Combination of novel HER2‐targeting antibody 1E11 with trastuzumab shows synergistic antitumor activity in HER2‐positive gastric cancer

The synergistic interaction of two antibodies targeting the same protein could be developed as an effective anti‐cancer therapy. Human epidermal growth factor receptor 2 (HER2) is overexpressed in 20–25% of breast and gastric cancer patients, and HER2‐targeted antibody therapy using trastuzumab is effective in many of these patients. Nonetheless, improving therapeutic efficacy and patient survival is important, particularly in patients with HER2‐positive gastric cancer. Here, we describe the development of 1E11, a HER2‐targeted humanized monoclonal antibody showing increased efficacy in a highly synergistic manner in combination with trastuzumab in the HER2‐overexpressing gastric cancer cell lines NCI‐N87 and OE‐19. The two antibodies bind to sub‐domain IV of the receptor, but have non‐overlapping epitopes, allowing them to simultaneously bind HER2. Treatment with 1E11 alone induced apoptosis in HER2‐positive cancer cells, and this effect was enhanced by combination treatment with trastuzumab. Combination treatment with 1E11 and trastuzumab reduced the levels of total HER2 protein and those of aberrant HER2 signaling molecules including phosphorylated HER3 and EGFR. The synergistic antitumor activity of 1E11 in combination with trastuzumab indicates that it could be a novel potent therapeutic antibody for the treatment of HER2‐overexpressing gastric cancers.     

Acquired resistance to EGFR-targeted therapies in colorectal cancer

Cetuximab and panitumumab are anti‐epidermal growth factor receptor (anti‐EGFR) monoclonal antibodies used as therapies for metastatic colorectal cancer patients. Intrinsic mechanisms of resistance, such as RAS mutations, can prevent patients from having a response with clinical benefit. The clinical efficacy of EGFR targeted antibodies is limited by the development of acquired (secondary) resistance, which typically occurs within 3–12 months from the start of therapy. Preclinical models and analyses of clinical samples have uncovered some of the alterations that confer a selective advantage to tumor cells when under the pressure of anti‐EGFR therapy. Molecular profiling of clinical specimens confirmed that genetic alterations of genes in the EGFR‐RAS‐RAF‐MEK signaling pathway and of receptor tyrosine kinases are mechanisms of acquired resistance to anti‐EGFR antibodies. The escape from anti‐EGFR blockade appears to converge on the (re)activation of MEK‐ERK or AKT as revealed in preclinical studies. Circulating tumor DNA and patient derived xenografts have proven useful tools to monitor patients for resistance to anti‐EGFR therapy and test combination therapies to overcome or reverse resistance.     

Recent progress of nanotechnology-based theranostic systems in cancer treatments

Theranostics that integrates therapy and diagnosis in one system to achieve accurate cancer diagnosis and treatment has attracted tremendous interest, and has been recognized as a potential breakthrough in overcoming the challenges of conventional oncotherapy. Nanoparticles are ideal candidates as carriers for theranostic agents, which is attributed to their extraordinary physicochemical properties, including nanoscale sizes, functional properties, prolonged blood circulation, active or passive tumor targeting, specific cellular uptake, and in some cases, excellent optical properties that ideally meet the needs of phototherapy and imaging at the same time. Overall, with the development of nanotechnology, theranostics has become a reality, and is now in the transition stage of “bench to bedside.” In this review, we summarize recent progress on nanotechnology-based theranostics, i.e., nanotheranostics, that has greatly assisted traditional therapies, and has provided therapeutic strategies emerging in recent decades, as well as “cocktail” theranostics mixing various treatment modalities.     

