Approval Of Immune Checkpoint Inhibitors Research Articles

Impact of Performance Status on Response and Survival Among Patients Receiving Checkpoint Inhibitors for Advanced Solid Tumors.

Clinical trials, which led to the approval of immune checkpoint inhibitors (ICI), have been almost exclusively performed in patients with good Eastern Cooperative Oncology Group performance status (ECOG PS of 0-1). However, ICI remains an attractive option for patients with advanced tumors and poor PS. We hypothesized that patients with ECOG PS ≥ 2 would have worse outcomes with ICI. We retrospectively identified patients with advanced solid tumors who were treated with ICI at our institution. The log-rank test compared the survival among patients with different ECOG PS. We used a proportional hazards model to assess association between ECOG PS and overall survival (OS) with adjustment for covariates including age, sex, malignancy type, time from advance disease diagnosis, and line of therapy. We compared overall response rates between groups with Pearson chi-square exact test. We also analyzed in-hospital mortality and hospice referral rates. We identified 257 patients treated with ICI. One hundred eighty-two patients had ECOG PS 0-1, and 75 had ECOG PS ≥ 2. The median overall survival was 12.6 months for the ECOG PS 0-1 group compared with 3.1 months for the ECOG PS ≥ 2 group (P < .001). The overall response rate for patients with ECOG PS 0-1 was 23% compared with 8% for those with poor PS (P = .005). Patients with poor PS treated with ICI had similar hospice referral rates (67% for ECOG PS ≥ 2 v 61.9% for ECOG PS 0-1, P = .50) but were more likely to have in-hospital death as compared with the good PS group (28.6% v 15.1%, P = .035). Despite the appeal of ICI in patients with advanced malignancy and poor PS, outcomes in this cohort were poor. Prospective trials defining the activity and role of ICI in poor PS are urgently needed.

Checkpoint Inhibitors in Relapsed/Refractory Classical Hodgkin Lymphoma

Even though classical Hodgkin lymphoma is highly curable, the outcome of patients with a refractory or relapsed disease has been disappointing. Multiple lines of therapy are available for patients after their first failure, and most respond to subsequent therapies. However, there is a sizable proportion that remains relapsing/recurrent even after several lines of therapy. The overall prognosis of patients with relapsing and recurrent classical Hodgkin lymphoma (rrcHL) has been very disappointing until recently. Immune checkpoint inhibitors such as the anti-programmed death 1 (PD-1) receptor antibodies have recently been approved to treat relapsed and refractory cHL and have significantly improved the outcome of patients with rrcHL. The approved immune checkpoint inhibitors for relapsed and refractory cHL are nivolumab and pembrolizumab. In the Checkmate 205 study nivolumab demonstrated an objective response rate of 69% with an acceptable safety profile. Similarly, pembrolizumab demonstrated an overall response rate (ORR) of 69% with a complete remission rate (CRR) of 22.4% in the KEYNOTE-087 study in heavily pretreated patients with rrcHL.

Health Care Utilization and Costs Associated With Systemic First-Line Metastatic Melanoma Therapies in the United States.

US Food and Drug Administration approvals of immune checkpoint inhibitors and targeted therapies revolutionized the treatment of metastatic melanoma. Our aim was to assess health care resource utilization and costs for patients with metastatic melanoma treated with systemic therapies in first line between January 2012 and December 2017. We conducted a retrospective cohort study of patients with metastatic melanoma using MarketScan data. We included patients diagnosed with melanoma and secondary malignant neoplasm who used pembrolizumab, nivolumab, ipilimumab, ipilimumab plus nivolumab, BRAF-inhibitor (BRAF-i) plus MEK inhibitor (MEK-i), BRAF-i or MEK-i monotherapy, or chemotherapy in first line. We compared health care utilization and costs per patient per month (PPPM) using two-part and generalized linear models. We identified 1,870 patients, including 185 pembrolizumab, 103 nivolumab, 689 ipilimumab, 185 nivolumab plus ipilimumab, 214 BRAF-i plus MEK-i, 240 BRAF-i or MEK-i monotherapy, and 254 chemotherapy users. Highest PPPM rates of hospitalizations, emergency room visits, and outpatient visits were observed in patients with ipilimumab plus nivolumab therapy (adjusted difference v pembrolizumab [aDiff], 0.18, 0.12, and 0.88, respectively; all P < .001). Ipilimumab monotherapy users (aDiff, 0.07 and 0.93; all P < .001) and chemotherapy users (aDiff, 0.10 and 2.63; all P < .001) showed higher PPPM rates of hospitalizations and outpatient visits compared with pembrolizumab users, respectively. Utilization rates in nivolumab, BRAF-i plus MEK-i, and BRAF-i or MEK-i groups were similar to the pembrolizumab group. Highest PPPM total costs and drug-related costs were observed in the ipilimumab group ($80,139 US dollars [USD] and $70,051 USD; all P < .001), followed by the ipilimumab plus nivolumab ($71,689 USD and $56,217 USD; all P < .001) and the BRAF-i plus MEK-i group ($31,184 USD and $19,648 USD; all P < .001). PPPM costs in the nivolumab group were similar to the pembrolizumab group. Significant differences in health care resource utilization and costs were found across first-line metastatic melanoma regimens. Utilization rates were highest in patients using ipilimumab-containing therapies. High drug costs constituted a major fraction of total PPPM health care costs.

