The treatment goal for patients with early-stage lung cancer is cure. Multidisciplinary discussions of surgical resectability and medical operability determine the modality of definitive local ...treatment (surgery or radiotherapy) and the associated systemic therapies to further improve the likelihood of cure. Trial evidence supports cisplatin-based adjuvant therapy either after surgical resection or concurrently with radiotherapy. Consensus guidelines support neoadjuvant chemotherapy in lieu of adjuvant chemotherapy and carboplatin-based regimens for patients who are ineligible for cisplatin. The incorporation of newer agents, now standard for patients with stage IV lung cancer, into the curative therapy paradigm has lagged owing to inefficient trial designs, the lengthy follow-up needed to assess survival end points and a developmental focus on the advanced-stage disease setting. Surrogate end points, such as pathological response, are being studied and might shorten trial durations. In 2018, the anti-PD-L1 antibody durvalumab was approved for patients with stage III lung cancer after concurrent chemoradiotherapy. Since then, the study of targeted therapies and immunotherapies in patients with early-stage lung cancer has rapidly expanded. In this Review, we present the current considerations in the treatment of patients with early-stage lung cancer and explore the current and future state of clinical research to develop systemic therapies for non-metastatic lung cancer.
Currently, there is no established guidance on how to process and evaluate resected lung cancer specimens after neoadjuvant therapy in the setting of clinical trials and clinical practice. There is ...also a lack of precise definitions on the degree of pathologic response, including major pathologic response or complete pathologic response. For other cancers such as osteosarcoma and colorectal, breast, and esophageal carcinomas, there have been multiple studies investigating pathologic assessment of the effects of neoadjuvant therapy, including some detailed recommendations on how to handle these specimens. A comprehensive mapping approach to gross and histologic processing of osteosarcomas after induction therapy has been used for over 40 years.
The purpose of this article is to outline detailed recommendations on how to process lung cancer resection specimens and to define pathologic response, including major pathologic response or complete pathologic response after neoadjuvant therapy. A standardized approach is recommended to assess the percentages of (1) viable tumor, (2) necrosis, and (3) stroma (including inflammation and fibrosis) with a total adding up to 100%. This is recommended for all systemic therapies, including chemotherapy, chemoradiation, molecular-targeted therapy, immunotherapy, or any future novel therapies yet to be discovered, whether administered alone or in combination. Specific issues may differ for certain therapies such as immunotherapy, but the grossing process should be similar, and the histologic evaluation should contain these basic elements. Standard pathologic response assessment should allow for comparisons between different therapies and correlations with disease-free survival and overall survival in ongoing and future trials. The International Association for the Study of Lung Cancer has an effort to collect such data from existing and future clinical trials. These recommendations are intended as guidance for clinical trials, although it is hoped they can be viewed as suggestion for good clinical practice outside of clinical trials, to improve consistency of pathologic assessment of treatment response.
We report a phase II study of 50 advanced non-small cell lung cancer (NSCLC) patients with point mutations or insertions in EGFR exon 20 treated with poziotinib (NCT03066206). The study achieved its ...primary endpoint, with confirmed objective response rates (ORRs) of 32% and 31% by investigator and blinded independent review, respectively, with a median progression-free survival of 5.5 months. Using preclinical studies, in silico modeling, and molecular dynamics simulations, we found that poziotinib sensitivity was highly dependent on the insertion location, with near-loop insertions (amino acids A767 to P772) being more sensitive than far-loop insertions, an observation confirmed clinically with ORRs of 46% and 0% observed in near versus far-loop, respectively (p = 0.0015). Putative mechanisms of acquired resistance included EGFR T790M, MET amplifications, and epithelial-to-mesenchymal transition (EMT). Our data demonstrate that poziotinib is active in EGFR exon 20-mutant NSCLC, although this activity is influenced by insertion location.