Increase of MET gene copy number confers resistance to a monovalent MET antibody and establishes drug dependence

The relevant role in cancer played by the tyrosine kinase receptor encoded by the MET oncogene led to the development of specific inhibitors, some of which are now in advanced phases of clinical trials. Previous experience has shown that the main limit to the efficacy of most targeted treatments is the advent of resistance. Mechanisms underlying resistance to MET‐specific small tyrosine kinase inhibitors (TKIs) have been already described, while nothing is known about resistance to MET monoclonal antibodies, nor about bypassing resistance to chemical TKIs by antibodies or vice‐versa. EBC1 lung cancer cells are MET‐addicted as a consequence of gene amplification and thus sensitive to MET inhibitors, including the monovalent form of a MET monoclonal antibody (MV‐DN30). We generated cells resistant to this antibody and found that resistance was due to a further increase of gene copy number and a dramatic overexpression of the MET receptor. Such an excess of expression saturated the ‘shedding’ activity of MV‐DN30, and prevented both the efficient down‐regulation of the MET receptor from the surface and the inhibition of the ensuing constitutive activation. Notably, antibody‐resistant cells remained MET‐‘addicted’ and were still sensitive to MET TKIs. Moreover, antibody‐resistant cells became ‘drug‐dependent’, since the removal of MV‐DN30 led them to death due to excess of signal. In the mirror experiment, cells made resistant to MET‐specific TKIs were still sensitive to treatment with the antibody MV‐DN30. These findings suggest that a discontinuous, combined treatment by antibodies and chemical kinase inhibitors may increase the clinical response and bypass resistance to anti‐MET targeted therapies.     

Optimizing Treatment De‐Escalation in Head and Neck Cancer: Current and Future Perspectives

Treatment of locoregionally advanced head and neck squamous cell carcinoma involves a multidisciplinary approach that combines surgery, radiotherapy, and systemic therapy. These curative strategies are associated with significant acute and long‐term toxicities. With the emergence of human papillomavirus (HPV) as an etiologic factor associated primarily with oropharyngeal squamous cell carcinoma, higher cure rates juxtaposed with substantial treatment‐related morbidity and mortality has led to interest in de‐escalated therapeutic strategies, with the goal of optimizing oncologic outcomes while reducing treatment‐related toxicity. Currently explored strategies include replacing, reducing, or omitting cytotoxic chemotherapy; reducing dose or volume of radiotherapy; and incorporation of less‐invasive surgical approaches. Potential biomarkers to select patients for treatment de‐escalation include clinical risk stratification, adjuvant de‐escalation based on pathologic features, response to induction therapy, and molecular markers. The optimal patient selection and de‐escalation strategy is critically important in the evolving treatment of locoregional head and neck cancer. Recently, two large phase III trials, RTOG 1016 and De‐ESCALaTE, failed to de‐escalate treatment in HPV‐associated head and neck cancer by demonstrating inferior outcomes by replacing cisplatin with cetuximab in combination with radiation. This serves as a cautionary tale in the future design of de‐escalation trials in this patient population, which will need to leverage toxicity and efficacy endpoints. Our review summarizes completed and ongoing de‐escalation trials in head and neck cancer, with particular emphasis on biomarkers for patient selection and clinical trial design.Implications for PracticeThe toxicity associated with standard multimodality treatment for head and neck cancer underscores the need to seek less‐intensive therapies with a reduced long‐term symptom burden through de‐escalated treatment paradigms that minimize toxicity while maintaining oncologic control in appropriately selected patients. Controversy regarding the optimal de‐escalation strategy and criteria for patient selection for de‐escalated therapy has led to multiple parallel strategies undergoing clinical investigation. Well‐designed trials that optimize multimodal strategies are needed. Given the absence of positive randomized trials testing de‐escalated therapy to date, practicing oncologists should exercise caution and administer established standard‐of‐care therapy outside the context of a clinical trial.     

Cancer therapeutic antibodies come of age: Targeting minimal residual disease

Ten years after the first clinical application of Rituximab, an anti‐CD20 recombinant monoclonal antibody, immunotherapy has become common practice in oncology wards. Thanks to the great diversity of the immune system and the powerful methodology of genetic engineering, the pharmacologic potential of antibody‐based therapy is far from exhaustion. The recent application of Trastuzumab, an antibody to a receptor tyrosine kinase, in adjuvant breast cancer therapy marks the beginning of a new phase in cancer treatment. Here we discuss molecular mechanisms of antibody‐based therapy, the emerging ability to target minimal disease and the therapeutic potential of combining antibodies with other modalities.     