Abstract 1853: A novel anti-CTLA-4 checkpoint inhibitor prodrug to address on-target off-tumor toxicity for cancer immunotherapy

Abstract As the first approved immune checkpoint inhibitor targeting CTLA-4, ipilimumab has achieved great clinical success in cancer immunotherapy, particularly in combination with anti-PD-1 therapy. However, ipilimumab can also induce severe and sometimes fatal immune-mediated adverse reactions due to autoimmune responses in normal tissues, which may involve any organ system and cause enterocolitis, hepatitis, dermatologic adverse effects, endocrinopathies, pneumonitis, and nephritis with renal dysfunction, restricting its clinical applications. Thus, development of next generation anti-CTLA-4 antibodies with enhanced antitumor efficacy and improved safety profile is urgently needed. ADG126 is a novel anti-CTLA-4 fully human IgG1 antibody prodrug generated with Adagene SAFEbody technology, which is designed to be activated preferentially in the tumor microenvironment, limiting on-target off-tumor toxicities in normal tissues. This is realized by attaching an optimized peptide through library screening to the N-terminus of the light chain consisting of a masking moiety followed by a cleavage moiety. The masking moiety functions to block ADG126 binding to CTLA-4, however, after cleavage by proteases known to be highly expressed and active in tumor tissues but not in normal tissues, the masking moiety is released, and the antibody is then activated and able to bind and inhibit CTLA-4 function in situ, which has the potential to minimize the side effects and widen the therapeutic window compared to traditional antibodies. Nonclinical pharmacological studies demonstrate that unmasked or activated ADG126 (but not masked or inactive ADG126) binds to a unique and conserved epitope of CTLA-4 with multiple species cross-reactivity and effectively blocks the CTLA-4/B7 ligands interactions. Activated ADG126 potentiates T cell activation inducing elevated IL-2 cytokine production in the presence of a primary stimulatory signal, depletes immunosuppressive Treg activity through enhanced ADCC, and reduces immunosuppressive Treg activity specifically in the tumor microenvironment to mediate anti-tumor responses. ADG126 demonstrates efficacious anti-tumor activity in multiple syngeneic murine tumor models as single agent, as well as in combination with other immune modulatory agents. Nonclinical toxicology studies demonstrate that ADG126 is well-tolerated in cynomolgus monkeys. These results suggest that the design to have activation of ADG126 prodrug preferentially in tumors may allow treatments to deliver higher efficacious dose levels specific to the local tumor microenvironment concomitant with a superior systemic safety profile compared with other traditional anti-CTLA-4 antibodies. Thus, ADG126 may hold great promises to achieve much better efficacy and safety profile for immunotherapy against a broad spectrum of human cancers. Citation Format: Guizhong Liu, Xiaohong She, Yan Li, Felix Du, Peter Luo. A novel anti-CTLA-4 checkpoint inhibitor prodrug to address on-target off-tumor toxicity for cancer immunotherapy [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 1853.

Adverse events in non-small cell lung cancer patients receiving immune checkpoint inhibitors: A single center, real-world study in China.

e21081 Background: Immune checkpoint inhibitors (ICIs) have improved clinical outcomes in non-small cell lung cancer (NSCLC), whereas they also can cause various adverse events (AEs). We reported the incidences, spectrum and severity of AEs in real-life practice after the approval of ICIs in Chinese NSCLC patients. Methods: In this single center, retrospective study, anonymized electronic medical record data were collected from the dedicated lung cancer immunotherapy outpatient clinic of Guangdong Provincial People’s Hospital through the LinkDoc database. The patients (≥18 years old) with pathologically diagnosed metastatic NSCLC who receiving ICIs between 1 June 2019 and 31 December 2020 were included. The immune-related adverse events (irAEs) were diagnosed and assessed by oncologists. All AEs were classified and graded according to the National Cancer Institute Common Toxicity Criteria for Adverse Events (CTCAE V5.0). Results: A total of 203 patients with a median age of 60.5 years were included in this study. Most patients were male (81.8%), smokers (49.8%), non-squamous histological type (51.7%). 61.1% of patients visited the outpatient clinic more than once. Pembrolizumab and Nivolumab were given to the majority of patients (80.8%). 114 patients (56.2%) received single-agent and 89 patients (43.8%) received combination therapy. The median duration of ICIs therapy was 271.2 days. In our study, 68.0% of patients experienced any-grade AEs, and 19.7% experienced grade≥3 AEs. The most commonly AEs were abnormal laboratory findings (57.1%), blood and lymphatic system disorders (25.1%), and respiratory disorders (19.7%). All of 93 patients (45.8%) experienced irAEs and 6 patients (8.4%) developed grade≥3 irAEs. The most frequent irAEs included blood and lymphatic system disorders (25.1%), hepatobiliary disorders (17.7%), and cardiac disorders (9.9%). Cough (3.4%), sputum (2.5%), and pain (2.0%) were the most frequent AEs which received treatment. Conclusions: Our results showed 68.0% and 45.8% patients experienced AEs and irAEs, respectively. The AEs and irAEs were primarily low grade. This study also demonstrated the information of AEs could be well collected and managed through our dedicated lung cancer immunotherapy outpatient clinic. [Table: see text]

