months vs 29.
1 months, HR=0.
68).

Retrospective studies have shown that only half of patients with stage III NSCLC receive chemoradiotherapy in clinical practice, while about two-thirds of these patients receive CCRT and about one-third receive sequential chemoradiotherapy (SCRT
).
In addition, due to PS status, disease progression, PD-L1 levels < 1%, etc.
, not all patients receiving CCRT are suitable for treatment with dullizumab
.
For patients who are not suitable for dullizumab consolidation therapy, there is an urgent need for a new treatment regimen
.

Studies suggest that about 20% of patients may not require additional treatment after CCRT, identifying unnecessary toxicity and medical costs ^[1].

Duvalizumab consolidation therapy

In the phase III PACIFIC trial, 709 patients were randomly assigned (2:1) to the dullizumab and placebo groups after completing treatment with CCRT (≥ 2 cycles of platinum-containing chemotherapy and 54-66 Gy radiotherapy
).
Sequentivolulizumab provided patients with long-term survival benefits, with 5-year OS and progression-free survival (PFS) rates of 42.
9% (33.
4% in placebo groups) and 33.
1% (19.
0% in placebo)
respectively.
The survival benefit was independent of PD-L1 expression levels (PD-L1 expression < 25% vs ≥25%)
.
The safety was good, with a total cause ≥ grade 3 adverse event (AE) incidence rate of 30% and 26%
in the dovalizumab and placebo groups, respectively.

The results of the PACIFIC study (n=1399) are further confirmed by the international, retrospective PACIFIC-R study that included patients receiving at least one cycle of valliumab and, in some countries, patients treated with SCRT were also allowed to enroll
.
The median PFS in the total population was 21.
7 months, and the median PFS for patients treated with CCRT (77%) and SCRT (14%) was 23.
7 months and 19.
4 months
, respectively.
The survival curve of the PACIFIC-R study is similar to that of PACIFIC, showing similar plateau periods and long-term benefits
.

A new immunotherapy strategy for unresectable stage III NSCLC

Studies are currently evaluating the efficacy and benefits of new strategies: PD-(L)1 monoclonal antibodies with different sequences of CCRT, consolidation immunotherapy after SCRT, induction immunotherapy prior to CCRT, immunotherapy
in conjunction with CCRT or SCRT.

In this case, the design of crossover trials is challenging: the timing of initiation of immunotherapy is different—before or after CCRT—and the different starting points
for evaluating PFS and OS consequently.
Figure 1 Calculation of PFS for different treatment strategies is differentTable1
Randomized controlled studies with completed or preliminary data in unresectable stage III NSCLC (from the references, not the latest data) Table 2 Ongoing Phase II/III studies in unresectable stage III NSCLC

Consolidation immunotherapy after synchronous or sequential CRT

The immunomonotherapy monotherapy

single-arm Phase II LUN14-179 trial (n=93) evaluated the results of 1-year treatment with pabolizumab in patients with unresectable NSCLC sequentially, and the study reached the primary endpoints: 30.
7 months to metastatic disease or death, median PFS to 18.
7 months, and median OS to 35.
8 months
.
Survival rates are estimated at 81.
2%, 62.
0% and 48.
5% at 1, 2 and 3 years
, respectively.

In a phase III GEMSTONE-301 (n=381) randomized controlled trial, patients who received CCRT or SCRT without progression were randomly assigned (2:1) to the shuglimab group or placebo group (treatment duration up to 2 years).

The latest data released by WCLC this year[2] shows that as of March 1, 2022, the median follow-up time was 27.
1 months and 23.
5 months in the Shugli and comfort groups, respectively, and the median PFS assessed by BICR was 10.
5 months and ^6.
2 months (HR = 0.
65).

The median PFS was 8.
1 months vs 4.
1 months (HR=0.
57) in the SCRT subgroup and 15.
7 vs 8.
3 months (HR=0.
71)
in the CCRT subgroup, respectively.
The median OS of shuglimab was not achieved compared to 25.
9 months (HR=0.
69) in the placebo group, the median OS in the SCRT subgroup was not achieved and 24.
1 months (HR=0.
60), respectively, and the median OS in the cCRT subgroup was not achieved and 32.
4 months (HR = 0.
75),
respectively.