Potent anti‐tumor response by targeting B cell maturation antigen (BCMA) in a mouse model of multiple myeloma

Multiple myeloma (MM) is an aggressive incurable plasma cell malignancy with a median life expectancy of less than seven years. Antibody‐based therapies have demonstrated substantial clinical benefit for patients with hematological malignancies, particular in B cell Non‐Hodgkin''s lymphoma. The lack of immunotherapies specifically targeting MM cells led us to develop a human‐mouse chimeric antibody directed against the B cell maturation antigen (BCMA), which is almost exclusively expressed on plasma cells and multiple myeloma cells. The high affinity antibody blocks the binding of the native ligands APRIL and BAFF to BCMA. This finding is rationalized by the high resolution crystal structure of the Fab fragment in complex with the extracellular domain of BCMA. Most importantly, the antibody effectively depletes MM cells in vitro and in vivo and substantially prolongs tumor‐free survival under therapeutic conditions in a xenograft mouse model. A BCMA‐antibody‐based therapy is therefore a promising option for the effective treatment of multiple myeloma and autoimmune diseases.     

Epidermal growth factor receptor mutation and diverse tumors: Case report and concise literature review

We document an EGFR mutation in a patient with papillary renal cell cancer with a history of multiple therapies, including interferon‐alfa, interleukin‐2, 5‐fluorouracil, and interferon‐alfa together with 13‐cis‐retinoic acid, to which floxuridine was later added, and thalidomide maintenance therapy for six years. We provide a succinct review of the PubMed‐derived literature on EGFR mutations in diverse tumors, which indicates that a subset of patients with various tumor types may harbor EGFR mutations. A 32‐year old woman with sporadic, metastatic papillary renal cancer was found to harbor an EGFR kinase domain mutation in addition to the MET kinase mutation typically found in this disease. Since lung cancer patients with EGFR mutations often respond well to EGFR inhibitor therapy and EGFR mutations occur in a variety of tumors, it should be worthwhile to assess EGFR status prospectively in other tumors and study the results of treatment with EGFR inhibitors in these patients.     

HER family kinase domain mutations promote tumor progression and can predict response to treatment in human breast cancer

Resistance to HER2‐targeted therapies remains a major obstacle in the treatment of HER2‐overexpressing breast cancer. Understanding the molecular pathways that contribute to the development of drug resistance is needed to improve the clinical utility of novel agents, and to predict the success of targeted personalized therapy based on tumor‐specific mutations. Little is known about the clinical significance of HER family mutations in breast cancer. Because mutations within HER1/EGFR are predictive of response to tyrosine kinase inhibitors (TKI) in lung cancer, we investigated whether mutations in HER family kinase domains are predictive of response to targeted therapy in HER2‐overexpressing breast cancer. We sequenced the HER family kinase domains from 76 HER2‐overexpressing invasive carcinomas and identified 12 missense variants. Patients whose tumors carried any of these mutations did not respond to HER2 directed therapy in the metastatic setting. We developed mutant cell lines and used structural analyses to determine whether changes in protein conformation could explain the lack of response to therapy. We also functionally studied all HER2 mutants and showed that they conferred an aggressive phenotype and altered effects of the TKI lapatinib. Our data demonstrate that mutations in the finely tuned HER kinase domains play a critical function in breast cancer progression and may serve as prognostic and predictive markers.     