Genomic predictors of response to PD-1 axis inhibitors in metastatic urothelial cancer (mUC) patients using machine learning analysis of tissue comprehensive genomic profiling (CGP).

4542 Background: Immune check point inhibitors (ICI), specifically PD-1 axis inhibitors, are an established treatment for mUC patients (pts), though molecular markers of response are not well-established. Probabilistic Graphical Models (PGMs) are artificial intelligence (AI) algorithms that capture multivariate, multi-level dependencies in complex patterns in large datasets while retaining human interpretability. We hypothesize that machine learning analysis can reveal biomarkers of response to ICI beyond Tumor Mutational Burden (TMB) and PD-L1 expression. Methods: Pts with mUC receiving systemic therapy and available tumor CGP were included in the analysis. CGP was performed by a CLIA validated NGS panel (Foundation Medicine). 17 clinically relevant variables were included in the analyses. Multilevel molecular and clinical interdependencies between ICI response were assessed using a Bayesian network (BN) machine learning approach. To account for high computational cost of the BN dependence structure discovery, variables were selected based on primary and secondary dependencies to ICI Objective Response Rate (ORR) via Hill Climbing Algorithm. Genes selected for analysis included those present in &gt; 5% of the cohort . All variants of unknown significance were removed. Kaplan-Meyer (KM) survival analysis was also performed. Results: 174 pts were eligible and included: median age was 67 (33 – 86), 54.6% were smokers, 27.6% male, 14.4% had upper tract disease at diagnosis and 77 pts were treated with an approved ICI. Results from BN analysis revealed strong positive interdependencies between ICI ORR and TMB ≥ 10 or mutated PIK3CA gene. KM analysis was in agreement with BN results, a low TMB ( &lt; 10 muts/MB) and wild-type PIK3CA were predictive of poor PFS (Table). PGMs will be presented at the meeting. Conclusions: BN and KM survival analysis supported TMB ≥ 10 as a biomarker of improved outcomes to ICI. Moreover, these results reveal mutated PIK3CA as a novel biomarker of improved outcomes to ICI. Study has limitations as expected in a retrospective analysis. These hypothesis-generating data require external validation.[Table: see text]

Avelumab in patients with previously treated Merkel cell carcinoma (JAVELIN Merkel 200): Updated overall survival data after more than five years of follow up.

9517 Background: Merkel cell carcinoma (MCC) is a rare and aggressive skin cancer. Although MCC is considered chemosensitive, patients typically have limited survival benefit with chemotherapy. Before the approval of immune checkpoint inhibitors, patients with metastatic MCC (mMCC) had a poor prognosis, with a historical 5-year overall survival (OS) rate of approximately 14%. Avelumab (anti–PD-L1) became the first approved treatment for patients with mMCC, based on efficacy and safety data observed in the phase 2 JAVELIN Merkel 200 trial (NCT02155647), in which patients with mMCC received avelumab monotherapy. We report the long-term OS data from the cohort of patients with mMCC whose disease had progressed after ≥1 prior line of chemotherapy. Methods: Eligible patients had histologically confirmed, measurable (per RECIST 1.1) stage IV MCC. Patients received avelumab 10 mg/kg by intravenous infusion every 2 weeks until confirmed disease progression, unacceptable toxicity, or withdrawal. Long-term OS was analyzed; updated data for other efficacy endpoints, including response and progression-free survival, were not obtained. Results: A total of 88 patients were enrolled and received avelumab treatment. As of September 25, 2020 (data cutoff), median follow-up was 65.1 months (range, 60.8-74.1 months). Median OS was 12.6 months (95% CI, 7.5-17.1 months); the 48- and 60-month OS rates were 30% (95% CI, 20%-40%) and 26% (95% CI, 17%-36%), respectively. At data cutoff, treatment was ongoing in 1 patient (1.1%) and an additional patient (1.1%) had reinitiated avelumab after previously discontinuing treatment. Reasons for treatment discontinuation were disease progression (n = 45 [51.1%]), adverse event (AE; n = 11 [12.5%]), death (n = 10 [11.4%]), withdrawal of consent (n = 9 [10.2%]), loss to follow-up (n = 1 [1.1%]), protocol noncompliance (n = 1 [1.1%]), and other reason (n = 10 [11.4%]). At data cutoff, 19 patients (21.6%) had discontinued treatment but remained in follow-up, and 63 patients (71.6%) had died; causes of death were disease progression (n = 49 [55.7%]), unknown reason (n = 9 [10.2%]), AE not related to study treatment (n = 3 [3.4%]), and other reason (n = 2 [2.3%]). In total, 26 patients (29.5%) received subsequent anticancer therapy; the most common subsequent therapies after trial discontinuation were avelumab (n = 4 [4.5%]), carboplatin and etoposide (n = 4 [4.5%]), and pembrolizumab (n = 4 [4.5%]). Conclusions: Avelumab monotherapy led to meaningful long-term OS in a subset of patients with mMCC whose disease had progressed after chemotherapy. These results further support the role of avelumab as a standard-of-care treatment for patients with mMCC. Clinical trial information: NCT02155647.