The single-armed, phase II, open-label PACIFIC-6 trial enrolled 120 ECOG PS≤2 patients who received dravarizumab (2 years) if they did not progress after SCRT therapy, with the primary endpoint being safety
.
Grade 3 or higher adverse events (AEs) occurred in 18.
8% of patients, and 10% discontinued treatment
due to pneumonia.
The median PFS and median OS were 10.
9 months and 25 months,
respectively.
Reasons for giving SCRT instead of CCRT include PS, radiation, complications, etc
.
It is important to note that only 2.
6% of patients have a PS of 2
.
Usually, patients with a PS of 0/1 are in good physical condition and can receive CCRT
.

The combination of immunotherapy
monoclonal antibodies and complementary mechanisms of action is one of the strategies for expanding the immunological benefit population and overcoming immune resistance (Figure 2).

As is more common in advanced patients, another potential advantage of dual immune checkpoint inhibitors is a longer response to
treatment.

Fig.
2 The mechanism of action of the combination immune strategy is open-label, and the randomized stage II BTCRC-LUN16-081 study (n=105) is exploring the efficacy
of
the CCRT sequential 6-month navulliumab + ipimumumab versus navulimumab alone.
The primary endpoint was 18 months of PFS, and the median PFS of the two groups was about 25 months, and the combination therapy did not appear to be an advantage
.

The CheckMate-73L study, a phase III randomized controlled study in which 888 patients (1:1:1) were randomly assigned to receive navurizumab + CCRT sequential navuliumab + ipimumab (group A), navurizumab + CCRT sequentia nuliumab (group B) and CCRT sequential valliumab (group C).

The main endpoints were PFS and OS (Group A vs Group C
).

The extracellular adenosine (eADO) signaling pathway in the tumor microenvironment strongly inhibits congenital and adaptive immune cells, facilitating tumor escape
.
CD73 converts extracellular adenosine monophosphate to eADO, a key enzyme in adenosine production, and is an attractive therapeutic target
.
Oleclumab is an anti-CD73 monoclonal antibody that promotes anti-tumor immunity
by lowering adenosine levels.
NKG2A is an inhibitory receptor
expressed on natural killing (NK) and T cells.
Its ligand, the non-classical major histocompatibility complex (MHC) class I molecule HLA-E, is also overexpressed on tumor cells and helps immune escape
.
Monalizumab is an antibody
that targets NKG2A receptors.

The COAST study was a three-armed, randomized (1:1:1) Phase II trial (n=189) designed to explore the efficacy
of patients without progression after CCRT receiving dulvalizumab + oleclumab (group A) or dulvarizumab + monalizumab (group B) or dulvalizumab alone (group C) after CCRT.
The primary endpoint was the overall response rate (ORR
).
The results showed that the ORR of group A and group B was 30.
0%, 35.
5% and 17.
9%,
respectively.
More studies are detailed in Table 2
.

CRT in combination with immunotherapy

The combination of the first three regimens (including immunotherapy) strategy makes sense for all patients who are eligible for CCRT, as disease progression can occur during CCRT in about 5% of patients, and up to 30% of patients are reported to have progression
at the first restage after receiving CCRT.


This combination strategy was first evaluated in the single-arm, phase II NICOLAS trial: 79 patients received three cycles of platinum-containing chemotherapy, simultaneous radiotherapy, navulluzumab starting from the second cycle of chemotherapy, and sequential navulyumab consolidation for 1 year
.
The primary endpoint was safety, defined as 33%
< incidence of pneumonia at 6 months after radiotherapy.
Overall, 11.
7% of patients develop grade 3 and above pneumonia
.
The 1-year PFS was 53.
7%, the median PFS was 12.
7 months, the median OS was 38.
8 months, and the 1-year and 2-year OS rates were 75.
7% and 63.
7%,
respectively.

The single-arm, Phase II DETERRED trial (n=52) was similar in design and the results were consistent
.
In addition, the Phase II KEYNOTE-799 study (n=216) evaluated the efficacy
of pabolizumab with CCRT sequential 1-year consolidation therapy with Pabolizumab.
Group A is a squamous and non-squamous histological type, and group B is a non-squamous histology
.
Both groups had an ORR of 70.
5%.

Overall, triple therapy has a good chance of success, and follow-up results are expected
.

Induction immunotherapy sequential CRT

The main advantage of this approach lies in the use of a "healthy" immune system: the body is not damaged
by chemotherapy and radiotherapy.
Preclinical studies have shown that a complete tumor itself may mean that there are more neoantigens that turn on the immune system
.


Although conventional doses of radiotherapy have been shown to increase neoantigens, especially in cases where the immune system is compromised, it does not necessarily translate into effective T cell infiltration
.
In addition, radiation therapy promotes or suppresses the immune system, depending on the dose, time, and radiation dose of organs involved in the immune response (Figure 3
).