Tumor‐infiltrating lymphocytes for the treatment of metastatic cancer

Over the past few years melanoma incidence has been rising steadily, resulting in an increase in melanoma related mortality. Until recently, therapeutic options for metastatic melanoma were scarce. Chemotherapy and, in some countries, IL‐2 were the only registered treatment modalities. In the last five years, treatment with immunotherapy (anti CTLA‐4, anti PD‐1, or the combination of these antibodies) has shown very promising results and was able to improve survival in patients with metastatic melanoma. Adoptive cell therapy using tumor‐infiltrating lymphocytes is yet another, but highly promising, immunotherapeutic strategy for patients with metastatic melanoma. This review will discuss the development of TIL as a treatment option for melanoma, its mode of action and simplification over time, and the possibilities to expand this therapy to other types of cancer. Also, the future directions of TIL based therapies will be highlighted.     

No longer an untreatable disease: How targeted and immunotherapies have changed the management of melanoma patients

The discovery that BRAF is a driver oncogene in cancer, and complementary improvements in our understanding of the immune system have resulted in new targeted and immune‐therapies for metastatic melanoma. Targeted therapies achieve impressive clinical results in carefully selected patients but the development of resistance seems inevitable in most cases. Conversely, immune‐checkpoints inhibitors can achieve long‐term remission and cures, but in a smaller proportion of patients, and biomarkers to predict which patients will respond are not available. Nevertheless, melanoma has led the evolution of cancer treatment from relatively nonspecific cytotoxic agents to highly selective therapies and here we review the lessons from this paradigm shift in treatment and the opportunities for further improvements in outcomes for melanoma patients.     

Clinical Outcomes of Patients with Metastatic Cancer Receiving Immune Checkpoint Inhibitors in the Inpatient Setting

BackgroundAs indications for immune checkpoint inhibitor (ICI) therapy have increased in recent years, so has the proportion of patients eligible for this type of therapy. However, a lack of data exists about the risks and benefits of ICI therapy in hospitalized patients, who tend to be frailer and sicker than patients enrolled in clinical trials.Material and MethodsWe conducted a retrospective cohort study among hospitalized patients with metastatic solid tumors who received ICI therapy at a large academic cancer center over the course of 4 years. We analyzed the characteristics and outcomes of these patients and identified demographic and clinical factors that could be used to predict mortality.ResultsDuring the 4‐year study period, 106 patients were treated with ICI therapy while admitted to the hospital; 70 (66%) had Eastern Cooperative Oncology Group Performance Status ≥2, which would have prevented them from enrolling in most clinical trials of ICIs. Fifty‐two patients (49%) died either during admission or within 30 days of discharge; median overall survival was 1.0 month from discharge, and 16 patients (15%) were alive 6 months after discharge. Independent predictors of death following receipt of inpatient ICI included a diagnosis of non‐small cell lung cancer relative to melanoma and prior treatment with two or more lines of therapy.ConclusionThe poor overall outcomes observed in this study may give clinicians pause when considering ICI therapy for hospitalized patients, particularly those with characteristics that are associated with a greater risk of mortality.Implications for PracticeImmunotherapy strategies for patients with cancer are rapidly evolving and their use is expanding, but not all patients will develop a response, and secondary toxicity can be significant and challenging. This is especially evident in hospitalized patients, where the economic cost derived from inpatient immune checkpoint inhibitor (ICI) administration is important and the clinical benefit is sometimes unclear. The poor overall outcomes evidenced in the ICI inpatient population in this study highlight the need to better identify the patients that will respond to these therapies, which will also help to decrease the financial burden imposed by these highly priced therapies.     

Therapeutic Potential of Afatinib in NRG1 Fusion‐Driven Solid Tumors: A Case Series

