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An article combing: Exploration of immunotherapy resistance mechanism and antimicrotherapy strategy of advanced NSCLC without driver gene mutation

 Last Update: 2023-02-02
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EGFR mutations, ALK fusions, and recently rapidly progressive KRAS mutations have redefined treatment strategies and prognosis
for NSCLC patients.
However, these therapies are not effective
in tumors without driver gene mutations.
In recent years, the treatment pattern of patients with non-driver gene NSCLC has also changed dramatically, and immunotherapy has been integrated into the treatment of patients without driver mutations, and the survival of patients has been prolonged, and the quality of life has been
improved.

For advanced NSCLC, current first-line standard treatment options include immunotherapy monotherapy (select population), immunotherapy in combination with chemotherapy, and dual immunotherapy
.
However, the choice of immunotherapy regimen is complex because data from head-to-head randomized controlled studies are scarce, and almost all approved immunization or combination regimens have shown superiority over chemotherapy alone
.
Disease progression also occurs in most patients receiving first-line immunotherapy, and effective follow-up treatment
options are lacking.
This article summarizes the mechanisms of drug resistance related to immunotherapy, the coping strategies currently explored, and future research directions
.

Primary and acquired resistance to immunotherapy

Although immunotherapy provides long-term benefit in patients, some patients do not benefit from immunotherapy (primary resistance).

In contrast, some patients develop relapse (acquired or secondary resistance)
after an initial response to immunotherapy.
Patients with stable disease (SD) should not be classified as heterogeneity
needs to be considered when evaluating using the RECIST criteria.
Patients with SD are likely to not respond to immunotherapy and should also be considered for primary resistance when first assessed for SD
.

Mechanisms associated with immunoresistance

When considering the characteristics of cancer cells themselves, resistance to immunotherapy may be attributed to intrinsic features (genomic or proteomic features) or extrinsic features (tumor microenvironment related) and may be primary or acquired
.
Some researchers believe that immune resistance is related to the degree of immune infiltration: "desert" (complete absence of immune cells), "excuded" (immune cells on the edge of invasion but not in the tumor bed) and inflammatory mode (immune cells in and around the tumor).

For the inherent characteristics of tumor cells, some oncogenic mutations are clearly associated
with primary resistance to immunotherapy.
For example, EGFR mutations/ALK fusions are associated with it, and KRAS mutations are associated
with different responses to immunotherapy.
High levels of neoantigen load due to tobacco exposure are associated with a partial response, while KRAS mutations, which often coexist with other mutations, also appear to play a role
.
Based on expression cluster characteristics, Skoulidis et al.
divided such tumors into the "KL" subgroup - KRAS coexisting mutations with STK11 and KEAP, the "KP" subgroup - KRAS and TP53 coexisting mutations, and the "KC" subgroup - CDKN2A/B inactivation + low expression of thyroid transcription factor-1 (TTF-1).

Among them, most of the "KL" tumors are immunologically inert, there are not many inflammatory T cells, and the expression level of PD-L1 is low
.
Examples of KRAS mutations may only reflect the tip of the iceberg of
immunotherapy response or drug resistance.

Other intrinsic mechanisms in tumor cells include reduced tumor antigen expression (e.
g.
, human leukocyte antigen [HLA] class I defects), epigenetic modifications, and genetic mutations (e.
g.
, mutations in the MAPK signaling pathway, PTEN deletion).

Extrinsic cellular mechanisms include alterations
in the tumor microenvironment (TME).
In addition to previously administered treatments (surgery, chemotherapy, or radiotherapy), the anti-tumor efficacy of immunotherapy may come from a number of factors, including the patient's genetic diversity, gut microbiome, and other environmental factors
.
These factors can influence tumor dynamics and interactions
with the host immune system.

Treatment options after first-line immunotherapy

Platinum-containing dual or single-agent chemotherapy
may be available after immunotherapy advances.
Another option that is common in clinical practice is chemotherapy + continued immunotherapy
.
In the pre-immunotherapy era, direct evidence supported the use of docetaxel
for third-line therapy.
Prior to the widespread use of immune monotherapy as a second-line option, combination strategies showed exciting results
compared to chemotherapy alone.
Follow-up researchers have also explored the safety and efficacy of anti-angiogenic drugs - bevacizumab (VEGF monomab), ramolucimab (VEGFR2 monoclonal antibody) and other combination chemotherapy (Table 1).