Repurposing infectious diseases vaccines against cancer.

e14564 Background: Vaccines used to prevent infection have long been known to stimulate immune responses to cancer as illustrated by the approval of the Bacillus Calmette–Guérin (BCG) vaccine to treat bladder cancer since the 1970s. The recent approval of immunotherapies has rejuvenated this research area with reports of anti-tumour responses with existing infectious diseases vaccines used as such, either alone or in combination with approved immune checkpoint inhibitors. This prompted us to review recent research activities using approved vaccines to treat cancer. Methods: PubMed and clinicaltrials.gov databases were queried for all 31 infectious diseases having at least one preventive vaccine approved, and all hits were reviewed for relevance. Only articles and trial registrations about infectious diseases vaccines used in an unmodified form as treatment for cancer, were included. The search was restricted in time, capturing articles from the year 2000 until November 2020. Results: A total of 1,754 PubMed abstracts and 549 trial registrations were screened. Data supporting a cancer therapeutic use was found for 16 of the 31 infectious diseases vaccines. For 10 (BCG, diphtheria, tetanus, human papillomavirus (HPV), influenza, measles, pneumococcus, smallpox, typhoid and varicella-zoster), clinical trials have been conducted or are ongoing. Within the remaining 6, preclinical evidence supports further evaluation of the rotavirus, yellow fever and pertussis vaccine in carefully designed clinical trials. The mechanistic evidence for the cholera vaccine, combined with the observational data in colorectal cancer, is also supportive of clinical translation. There is limited data for the hepatitis B vaccine and for the mumps vaccine alone. Four findings are worth highlighting: first, the superiority of intra-vesical typhoid vaccine instillations over BCG instillations in a preclinical bladder cancer model, which is now the subject of a phase I trial; second, the perioperative use of the influenza vaccine to limit and prevent the NK cell dysfunction induced by cancer surgery; third, objective responses following intra-tumoral injections of the measles vaccine in cutaneous T-cell lymphoma; fourth, objective responses induced by the HPV vaccine in skin squamous cell carcinoma. Conclusions: Sixteen infectious diseases vaccines have been or are currently being explored for repurposing in oncology. All vaccines are intended to induce or improve an anti-tumour (immune) response. Next to biological and immunological mechanisms, that are very different from one vaccine to another, also the mode of administration and combinations and sequence with other (immuno-)therapies deserve more attention in future research.

Artificial intelligence-powered spatial analysis of tumor infiltrating lymphocytes (TIL) to reflect target gene expressions of novel immuno-oncology agents.