BackgroundNeuregulin 1 (NRG1) fusions, which activate ErbB signaling, are rare oncogenic drivers in multiple tumor types. Afatinib is a pan‐ErbB family inhibitor that may be an effective treatment for NRG1 fusion‐driven tumors.Patients and MethodsThis report summarizes pertinent details, including best tumor response to treatment, for six patients with metastatic NRG1 fusion‐positive tumors treated with afatinib.ResultsThe six cases include four female and two male patients who ranged in age from 34 to 69 years. Five of the cases are patients with lung cancer, including two patients with invasive mucinous adenocarcinoma and three patients with nonmucinous adenocarcinoma. The sixth case is a patient with colorectal cancer. NRG1 fusion partners for the patients with lung cancer were either CD74 or SDC4. The patient with colorectal cancer harbored a novel POMK‐NRG1 fusion and a KRAS mutation. Two patients received afatinib as first‐ or second‐line therapy, three patients received the drug as third‐ to fifth‐line therapy, and one patient received afatinib as fifteenth‐line therapy. Best response with afatinib was stable disease in two patients (duration up to 16 months when combined with local therapies) and partial response (PR) of >18 months in three patients, including one with ongoing PR after 27 months. The remaining patient had a PR of 5 months with afatinib 40 mg/day, then another 6 months after an increase to 50 mg/day.ConclusionThis report reviews previously published metastatic NRG1 fusion‐positive tumors treated with afatinib and summarizes six previously unpublished cases. The latter include several with a prolonged response to treatment (>18 months), as well as the first report of efficacy in NRG1 fusion‐positive colorectal cancer. This adds to the growing body of evidence suggesting that afatinib can be effective in patients with NRG1 fusion‐positive tumors.Key Points

• NRG1 fusions activate ErbB signaling and have been identified as oncogenic drivers in multiple solid tumor types. Afatinib is a pan‐ErbB family inhibitor authorized for the treatment of advanced non‐small cell lung cancer that may be effective in NRG1 fusion‐driven tumors.
• This report summarizes six previously unpublished cases of NRG1 fusion‐driven cancers treated with afatinib, including five with metastatic lung cancer and one with metastatic colorectal cancer.
• Several patients showed a prolonged response of >18 months with afatinib treatment. This case series adds to the evidence suggesting a potential role for afatinib in this area of unmet medical need.

     

Overcoming the senescence‐associated secretory phenotype (SASP): a complex mechanism of resistance in the treatment of cancer

Senescence is a cellular state in which cells undergo persistent cell cycle arrest in response to nonlethal stress. In the treatment of cancer, senescence induction is a potent method of suppressing tumour cell proliferation. In spite of this, senescent cancer cells and adjacent nontransformed cells of the tumour microenvironment can remain metabolically active, resulting in paradoxical secretion of pro‐inflammatory factors, collectively termed the senescence‐associated secretory phenotype (SASP). The SASP plays a critical role in tumorigenesis, affecting numerous processes including invasion, metastasis, epithelial‐to‐mesenchymal transition (EMT) induction, therapy resistance and immunosuppression. With increasing evidence, it is becoming clear that cell type, tissue of origin and the primary cellular stressor are key determinants in how the SASP will influence tumour development and progression, including whether it will be pro‐ or antitumorigenic. In this review, we will focus on recent evidence regarding therapy‐induced senescence (TIS) from anticancer agents, including chemotherapy, radiation, immunotherapy, and targeted therapies, and how each therapy can trigger the SASP, which in turn influences treatment efficacy. We will also discuss novel pharmacological manipulation of senescent cancer cells and the SASP, which offers an exciting and contemporary approach to cancer therapeutics. With future research, these adjuvant options may help to mitigate many of the negative side effects and protumorigenic roles that are currently associated with TIS in cancer.     

Sustained compensatory p38 MAPK signaling following treatment with MAPK inhibitors induces the immunosuppressive protein CD73 in cancer: combined targeting could improve outcomes

RAS‐MAPK signaling promotes immune evasion and cancer cell survival, and MAPK inhibitors (MAPKis) are frequently used as cancer therapies. Despite progress elucidating the direct effects of MAPKi on immune cells, their indirect effect on the tumor microenvironment (TME) through changes in tumor cells remains incompletely understood. Here, we present evidence of a rapid compensatory response to MAPKi that is driven by sustained p38 MAPK signaling and by which cancer cells can upregulate the immunosuppressive protein CD73 to reduce the antitumor immune response. This compensatory response also results in decreased sensitivity toward MAPKi, and, accordingly, combining anti‐CD73 antibodies and MAPKi significantly enhances the antitumor effect compared to single‐agent treatment in vivo. Combining MAPKi and anti‐CD73 was accompanied by significant alterations in intratumor immune cell composition, supporting the effect of MAPKi‐induced CD73 expression on the TME. We show that high CD73 expression significantly correlates with worse outcome in MAPKi‐treated colorectal cancer patients, highlighting the potential clinical importance of increased CD73 expression following MAPKi treatment. Our findings may explain the diminished effect of MAPKi in cancer patients and provides further rationale for combined anti‐CD73 and MAPKi treatment.     