However, given the limited benefits and relatively high cost, some drugs are not widely used
.
Figure 1 Current treatment strategies
to inhibit the "parallel pathway" are currently being
explored.
To overcome immunotherapy resistance, multiple clinical studies are being explored as potential treatment options
in the future.

Combination immunotherapy

The mechanism by which checkpoint inhibitors are combined with other immunotherapies is that different tumors have different selective targets including co-inhibitory and co-stimulatory receptors, and tumors that do not respond to current immunotherapies may utilize immunosuppressive pathways
outside the PD-1/PD-L1 signaling pathway.

Joint co-inhibitory molecules

A phase II trial (NCT03262779) of CTLA-4
evaluated the efficacy
of ipilimumab plus nivolumab in PD-1 primary resistant patients.
The study included that the optimal clinical response to PD-1 monoclonal antibody was disease progression or disease stabilization (primary resistance) at less than 24 weeks
.
Another cohort included patients with acquired resistance, defined as the optimal clinical response to PD-1 monoclonal antibody at least 24 weeks with SD or partial response (PR) or complete response
.
We look forward to the publication of the results of the study
.
TIM-3 T cell immunoglobulin and mucin domain protein 3 (TIM-3
) are inhibitory receptors expressed on debilitating CD8+ T cells and also in most other immune cell populations, including CD4+, Tregs, Th17, dendritic cells, B cells, macrophages, and NK cells
.
Phase I/II studies are evaluating the efficacy
of TIM-3 antagonists + PD(L)-1 in NSCLC.
Preliminary data from the Phase I AMBER study show that TSR-022 (TIM-3 monoclonal antibody) + TSR-042 (PD-1 inhibitor) (NCT02817633) shows good safety and promising clinical activity
in NSCLC after immunotherapy progression.
In addition, researchers are exploring the effectiveness of PD-1/TIM-3 bispecific antibody (RO7121661) in solid tumors (NCT03708328).
LAG-3 lymphocyte activating gene 3 (LAG-3
or CD223) is a transmembrane protein
that binds to MHC class II molecules.
CD8+ T cells and NK cells are highly expressed PD-1 and LAG-3, and PD-1 and LAG-3 are also highly expressed in T-regs cells, suggesting that Treg cells may have additional cell-specific inhibition and may play a role
in the formation of immune tolerance.

IN A RECENT PHASE III RELATIVITY STUDY, NIVOLUMAB IN COMBINATION WITH LAG-3 MONOCLONAL ANTIBODY (RELATLIMAB) HAS SHOWN CLINICAL BENEFIT
IN MELANOMA.
PFS and ORR were significantly improved in patients compared with nivolumab, which provides a new treatment option
for melanoma patients.

Recent results from the TACTI-002 study, which included unscreened patients, showed that eftigimod alpha + pembrolizumab was safely tolerated in the late-treatment-naïve NSCLC cohort and showed activity in all patients, particularly in PD-L1>50% (ORR 54.
5%)
.
A phase I/II study showed that LAG525+spartalizumab showed good tolerability
in metastatic malignancies.
Another phase II study is currently exploring the efficacy
of relatlimab + nivolumab in patients with treatment-naïve, immunotherapy-resistant metastatic NSCLC.
Another phase I clinical trial is exploring the efficacy of a PD-1/LAG-3 bispecific antibody in solid tumors (NCT04140500).
TIGIT T cell immunoglobulins and ITIM domain (TIGIT
) proteins are inhibitor receptors
that are essential for the development of immune tolerance in T cells and natural killer (NK) cells.
TIGIT-positive NK cells are associated with
tumor progression.
Preclinical studies have shown that blocking TIGIT and PD-L1 can enhance the effects of CD8+ T cells, resulting in a significant anti-tumor response, making TIGIT an attractive potential therapeutic target
.