e14534 Background: Novel immuno-oncology (IO) agents are promising but showing their efficacy in early phase clinical trials has been challenging due to limited enrichment strategies using practical biomarker platforms. We hypothesize that an artificial intelligence (AI)-powered spatial analysis of TIL using practically feasible H&amp;E slides, can reflect a specific target gene expression derived from RNA sequencing. This enhances its potential application in early development of novel IO agents. Methods: An AI-powered spatial TIL analyzer, namely Lunit SCOPE IO, was developed with data from 2.8 x 109 micrometer2 H&amp;E-stained tissue regions and 5.9 x 106 TILs from 3,166 whole slide images of multiple cancer types, annotated by board-certified pathologists. Inflamed Score and Immune-Excluded Score was defined as the proportion of all tumor-containing 1 mm2-size tiles within a WSI classified as being of inflamed immune phenotype (high TIL density within cancer epithelium) and immune-excluded phenotype (low TIL density within cancer epithelium, but high TIL density within stroma), respectively. We used RNA sequencing data and H&amp;E images from The Cancer Genome Atlas database, excluding those of mesenchymal origin (n = 7,467). Spearman's rank correlation between each gene expression and IS or IES, respectively, was calculated. Correlation coefficient &gt; 0.2 and false discovery rate (FDR) &lt; 1% was considered as a significant correlation. Results: In a total of 20,304 genes, 871 (4.3%) and 1,155 (5.7%) genes were significantly correlated with Inflamed Score (IS) and Immune-Excluded Score (IES), respectively. The IS was highly related to genes reflecting immune cytolytic activity and targets of approved immune checkpoint inhibitors (Table). Interestingly, it was also significantly correlated with target genes of novel IO such as TIGIT, LAG3, TIM3, IDO, Adenosine receptor A2A, OX40, ICOS, M-CSF, IL2, IL7, and IL12. Moreover, the IES was exclusively correlated with the target genes of CEACAM, TGFB, and IL1. Conclusions: Expression levels of novel I-O target genes are correlated with three scores derived from AI-powered TIL analysis using H&amp;E slides, which can be easily applied to clinical research.[Table: see text]

Performance of Different Diagnostic PD-L1 Clones in Head and Neck Squamous Cell Carcinoma.

Background: The approval of immune checkpoint inhibitors in combination with specific diagnostic biomarkers presents new challenges to pathologists as tumor tissue needs to be tested for expression of programmed death-ligand 1 (PD-L1) for a variety of indications. As there is currently no requirement to use companion diagnostic assays for PD-L1 testing in Germany different clones are used in daily routine. While the correlation of staining results has been tested in various entities, there is no data for head and neck squamous cell carcinomas (HNSCC) so far.Methods: We tested five different PD-L1 clones (SP263, SP142, E1L3N, 22-8, 22C3) on primary HNSCC tumor tissue of 75 patients in the form of tissue microarrays. Stainings of both immune and tumor cells were then assessed and quantified by pathologists to simulate real-world routine diagnostics. The results were analyzed descriptively and the resulting staining pattern across patients was further investigated by principal component analysis and non-negative matrix factorization clustering.Results: Percentages of positive immune and tumor cells varied greatly. Both the resulting combined positive score as well as the eligibility for certain checkpoint inhibitor regimens was therefore strongly dependent on the choice of the antibody. No relevant co-clustering and low similarity of relative staining patterns across patients was found for the different antibodies.Conclusions: Performance of different diagnostic anti PD-L1 antibody clones in HNSCC is less robust and interchangeable compared to reported data from other tumor entities. Determination of PD-L1 expression is critical for therapeutic decision making and may be aided by back-to-back testing of different PD-L1 clones.

Hepatocellular Carcinoma Immune Landscape and the Potential of Immunotherapies.

Hepatocellular carcinoma (HCC) is the most common liver tumor and among the deadliest cancers worldwide. Advanced HCC overall survival is meager and has not improved over the last decade despite approval of several tyrosine kinase inhibitors (TKi) for first and second-line treatments. The recent approval of immune checkpoint inhibitors (ICI) has revolutionized HCC palliative care. Unfortunately, the majority of HCC patients fail to respond to these therapies. Here, we elaborate on the immune landscapes of the normal and cirrhotic livers and of the unique HCC tumor microenvironment. We describe the molecular and immunological classifications of HCC, discuss the role of specific immune cell subsets in this cancer, with a focus on myeloid cells and pathways in anti-tumor immunity, tumor promotion and immune evasion. We also describe the challenges and opportunities of immunotherapies in HCC and discuss new avenues based on harnessing the anti-tumor activity of myeloid, NK and γδ T cells, vaccines, chimeric antigen receptors (CAR)-T or -NK cells, oncolytic viruses, and combination therapies.

A Randomized Phase II Trial Comparing the Efficacy and Safety of Pioglitazone, Clarithromycin and Metronomic Low-Dose Chemotherapy with Single-Agent Nivolumab Therapy in Patients with Advanced Non-small Cell Lung Cancer Treated in Second or Further Line (ModuLung).