Bringing in health technology assessment and cost‐effectiveness considerations at an early stage of drug development

This paper reviews the issues involved in undertaking HTA studies early in the development of new cancer therapies, and discusses the data and methods for estimating the cost‐effectiveness of new diagnostics and treatments. The value for patients of new cancer therapies is based on access to the treatment and optimal use. Realising potential value depends on successful completion of a series of steps, from the initial economic evaluations based on clinical trial data, to the reimbursement decisions based on the evaluations and the implementation of these decisions in clinical practice. Considerable resources have been devoted to the study of the cost‐effectiveness of new cancer drugs as a basis for decisions about payment and use. Such resources could be used much more effectively if industry and HTA agencies were to collaborate at an early stage in the development process. The traditional clinical trial approach of using progression‐free survival and cross‐overs has serious shortcomings, producing data that cannot be used to determine outcomes and, so, cost‐effectiveness. A new standard is needed; both regulatory and HTA authorities should be involved in its development.     

Treatment of Cancer‐Associated Venous Thromboembolism with Low‐Molecular‐Weight Heparin or Direct Oral Anticoagulants: Patient Selection,Controversies, and Caveats

The treatment of venous thromboembolism (VTE) in patients with cancer is challenging because these patients have increased risks of both recurrent VTE and major bleeding, along with patient‐specific and cancer‐related factors that influence the approach to treatment. Historically, anticoagulant therapy with low‐molecular‐weight heparin (LMWH), given for both initial and long‐term treatment, has been the preferred approach recommended by practice guidelines. Most recently, the National Comprehensive Cancer Network (NCCN) guidelines indicate that the direct oral anticoagulants (DOACs) apixaban, edoxaban, or rivaroxaban are preferred for patients without gastric or gastroesophageal lesions. DOACs have been associated with an increased risk of major bleeding in patients with gastrointestinal and possibly genitourinary cancers, and DOACs should either not be used (especially in those with intact intraluminal tumors) or be used with caution in patients with these cancers. Fatal or life‐threatening bleeding occurs with similar frequency with DOACs or LMWH, and most major bleeding with DOACs can be managed with transfusion and standard measures. The patient''s willingness and ability to comply with LMWH injections, and their treatment preference, should also be considered. Patients with cancer who have VTE should be treated with anticoagulation for a minimum of 6 months. Anticoagulation should be continued indefinitely while cancer is active or under treatment or if there are persistent risk factors for recurrent VTE. This article summarizes the evidence from clinical trials of LMWH and DOACs that underpins the NCCN guideline recommendations, addresses several controversies and caveats regarding anticoagulant treatment, and offers evidence‐based, practical suggestions on patient selection for treatment with DOACs.Implications for PracticeSeveral randomized trials support the addition of direct oral anticoagulants (DOACs) to the therapeutic armamentarium for cancer‐associated venous thromboembolism (VTE). These agents come with unique risks and patient‐ and cancer‐specific variables that must be evaluated during the course of a patient''s cancer care. This narrative review discusses findings from clinical trials of low‐molecular‐weight heparin and DOACs for the treatment of cancer‐associated VTE, evidence that supports the recent National Comprehensive Cancer Network guideline recommendations. A personalized approach to treatment is proposed that addresses patient selection for treatment with DOACs, factors that influence efficacy and safety, controversies and caveats, and suggestions for their resolution in clinical practice.