In the Phase II AFT-16 trial (n=64), stage III patients received two cycles of artilizumab and then re-staged and, if no progression, two more sessions of altelizumab treatment, sequentially CCRT, followed by 1-year pentilizumab consolidation therapy
.
If the patient progresses during the first re-stage, receive CCRT
immediately.
The primary endpoint was the 12-week disease control rate (after the end of induced actizizumab
).
The results showed that the median PFS was 23.
7 months, the 1-year and 18-month PFS rates were 66% and 57%, respectively, and the 18-month OS rate was 84%.

Figure 3 Conventional doses of radiation therapy (RT) and stereotactic radiation therapy (SBRT) induce lymphopenia by directly killing circulating lymphocytes and stem cells

Downtime strategy

Phase-III NSCLC down-stage strategies (e.
g.
, using immunotherapy to replace chemotherapy or reduce chemotherapy and radiation doses) require further exploration because of CCRT toxicity and the ability of immunotherapy to provide long-term survival
in patients with stage IV NSCLC.
Down-of-phase strategies have the potential to reduce therapeutic toxicity, particularly in frail patients, while still giving patients radical treatment and long-term survival
.
Preclinical studies have shown that lower radiation doses still guarantee local control due to simultaneous administration of immunotherapy, but this approach has not been clinically studied
.
This approach is applied if feasible to patients who are not suitable for CCRT and/or who are most likely to benefit from immunotherapy (e.
g.
, high PD-L1 levels
).

The Phase II SPRINT study is exploring chemotherapy-free regimens ≥in 50% (n=25) patients expressing PD-L1, with enrolled patients receiving 3 cycles of pabolizumab induction therapy sequential radiotherapy followed by 12 cycles of pabolizumab
.
At the time of the first interim analysis, the 1-year PFS rate and the 1-year OS rate were 73% and 91%,
respectively.
The study also included PD-L1<50% (n=38) patients receiving standard treatment
.
Notably, at re-staging after 3-cycle pabolizumab induction therapy, 100% 1-year PFS for patients with PET-CT showing partial remission (n=12) versus 61% for patients with stable disease or PD, highlighting the need to explore early treatment
.

Immunotherapy in patients with drive mutations in stage III NSCLC

Patients with stage IV NSCLC who do not smoke-related driver mutations (egfr exon 19 deletion and exon 21 ex-related point mutations, ALK rearrangement, and ROS1 rearrangement) rarely benefit
from immunotherapy.
Data on immunotherapy in unresectable stage III NSCLC came mainly from subgroup analyses and retrospective analyses
.
The PACIFIC trial included 43 patients with EGFR mutation (6% of the total population).

The results showed that the PFS HR and OS HR were 0.
97
compared to the placebo group.

Based on the results of multiple studies, consolidation immunotherapy is not recommended in patients with classical EGFR mutations and ALK rearrangement
.
The Phase III LAURA trial is exploring the efficacy
of CCRT sequential ositinib in patients with EGFR-sensitive mutation Phase III.

Future directions

The PACIFIC trial opens up new directions
for immunotherapy in stage III NSCLC.
There are currently a number of studies underway, the future is expected to expand the immunotherapy beneficiary population, and the release of more Phase III clinical research results in the future has the potential to change the current clinical practice
.
The duration of consolidation immunotherapy 1 year after CCRT is also debatable
.
Studies have been conducted to explore the efficacy
of consolidation therapy at 6 months, 12 months and 24 months.
Nonbiomarker drivers are one of the main limiting factors in ongoing randomized controlled studies, and a "one-size-fits-all" treatment model is unlikely to be the best solution
to better improve patient survival.
A deep understanding of tumor biology and behavior could revolutionize the current landscape of
treatment.
Identifying different patient subpopulations to develop an individualized antitumor regimen is imperative and key
to further prolonging survival in patients with locally advanced NSCLC.

References: 1.
F.
Cortiula, B.
Reymen, S.
Peters, P.
et al.
Immunotherapy in unresectable stage III non-small-cell lung cancer: state of the art and novel therapeutic approaches,Annals of Oncology,2022,ISSN 0923-7534,https://doi.
org/10.
1016/ j.
annonc.
2022.
06.
013.

2.
 OA02.
05 - Sugemalimab vs Placebo after cCRT or sCRT in pts with Unresectable Stage III NSCLC: Final PFS Analysis of a Phase 3 Study.
 2022 WCLC.

Editor: Xiaoyuan Typesetting: Xiaoyuan
Execution: Youshi END