Background: Most non-small cell lung cancers occur in elderly and frequently comorbid patients. Therefore, it is necessary to evaluate the efficacy of biomodulatory active therapy regimen, concertedly interfering with tumor-associated homeostatic pathways to achieve tumor control paralleled by modest toxicity profiles. Patients and Methods: The ModuLung trial is a national, multicentre, prospective, open-label, randomized phase II trial in patients with histologically confirmed stage IIIB/IV squamous (n = 11) and non-squamous non-small cell (n = 26) lung cancer who failed first-line platinum-based chemotherapy. Patients were randomly assigned on a 1:1 ratio to the biomodulatory or control group, treated with nivolumab. Patients randomized to the biomodulatory group received an all-oral therapy consisting of treosulfan 250 mg twice daily, pioglitazone 45 mg once daily, clarithromycin 250 mg twice daily, until disease progression or unacceptable toxicity. Results: The study had to be closed pre-maturely due to approval of immune checkpoint inhibitors (ICi) in first-line treatment. Thirty-seven patients, available for analysis, were treated in second to forth-line. Progression-free survival (PFS) was significantly inferior for biomodulation (N = 20) vs. nivolumab (N = 17) with a median PFS (95% confidence interval) of 1.4 (1.2–2.0) months vs. 1.6 (1.4–6.2), respectively; with a hazard ratio (95% confidence interval) of 1.908 [0.962; 3.788]; p = 0.0483. Objective response rate was 11.8% with nivolumab vs. 5% with biomodulation, median follow-up 8.25 months. The frequency of grade 3–5 treatment related adverse events was 29% with nivolumab and 10% with biomodulation. Overall survival (OS), the secondary endpoint, was comparable in both treatment arms; biomodulation with a median OS (95% confidence interval) of 9.4 (6.0–33.0) months vs. nivolumab 6.9 (4.6–24.0), respectively; hazard ratio (95% confidence interval) of 0.733 [0.334; 1.610]; p = 0.4368. Seventy-five percent of patients in the biomodulation arm received rescue therapy with checkpoint inhibitors. Conclusions: This trial shows that the biomodulatory therapy was inferior to nivolumab on PFS. However, the fact that OS was similar between groups gives rise to the hypothesis that the well-tolerable biomodulatory therapy may prime tumor tissues for efficacious checkpoint inhibitor therapy, even in very advanced treatment lines where poor response to ICi might be expected with increasing line of therapy.

If Virchow and Ehrlich Had Dreamt Together: What the Future Holds for KRAS-Mutant Lung Cancer.

Non-small-cell lung cancer (NSCLC) with Kirsten rat sarcoma (KRAS) mutations has notoriously challenged oncologists and researchers for three notable reasons: (1) the historical assumption that KRAS is “undruggable”, (2) the disease heterogeneity and (3) the shaping of the tumor microenvironment by KRAS downstream effector functions. Better insights into KRAS structural biochemistry allowed researchers to develop direct KRAS(G12C) inhibitors, which have shown early signs of clinical activity in NSCLC patients and have recently led to an FDA breakthrough designation for AMG-510. Following the approval of immune checkpoint inhibitors for PDL1-positive NSCLC, this could fuel yet another major paradigm shift in the treatment of advanced lung cancer. Here, we review advances in our understanding of the biology of direct KRAS inhibition and project future opportunities and challenges of dual KRAS and immune checkpoint inhibition. This strategy is supported by preclinical models which show that KRAS(G12C) inhibitors can turn some immunologically “cold” tumors into “hot” ones and therefore could benefit patients whose tumors harbor subtype-defining STK11/LKB1 co-mutations. Forty years after the discovery of KRAS as a transforming oncogene, we are on the verge of approval of the first KRAS-targeted drug combinations, thus therapeutically unifying Paul Ehrlich’s century-old “magic bullet” vision with Rudolf Virchow’s cancer inflammation theory.

If small molecules immunotherapy comes, can the prime be far behind?

Anti-cancer immunotherapy, which includes cellular immunotherapy, immune checkpoint inhibitors and cancer vaccines, has transformed the treatment strategies of several malignancies in the past decades. Immune checkpoints blockade (ICB) is the most commonly tested therapy and has the potential to induce a durable immune response in different types of cancers. However, all approved immune checkpoint inhibitors (ICIs) are monoclonal antibodies (mAbs), which are fraught with disadvantages including lack of oral bioavailability, prolonged tissue retention and poor membrane permeability. Therefore, the research focus has shifted to developing small molecule inhibitors to obviate the limitations of mAbs. Given the complexity of the tumor micro-environment (TME), the combination of ICIs with various small molecule agonists/inhibitors are currently being tested in clinical trials to improve treatment outcomes and prevent tumor recurrence. In this review, we have summarized the mechanisms and therapeutic potential of several molecular targets, along with the current status of small molecule inhibitors.

Role of Immunotherapy in Stage IV Large Cell Neuroendocrine Carcinoma of the Lung.