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•Poziotinib yields a 32% response rate in EGFR exon 20-mutant NSCLC•Poziotinib sensitivity is highly dependent on insertion location•Near-loop exon 20 insertions are more sensitive to poziotinib than far-loop insertions•Mechanisms of acquired poziotinib resistance include EGFR T790M and MET amplifications
Elamin et al. show that poziotinib is active in EGFR exon 20-mutant non-small cell lung cancer. The activity of poziotinib is influenced by insertion location in exon 20, with near-loop insertion being more sensitive than far-loop insertion. Poziotinib acquired resistance is mediated via EGFR-dependent and -independent mechanisms.
BackgroundNon-small cell lung cancer (NSCLC) patients bearing targetable oncogene alterations typically derive limited benefit from immune checkpoint blockade (ICB), which has been attributed to low ...tumor mutation burden (TMB) and/or PD-L1 levels. We investigated oncogene-specific differences in these markers and clinical outcome.MethodsThree cohorts of NSCLC patients with oncogene alterations (n=4189 total) were analyzed. Two clinical cohorts of advanced NSCLC patients treated with ICB monotherapy MD Anderson (MDACC; n=172) and Flatiron Health-Foundation Medicine Clinico-Genomic Database (CGDB; n=894 patients) were analyzed for clinical outcome. The FMI biomarker cohort (n=4017) was used to assess the association of oncogene alterations with TMB and PD-L1 expression.ResultsHigh PD-L1 expression (PD-L1 ≥50%) rate was 19%–20% in classic EGFR, EGFR exon 20 and HER2-mutant tumors, and 34%–55% in tumors with ALK, BRAF V600E, ROS1, RET, or MET alterations. Compared with KRAS-mutant tumors, BRAF non-V600E group had higher TMB (9.6 vs KRAS 7.8 mutations/Mb, p=0.003), while all other oncogene groups had lower TMB (p<0.001). In the two clinical cohorts treated with ICB, molecular groups with EGFR, HER2, ALK, ROS1, RET, or MET alterations had short progression-free survival (PFS; 1.8–3.7 months), while BRAF V600E group was associated with greater clinical benefit from ICB (CGDB cohort: PFS 9.8 months vs KRAS 3.7 months, HR 0.66, p=0.099; MDACC cohort: response rate 62% vs KRAS 24%; PFS 7.4 vs KRAS 2.8 months, HR 0.36, p=0.026). KRAS G12C and non-G12C subgroups had similar clinical benefit from ICB in both cohorts. In a multivariable analysis, BRAF V600E mutation (HR 0.58, p=0.041), PD-L1 expression (HR 0.57, p=0.022), and high TMB (HR 0.66, p<0.001) were associated with longer PFS.ConclusionsHigh TMB and PD-L1 expression are predictive for benefit from ICB treatment in oncogene-driven NSCLCs. NSCLC harboring BRAF mutations demonstrated superior benefit from ICB that may be attributed to higher TMB and higher PD-L1 expression in these tumors. Meanwhile EGFR and HER2 mutations and ALK, ROS1, RET, and MET fusions define NSCLC subsets with minimal benefit from ICB despite high PD-L1 expression in NSCLC harboring oncogene fusions. These findings indicate a TMB/PD-L1-independent impact on sensitivity to ICB for certain oncogene alterations.
With recent strides made within the field of thoracic oncology, the management of NSCLC is evolving rapidly. Careful patient selection and timing of multi-modality therapy to permit the optimization ...of therapeutic benefit must be pursued. While chemotherapy and radiotherapy continue to have a role in the management of lung cancer, surgical therapy remains an essential component of lung cancer treatment in early, locally and regionally advanced, as well as in selected, cases of metastatic disease. Recent and most impactful advances in the treatment of lung cancer relate to the advent of immunotherapy and targeted therapy, molecular profiling, and predictive biomarker discovery. Many of these systemic therapies are a part of the standard of care in metastatic NSCLC, and their indications are expanding towards surgically operable lung cancer to improve survival outcomes. Numerous completed and ongoing clinical trials in the surgically operable NSCLC speak to the interest and importance of the multi-modality therapy even in earlier stages of NSCLC. In this review, we focus on the current standard of care indications for surgical therapy in stage I-IV NSCLC as well as on the anticipated future direction of multi-disciplinary lung cancer therapy.