Phase II studies showed that TIGIT monoclonal antibody tiragolumab + atezolizumab showed higher activity
.
HOWEVER, THE SUBSEQUENT PHASE III SKYSCRAPER-01 STUDY DID NOT MEET THE COMMON PRIMARY ENDPOINT PFS
.
The SKYSCRAPER-03 study is exploring the efficacy
of tiragolumab + atezolizumab contrast valimumab after standard chemoradiotherapy in patients with stage III NSCLC.
In addition, in second-line or other treatment line regimens, researchers are also exploring the efficacy
of adding TIGIT monoclonal antibody to nivolumab (NCT03119428) or zimbrelimab (a novel PD-1 monoclonal antibody) (NCT03628677).

Joint co-stimulatory molecules

OX-40 OX-40

is a member of the tumor necrosis factor receptor (TNFR) family, expressed in activated CD4+ T cells and CD8+ T cells (antigen-specific initiation phase), and when activated, acts as a co-stimulator for CD4+ T cell and CD8+ T cell activation, clonal division, cytokine production, and memory T cell development
.

The prognosis of OX-40 and NSCLC is significantly correlated
.
For example, in patients who are resectable by surgery, OX-40 expression in the immunoinvasive state of tumor is associated
with good prognosis.
In addition, high levels of OX-40 and OX-40 ligands (OX-40L) in the blood were associated with
a poor prognosis.
Clinical trials are being conducted to explore the efficacy
of PD-1/PD-L1 monoclonal antibody + OX-40 monoclonal antibody.
A phase I study showed that MEDI0592, a humanized IgG1k OX40 monoclonal antibody + tremelimumab or durvalumab, was effective
in multi-line treatment of solid tumors.
The median OS of MEDI0592+ dupaliumab or tremelimumab was 17.
4 and 11.
9 months
, respectively.
SD was achieved in nine patients in each of the two cohorts (34.
6% versus 29.
0%)
.
ICOS induces co-stimulators (ICOS
; CD278) is a positive regulator of T cells, a component of the CD28/CTLA immunoglobulin superfamily, which is highly expressed
in CD4+ and CD8+ T cells.
A randomized phase II trial is currently evaluating ICOS agonists (GSK3359609) + docetaxel versus docetaxel in patients with immunotherapy and chemotherapy progressing to NSCLC
.
In another phase I/II trial, IgG1 ICOS antibody (KY1044) + atezolizumab showed potential
.

An interesting study showed that the vopratelimab-specific peripheral blood efficacy biomarker, ICOS-hi CD4 T cells, was associated with
OS improvement in some patients.
In a follow-up phase II study, the investigators are exploring the efficacy
of JTX-4014, a novel PD-1 monoclonal antibody, ± vopratelimab, in patients with high ICOS expression, EGFR wild-type, platinum-containing therapy progression, and no immunotherapy NSCLC.

Combined cancer vaccine

Preclinical studies have shown that cancer vaccines upregulate PD-L1 expression in TME while "heating" cold tumors
.
The Phase I/II DURGA trial explored the efficacy
of Viagenpumatucel-L (HS-110) + nivolumab in patients with advanced NSCLC after treatment.
Preliminary results showed that the combination therapy showed high efficacy in the immunoresistance cohort with a DCR of 55%, PFS of 2.
7 months, median OS not achieved, and good
tolerability.
TG4010 is a viral vector cancer vaccine encoding MUC-1 and IL-2, and the efficacy and safety
of this therapy + nivolumab are being explored.

Combined immunomodulators

Immunometabolic pathway: IDO-1

In lung cancer, IDO overexpression is detectable after progression of PD-1/PD-L1 therapy and is associated with a poorer prognosis, suggesting that IDO may play a role
in acquired resistance.

At present, studies are exploring the activity and safety
of IDO-1 monoclonal antibody epacadostat + pembrolizumab in 14 solid tumors.
However, the combination of related drugs with PD-1 monoclonal antibody did not show a survival benefit, including frustration in melanoma
.
However, researchers remain interested in this signaling pathway, and selective IDO1 inhibitors (BMS-986, 205, IDO/TDO inhibitors [RG70099 and IOM-D], and indoximod+PD-1 monoclonal antibody are in clinical development
.

In addition, strategies for combining cytokines, including TGF-β, IL-2, and STING pathways and DNA damage signaling pathway correlated factors, are being explored
.