Background:Despite approvals of immune checkpoint inhibitors in both small cell and non-small cell lung cancers, the role of immunotherapy in large cell neuroendocrine carcinoma (LCNEC) in lung is undefined. Methods:Using the National Cancer Database (NCDB), Stage IV lung LCNEC cases diagnosed from 2014 to 2016 were analyzed. Information regarding cancer treatment was limited to first course of therapy, including surgery for primary lesion, radiation, chemotherapy, and immunotherapy. Survival analysis was performed using Kaplan-Meier curves and Log-rank tests. Cox proportional hazard model was used for multivariate analysis. Results:Among 661 eligible cases, 37 patients were treated with immunotherapy. No significant association between use of immunotherapy and clinical demographics was observed except for use of chemotherapy (p=0.0008). Chemotherapy was administered in 34 (92%) and 406 (65%) in immunotherapy and non-immunotherapy groups, respectively. Use of immunotherapy was associated with improved overall survival (Log-rank p=0.0018). Landmark analysis in the immunotherapy group showed 12 and 18-month survivals of 34.0% and 29.1%, respectively, whereas those in the non-immunotherapy group were 24.1% and 15.0%, respectively. Multivariate analysis demonstrated that female sex (HR=0.79, p=0.0063), liver metastases (HR=0.75, p=.0392), surgery (HR= 0.50, p<0.0001) use of chemotherapy (HR= 0.44, p<0.0001), and use of immunotherapy (HR=0.64, p=0.0164) had statistical significance. Propensity score matching in overall survival analysis showed a nonsignificant trend (p=0.0733) in favor of immunotherapy treatment. Conclusion:This retrospective study using NCDB suggests that use of immunotherapy may improve survival of LCNEC patients.

Novel Combination Therapies for the Treatment of Bladder Cancer.

Bladder cancer is the ninth most frequently diagnosed cancer world-wide and ranks 13th in cancer-related deaths. Two tremendous breakthroughs in bladder cancer therapy over the last decades are the approval of immune checkpoint inhibitors(ICIs)and the fibroblast growth factor receptor tyrosine kinase inhibitor (FGFR-TKI) erdafitinib for treating this deadly disease. Despite the beneficial effects of these approaches, the low response rate and the potential resistance of the cancer are major concerns. Hence, novel combination therapies to overcome these limitations have been investigated. In this context, combining immunotherapy with targeted drugs is an appealing therapeutic option to improve response and reduce the emergence of resistance in the management of bladder cancer. In this review, the rationale of using different therapeutic combinations is discussed according to the mechanistic differences, emphasizing the efficacy and safety based on evidence collected from preclinical and clinical studies. Finally, we highlight the limitations of these combinations and provide suggestions for further efforts in this challenging field.

Hepatobiliary and Pancreatic Adverse Events.

The expanded approval of immune checkpoint inhibitors (ICIs) for the treatment of multiple cancer types has offered patients more opportunities in treatment selection and survival.Hepatotoxicity is a well-recognized immune-related adverse event (irAE) associated with treatment with ICI. It is considered a type of drug-induced liver injury (DILI). Depending on the specific ICI and whether the patient receives single- or dual-drug therapy, the incidence of hepatotoxicity in general could be as high as 30%. As more patients receive treatment with ICI, more cases of hepatotoxicity are expected to occur. Clinicians must exercise close pharmacovigilance to recognize liver-related irAEs early.ICI-mediated hepatobiliary toxicity (or "IMH")generally presents as asymptomatic elevations of alanine transaminase and aspartate transaminase, with or without alkaline phosphatase elevation. Some patients may present with jaundice, fever, or malaise. Rarely, it may cause liver failure and death. The diagnosis of IMH is made after careful exclusion of other causes of acute hepatitis based on medical history, laboratory evaluation, imaging, and liver histological findings. In clinically significant cases of IMH, the management involves discontinuation of ICI followed by close monitoring and the initiationof immunosuppression. Current society guidelines, which are not based on robust evidence, specify treatment recommendations depending on the grade of liver injury, according to the Common Terminology Criteria for Adverse Events (CTCAE)version 5.0. However, our clinical experience suggests possible alternatives, including lower corticosteroid dosing with adjunct therapies. Whereas current guidelines endorse permanent cessation of future ICI treatment in patients diagnosed with grades 3-4 IMH, published clinical experience suggests potential for flexibility when assessing for candidacy of resuming ICI.Because histologic bile duct injury has been observed in cases ascribed to IMH, ICI-mediated cholangiopathic disease probably exists on a spectrum within IMH. Even extrahepatic bile duct involvement has been observed. This phenotype warrants special considerations in treatment and surveillance.ICI-related cholecystitis has been rarely reported in the literature. Management follows current standards of care for typical cases of cholecystitis. No relationship with ICI-mediated cholangiopathic disease has been observed.Assessing for and managing ICI-associated pancreatic injury remainchallenging to the clinician. Many cases of asymptomatic serum lipase elevation are detected on routine labs without clinical signs or symptoms of typical acute pancreatitis. However, symptomatic patients should be initially managed like traditional cases of acute pancreatitis requiring hospitalization for evaluation and inpatient management.

Combination of molecularly targeted therapies and immune checkpoint inhibitors in the new era of unresectable hepatocellular carcinoma treatment.