Immune checkpoint inhibitors are associated with immune-related adverse events (irAEs), including arthritis (arthritis-irAE). Management of arthritis-irAE is challenging because immunomodulatory ...therapy for arthritis should not impede antitumor immunity. Understanding of the mechanisms of arthritis-irAE is critical to overcome this challenge, but the pathophysiology remains unknown. Here, we comprehensively analyze peripheral blood and/or synovial fluid samples from 20 patients with arthritis-irAE, and unmask a prominent Th1-CD8
T cell axis in both blood and inflamed joints. CX3CR1
CD8
T cells in blood and CXCR3
CD8
T cells in synovial fluid, the most clonally expanded T cells, significantly share TCR repertoires. The migration of blood CX3CR1
CD8
T cells into joints is possibly mediated by CXCL9/10/11/16 expressed by myeloid cells. Furthermore, arthritis after combined CTLA-4 and PD-1 inhibitor therapy preferentially has enhanced Th17 and transient Th1/Th17 cell signatures. Our data provide insights into the mechanisms, predictive biomarkers, and therapeutic targets for arthritis-irAE.
Abstract
Radiographic imaging is the standard approach for evaluating the disease involvement of lymph nodes in patients with operable NSCLC although the impact of neoadjuvant immune checkpoint ...inhibitors (ICIs) on lymph nodes has not yet been characterized. Herein, we present an ad hoc analysis of the NEOSTAR trial (NCT03158129) where we observed a phenomenon we refer to as “nodal immune flare” (NIF) in which patients treated with neoadjuvant ICIs demonstrate radiologically abnormal nodes post-therapy that upon pathological evaluation are devoid of cancer and demonstrate de novo non-caseating granulomas. Abnormal lymph nodes are analyzed by computed tomography and
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F-fluorodeoxyglucose positron emission tomography/computer tomography to evaluate the size and the maximum standard uptake value post- and pre-therapy in NEOSTAR and an independent neoadjuvant chemotherapy cohort. NIF occurs in 16% (7/44) of patients treated with ICIs but in 0% (0/28) of patients after neoadjuvant chemotherapy. NIF is associated with an inflamed nodal immune microenvironment and with fecal abundance of genera belonging to the family Coriobacteriaceae of phylum Actinobacteria, but not with tumor responses or treatment-related toxicity. Our findings suggest that this apparent radiological cancer progression in lymph nodes may occur due to an inflammatory response after neoadjuvant immunotherapy, and such cases should be evaluated by pathological examination to distinguish NIF from true nodal progression and to ensure appropriate clinical treatment planning.
Abstract
Surgical resection is the preferred treatment for patients with operable early-stage non-small cell lung cancer (NSCLC). Unfortunately, however, more than 50% of patients who are treated ...with surgery alone will relapse, which reduces overall survival (OS). Perioperative (neoadjuvant or adjuvant) chemotherapy to prevent disease recurrence after surgery provides only a modest (~5%) improvement in five-year OS and is also a source of toxicity. Efforts to test new therapeutic strategies for patients with operable NSCLC have proved challenging because using OS as a measure of clinical benefit requires large patient numbers and increased time of follow-up. Recently, we and others demonstrated that a major pathologic response (MPR), defined as ≤ 10% viable tumor in resected specimens, provides an objective criterion of response of early-stage NSCLC to neoadjuvant chemotherapy and correlates with long-term survival outcomes. We also generated preclinical models of spontaneously metastatic and resectable NSCLC that provide a readout of tumor antigen-specific immune responses in mice treated with neoadjuvant therapy. Preclinical studies using these models revealed that a neoadjuvant strategy that inhibited both PD-1 and CTLA-4 immune checkpoint proteins was superior to either monotherapy or adjuvant combined therapy at reducing the frequency of lung metastases, improving survival and enhancing the tumor-specific and total CD8+ T cell infiltrate. Clinical studies in patients with advanced NSCLC demonstrated that combined nivolumab (anti-PD-1) plus ipilimumab (anti-CTLA-4) also produced greater response rates compared with nivolumab monotherapy, and first-line nivolumab plus ipilimumab treatment induced longer OS than chemotherapy in some patients. The abovementioned studies prompted us to launch the NEOSTAR study, the first reported phase 2 randomized trial evaluating neoadjuvant nivolumab and nivolumab plus ipilimumab in 44 patients with resectable NSCLC (NCT03158129) with MPR as primary endpoint. The MPR rate for each treatment arm was tested against historical controls of neoadjuvant chemotherapy (conservative rate 15%) in localized NSCLC. The addition of ipilimumab to nivolumab crossed the prespecified efficacy trial boundary by producing an MPR rate of 38% in 21 treated