Combined antiangiogenesis

Intrinsic resistance mechanisms in tumor cells can lead to primary and acquired resistance to immunotherapy
.
Receptor tyrosine kinases mediate immunosuppressive mechanisms
in TME.
Therefore, targeting vascular endothelial growth factor receptors or fibroblast growth factor receptors may lead to resensitivity of immunotherapy and is a promising therapeutic strategy
.

Sitravatinib may enhance anti-tumor immune responses
by inhibiting several closely related kinases, including the TAM family (TYRO3, AXL, and MERTK), VEGFR2, KIT, and MET.
In a phase II trial of 46 patients with NSCLC who had previously received immunotherapy, 84% showed tumor shrinkage and 28% showed partial response (PR).

The Phase III SAPPHIRE study is exploring the efficacy
of sitravatinib + nivolumab in patients with advanced NSCLC following advances in platinum-containing chemotherapy and immunotherapy.
Lenvatinib is a multi-targeted TKI targeting FGFR 1-4, PDGFRα, RET and KIT with antitumor and antiangiogenic activity, and the efficacy of lenvatinib ± pembrolizumab in patients following immunotherapy progression is currently being evaluated in the LEAP-008 study, with a 24-week ORR of 33%
in the NSCLC cohort.

Cabozantinib is another multi-target (MET, VEGFR, AXL, and RET) inhibitor
.
The phase II EA5191 study explored the efficacy
of cabozantinib ± nivolumab compared to investigator-selected standard chemotherapy in patients with platinum-containing and immunotherapy progressing NSCLC.
At the 2022 ASCO Congress, the results of the Lung-MAP study were announced, which evaluated the efficacy and safety
of pembrolizumab + ramolurumab in advanced NSCLC previously treated with ICI.
Compared with standard care, there was a significant improvement in OS in the combination group (HR=0.
69), and median OS in the combination and standard care groups was 14.
5 and 11.
6 months, respectively, while there was no difference
in ORR or PFS.

Also at the 2022 ASCO Congress, the Phase Ib COSMIC-021 study presented the results of Cohort 7 studies
.
The aim of this study was to evaluate the efficacy
of cabozitinib + atezolizumab in advanced solid tumors.
Cohort 7 (including previous immunotherapy) showed an ORR of 19% and a median OS of 13.
8 months
in the combination group.

Other novel combination therapies

The HUDSON trial is a phase II umbrella study that includes patients
with NSCLC following platinum-containing and immunotherapy advances.
The study is evaluating the results of drug + dulvalumab with multiple mechanisms of action, including olaparib, AZD9150 (JAK-STAT3 inhibitor), ceralasertib (ATR kinase inhibitor), vistusertib (mTOR inhibitor), oleclumab (anti-CD73), Trastuzumab-deruxtecan (antibody-drug conjugate) and cediranib (anti-VEGFR-1-3) (NCT03334617).

The Phase I/II CheckMate 79X study is exploring the efficacy and safety
of chemotherapy versus nivolumab + different agents (ipilimumab, cabozantinib, docetaxel + ramolucimal, docetaxel + lucitanib).
The research of new drugs is currently a hot research area
.
Other therapies being explored include oncolytic viruses, other vaccines, cell therapies, and other antibody-drug conjugates (Figure 2).

Figure 2 Known and potential therapeutic targets in the field of NSCLCL

epilogue

Immunotherapy has dramatically changed the outlook and clinical outcomes
for patients with advanced NSCLC without driver mutations.
While significant advances and survival advantages have been achieved, only a small percentage of patients develop a long-term response to immunotherapy, and most patients experience disease progression
some time after response.
As there is currently no standard treatment strategy and a clear and effective strategy, immunotherapy resistance should be considered for clinical studies
.
Effective strategies after immunotherapy resistance are currently unmet clinical needs and one of the
most important clinical needs.
Future research should focus on the mechanism of immunotherapy resistance, so as to identify potential biomarkers and screen patients, and ultimately realize new personalized treatment strategies
.

References: Jose Luis Leal, Thomas John, Immunotherapy in advanced NSCLC without driver mutations: available therapeutic alternatives after progression and future treatment options, Clinical Lung Cancer (2022), doi:https://doi.
org/10.
1016/j.
cllc.
2022.
08.
009

Editor: Yuna

Typesetting: Yuna

Execution: Babel

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