Multikinase inhibitors (MKIs) have been the only first-line treatment for advanced hepatocellular carcinoma (HCC) for more than a decade, until the approval of immune checkpoint inhibitors (ICIs). Moreover, the combination regimen of atezolizumab (anti-programmed cell death protein ligand 1 antibody) plus bevacizumab (anti-vascular endothelial growth factor monoclonal antibody) has recently been demonstrated to have superior efficacy when compared with sorafenib monotherapy. The remarkable efficacy has made this combination therapy the new standard treatment for advanced HCC. In addition to MKIs, many other molecularly targeted therapies are under investigation, some of which have shown promising results. Therefore, in the era of immuno-oncology, there is a significant rationale for testing the combinations of molecularly targeted therapies and ICIs. Indeed, numerous preclinical and clinical studies have shown the synergic antitumor efficacy of such combinations. In this review, we aim to summarize the current knowledge on the combination of molecularly targeted therapies and immune checkpoint therapies for HCC from both preclinical and clinical perspectives.

MMP-7 Serum and Tissue Levels Are Associated with Poor Survival in Platinum-Treated Bladder Cancer Patients.

Chemotherapy resistance is a main cause of therapeutic failure and death in bladder cancer. With the approval of immune checkpoint inhibitors, prediction of platinum treatment became of great clinical importance. Matrix metalloproteinase-7 (MMP-7) was shown to be involved in cisplatin resistance. Therefore, tissue and circulating MMP-7 levels were evaluated in 124 bladder cancer patients who received postoperative platinum-based chemotherapy. Tissue MMP-7 levels were analyzed by immunohistochemistry in 72 formalin-fixed, paraffin-embedded chemo-naïve tumor samples, while MMP-7 serum concentrations were determined in 132 serum samples of an independent cohort of 52 patients. MMP-7 tissue and serum levels were correlated with clinicopathological and follow-up data. MMP-7 gene expression was determined by RT-qPCR in 20 urothelial cancer cell lines and two non-malignant urothelial cell lines. MMP-7 was overexpressed in RT-112 and T-24 cells by stable transfection, to assess its functional involvement in platinum sensitivity. High MMP-7 tissue expression and pretreatment serum concentrations were independently associated with poor overall survival (tissue HR = 2.296, 95%CI = 1.235–4.268 and p = 0.009; serum HR = 2.743, 95%CI = 1.258–5.984 and p = 0.011). Therefore, MMP-7 tissue and serum analysis may help to optimize therapeutic decisions. Stable overexpression in RT-112 and T-24 cells did not affect platinum sensitivity.

Assessment of Trends in Second Primary Cancers in Patients With Metastatic Melanoma From 2005 to 2016

To date, the risk of developing second primary cancers (SPCs) after the first primary melanoma has not been studied in the era of immune checkpoint inhibitors (ICIs). To assess differences in the risk of SPCs in patients with primary melanoma before (2005-2010) and after (2011-2016) the introduction and approval of ICIs. Population-based cohort study using the Surveillance, Epidemiology, and End Results database from January 2005 to December 2016 of patients diagnosed with metastatic melanoma. Data were analyzed from January 4 to June 30, 2020. Receipt of immunotherapy or other anticancer agents. The primary outcome was the development of second primary cancers in patients with melanoma. Standardized incidence ratios (SIRs) were calculated for the development of SPCs before and after the introduction of ICIs. Among 5016 patients with diagnosed metastatic melanoma, 2888 (58%) were younger than 65 years at the time of diagnosis, and 3441 (69%) were male. From 2005 to 2010, SIRs were 3.24 (95% CI, 0.08-18.04) for small intestine cancer, 1.93 (95% CI, 1.14-3.05) for lung and bronchus cancer, 2.77 (95% CI, 1.02-6.03) for kidney cancer, and 7.29 (95% CI, 2.93-15.02) for myeloma. From 2011 to 2016, SIRs were 9.23 (95% CI, 1.12-33.35) for small intestine cancer, 1.54 (95% CI, 0.71-2.93) for lung and bronchus cancer, 2.66 (95% CI, 0.73-6.82) for kidney cancer, and 5.90 (95% CI, 1.61-15.10) for myeloma. The overall risk of developing SPCs in individuals who survived the first primary melanoma was 65% higher (SIR, 1.65; 95% CI, 1.35-2.00) in the pre-ICIs period and 98% higher (SIR, 1.98; 95% CI, 1.57-2.45) in the post-ICIs period than the overall cancer incidence rate in the general population. In this study, an increase in the overall risk of second primary cancers after melanoma after the introduction of immune checkpoint inhibitors was observed. The pattern of SPCs has been altered in the era of systemic therapy. Close monitoring and screening for SPCs may be warranted in patients with metastatic melanoma.