patients. Nivolumab monotherapy produced an MPR rate of 22% in 23 treated patients. The combination also induced twice as many MPRs in resected patients compared with nivolumab alone (50% vs. 24%) and a greater rate of pathologic complete responses (pCRs) compared with nivolumab (38% vs. 10%). To put this into context, several clinical trials of neoadjuvant platinum doublet chemotherapy reported a median pCR rate of only 4%. Exploratory biomarker studies revealed that overall elevated tumor PD-L1 expression at baseline was associated with responses to neoadjuvant ICIs. However, we also observed responses in patients lacking pretreatment tumor PD-L1, suggesting the need for additional PD-L1 validation studies in larger clinical cohorts. Nivolumab and ipilimumab exert their effects through distinct non-redundant mechanisms and we noted differences in the immune composition of tumors in patients treated with nivolumab plus ipilimumab compared with those treated with only nivolumab. We found that tumors treated with combination therapy possessed higher frequencies of CD3+ T cells, CD4+ (non-Treg) CD103+ and CD8+CD103+ tissue-resident memory and effector memory T cells by flow cytometry. Furthermore, multiplex immunofluorescent staining of tumor samples revealed increased densities of CD3+, CD3+CD8+ and effector memory T cells in tumors treated with combination therapy as compared to baseline. We also noted that distinct gut microbiome signatures were associated with pathologic responses. The relative abundance of certain bacteria, including Ruminococcus and Akkermansia spp., was associated with pathologic responses to neoadjuvant combination ICIs and with T cell clonality in resected tumors. Further studies are needed to determine the mechanisms between microbial signatures and antitumor immune responses in these tumors. We noted that some patients enrolled in the NEOSTAR trial developed a phenomenon we referred to as nodal immune flare (NIF). NIF is characterized by the radiographic appearance of disease progression in lymph nodes that were histologically negative at baseline and became enlarged and/or FDG avid after neoadjuvant ICIs. Invasive pathologic examination of the flaring nodes after treatment demonstrated de novo non-caseating granulomas that are devoid of malignant cells. The overall incidence of NIF on imaging following neoadjuvant ICIs in our study was 16% (7/44). I will discuss new results from an independent clinical cohort of patients with resected NSCLC that suggest NIF does not occur following neoadjuvant chemotherapy, and thus may strictly be an ICI-related phenomenon. There was no significant association between NIF and response to therapy, perhaps indicating that the cellular and molecular mechanisms of systemic immunity driving NIF and the antitumor immune response may be distinct from one another. Recent studies suggest chemotherapy may be synergistic with ICIs and further enhance antitumor responses. We demonstrated that neoadjuvant chemotherapy induces higher densities of CD3+ lymphocytes and enhanced PD-L1 expression in resected NSCLC. Front-line nivolumab plus ipilimumab combined with chemotherapy improved survival compared with chemotherapy alone in patients with advanced NSCLC. Results from recent phase 2 chemo-immunotherapy studies have demonstrated robust MPR rates ranging from 57% after neoadjuvant atezolizumab plus chemotherapy (NCT02716038) to 83% following neoadjuvant nivolumab plus chemotherapy in the NADIM study (NCT03081689). Based on these results, we expanded our NEOSTAR trial to a modular, platform design of modular single-arm studies to expedite testing of promising neoadjuvant therapies using MPR as primary endpoint. We have tested neoadjuvant platinum-based chemotherapy plus nivolumab in 22 patients with resectable NSCLC (Arm C) and we are currently evaluating neoadjuvant chemotherapy combined with nivolumab plus ipilimumab. Randomized phase 3 studies are testing neoadjuvant chemotherapy compared to chemotherapy plus ICI (+/- adjuvant ICI) using event-free survival plus OS or MPR/pCR as primary endpoints and will prospectively validate the use of surrogate endpoints to predict improvements in outcomes. I will present unpublished results from the NEOSTAR study, including the clinical outcomes in patients treated with neoadjuvant platinum-based chemotherapy plus nivolumab, as well as in patients whose tumors harbor oncogenic drivers. I will compare the pathological tumor regression, and the MPR and pCR rates from neoadjuvant nivolumab plus chemotherapy arm with those from nivolumab monotherapy and nivolumab combined with ipilimumab. I will also discuss some of the challenges that we face as we strive to further improve clinical outcomes for patients with early-stage NSCLC and maximize the clinical effectiveness of ICIs, including intertrial variability in assessing tumor pathological regression and biomarkers of therapeutic response. Potential future directions for the field will also be considered.
Citation Format: Tina Cascone. Neoadjuvant immunotherapy for operable non-small cell lung cancer: Lessons learned and current challenges abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr SY13-03.
•Highlights the problems and challenges of pathologic examination of resected NSCLC in the era of neoadjuvant chemo and/or immunotherapy.•The handling and interpretation of such cases is not well ...defined and current guidelines are largely based not evidence-based.•Many clinical trials rely on pathologic response as a surrogate endpoint of efficacy for novel neoadjuvant agents.•Lack of a standardized approaches raises concerns about the validity, reproducibility and comparability of the results of clinical trials.•Discusses the difficulties encountered during pathologic examination of such specimens and critically reviews recently published guidelines.
New therapy approaches in the treatment of surgically resectable non-small cell lung cancer (NSCLC) challenge the traditional handling and examination of pathology specimens. The increasingly common use of neoadjuvant therapies before surgical resection, due to advantages in novel drug administration, tolerance, and measurement of radiographic and pathologic response compared to adjuvant treatment, has the potential to alter the microscopic tumor appearance and its biology. Currently, many clinical trials use pathologic response as a surrogate endpoint of clinical efficacy, since the extent of residual viable tumor appears to correlate with outcome in patients treated with neoadjuvant chemotherapy. Consequently, pathologic assessment of the extent of residual viable tumor is of paramount importance. However, high level evidence-based guidelines on how to process and evaluate such specimens are lacking. Moreover, while pathologic response has been shown to be associated with survival after chemotherapy, its significance after immunotherapy remains to be determined. Additionally, many clinical trials do not routinely include pathologists in trial design, which may lead to non-standardized evaluation of pathologic response. Although recently, several algorithms have been proposed to address these issues, none of them represents evidence-based recommendations or is universally applied. Therefore, controversies and challenges continue to exist, raising concerns about the validity, reproducibility, and comparability of the results of many neoadjuvant clinical trials. Herein, we discuss the current difficulties in pathologic specimen evaluation following neoadjuvant therapy in NSCLC and propose potential approaches to overcome these challenges.
The role of combination chemotherapy with immune checkpoint inhibitors (ICI) (ICI-chemo) over ICI monotherapy (ICI-mono) in non-small cell lung cancer (NSCLC) remains underexplored. In this ...retrospective study of 1133 NSCLC patients, treatment with ICI-mono vs ICI-chemo associate with higher rates of early progression, but similar long-term progression-free and overall survival. Sequential vs concurrent ICI and chemotherapy have similar long-term survival, suggesting no synergism from combination therapy. Integrative modeling identified PD-L1, disease burden (Stage IVb; liver metastases), and STK11 and JAK2 alterations as features associate with a higher likelihood of early progression on ICI-mono. CDKN2A alterations associate with worse long-term outcomes in ICI-chemo patients. These results are validated in independent external (n = 89) and internal (n = 393) cohorts. This real-world study suggests that ICI-chemo may protect against early progression but does not influence overall survival, and nominates features that identify those patients at risk for early progression who may maximally benefit from ICI-chemo.
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