The success of immune checkpoint blockade in patients with a wide variety of malignancies has changed the treatment paradigm in oncology. However, combination therapies with immune checkpoint ...blockade will be needed to overcome resistance and broaden the clinical utility of immunotherapy. Here we discuss a framework for rationally designing combination therapy strategies based on enhancing major discriminatory functions of the immune system that are corrupted by cancer—namely, antigenicity, adjuvanticity, and homeostatic feedback inhibition. We review recent advances on how conventional genotoxic cancer therapies, molecularly targeted therapies, epigenetic agents, and immune checkpoint inhibitors can restore these discriminatory functions. Potential barriers that can impede response despite combination therapy are also discussed.
Patel and Minn present a conceptual framework for the design of combination therapies wherein combination approaches are aimed at restoring discriminatory functions of the immune system that are corrupted by cancer—antigenicity, adjuvanticity, and feedback inhibition.
During the past century it has been established that regions within solid tumours experience mild to severe O(2) deprivation owing to aberrant vascular function. These hypoxic regions are associated ...with altered cellular metabolism, as well as increased resistance to radiation and chemotherapy. As discussed in this Timeline, over the past decade work from many laboratories has elucidated the mechanisms by which hypoxia-inducible factors (HIFs) modulate tumour cell metabolism, angiogenesis, growth and metastasis. The central role played by intra-tumoural hypoxia and HIF in these processes has made them attractive therapeutic targets in the treatment of multiple human malignancies.
Despite recent advances in first-line treatment for small-cell lung cancer (SCLC), durable responses remain rare. The DNA repair enzyme poly-(ADP)-ribose polymerase (PARP) was identified as a ...therapeutic target in SCLC using unbiased preclinical screens and confirmed in human and mouse models. Early trials of PARP inhibitors, either alone or in combination with chemotherapy, showed promising but limited responses, suggesting that selecting patient subsets and treatment combinations will prove critical to further clinical development. Expression of SLFN11 and other components of the DNA damage response (DDR) pathway appears to select for improved responses. Combining PARP inhibitors with agents that damage DNA and inhibit DDR appears particularly effective in preclinical and early trial data, as well as strategies that enhance antitumor immunity downstream of DNA damage. A robust understanding of the mechanisms of DDR in SCLC, which exhibits intrinsic replication stress, will improve selection of agents and predictive biomarkers. The most effective combinations will target multiple nodes in the DNA damage/DDR/immune activation cascade to minimize toxicity from synthetic lethality.
Hypoxia-inducible factor 1α (HIF-1α) and HIF-2α display unique and sometimes opposing activities in regulating cellular energy homeostasis, cell fate decisions, and oncogenesis. Macrophages exposed ...to hypoxia accumulate both HIF-1α and HIF-2α, and overexpression of HIF-2α in tumor-associated macrophages (TAMs) is specifically correlated with high-grade human tumors and poor prognosis. However, the precise role of HIF-2α during macrophage-mediated inflammatory responses remains unclear. To fully characterize cellular hypoxic adaptations, distinct functions of HIF-1α versus HIF-2α must be elucidated. We demonstrate here that mice lacking HIF-2α in myeloid cells (Hif2a.sup.Δ/Δ mice) are resistant to lipopolysaccharide-induced endotoxemia and display a marked inability to mount inflammatory responses to cutaneous and peritoneal irritants. Furthermore, HIF-2α directly regulated proinflammatory cytokine/chemokine expression in macrophages activated in vitro. Hif2a.sup.Δ/Δ mice displayed reduced TAM infiltration in independent murine hepatocellular and colitisassociated colon carcinoma models, and this was associated with reduced tumor cell proliferation and progression. Notably, HIF-2α modulated macrophage migration by regulating the expression of the cytokine receptor M-CSFR and the chemokine receptor CXCR4, without altering intracellular ATP levels. Collectively, our data identify HIF-2α as an important regulator of innate immunity, suggesting it may be a useful therapeutic target for treating inflammatory disorders and cancer.
Purpose of Review
Residual disease after neoadjuvant chemotherapy is a poor prognostic factor; however, proven strategies to reduce recurrence risk and improve overall survival in this patient ...population are limited. Previous studies of residual disease have illustrated the importance of tumor intrinsic subtypes in treatment response and mechanisms of resistance. This review summarizes the rationale for various therapeutic approaches as well as completed and ongoing clinical trials for this high-risk group of patients.
Recent Findings
Regimens utilizing additional chemotherapy and targeted therapies (such as PARP inhibitors or bisphosphonates) have met with limited efficacy. Notably, a recently published randomized study of capecitabine in patients with residual disease demonstrated an improvement in disease-free survival and overall survival.
Summary
While the results for capecitabine are promising, particularly for patients with triple-negative disease, the generalizability of these findings is an open question. Meanwhile, ongoing trials with novel agents that target specific tumor subtypes and the biology of residual disease may improve outcomes for other patient populations.
Background
Adavosertib (AZD1775) is an inhibitor of the Wee1 kinase. The authors conducted a phase 1b trial to evaluate the safety of adavosertib in combination with definitive chemoradiotherapy for ...patients with newly diagnosed, intermediate‐risk/high‐risk, locally advanced head and neck squamous cell carcinoma (HNSCC).
Methods
Twelve patients with intermediate‐risk/high‐risk HNSCC were enrolled, including those with p16‐negative tumors of the oropharynx, p16‐positive tumors of the oropharynx with ≥10 tobacco pack‐years, and tumors of the larynx/hypopharynx regardless of p16 status. All patients were treated with an 8‐week course of concurrent intensity‐modulated radiotherapy at 70 grays (Gy) (2 Gy daily in weeks 1‐7), cisplatin 30 mg/m2 weekly (in weeks 1‐7), and adavosertib (twice daily on Monday, Tuesday, and Wednesday of weeks 1, 2, 4, 5, 7, and 8). The primary objective was to determine the maximum tolerated dose and the recommended phase 2 dose of adavosertib given concurrently with radiation and cisplatin. Secondary objectives were to determine the 12‐week objective response rate and progression‐free and overall survival.
Results
Three patients (25%) experienced a dose‐limiting toxicity, including febrile neutropenia (n = 2) and grade 4 thromboembolism (n = 1). Two dose‐limiting toxicities occurred with adavosertib at 150 mg. The median follow‐up was 14.7 months. The 12‐week posttreatment objective response rate determined by positron emission tomography/computed tomography was 100%. The 1‐year progression‐free and overall survival rates were both 90%. The maximum tolerated dose of adavosertib was 100 mg.
Conclusions
Adavosertib 100 mg (twice daily on Monday, Tuesday, and Wednesday of weeks 1, 2, 4, 5, 7, and 8), in combination with 70 Gy of intensity‐modulated radiotherapy and cisplatin 30 mg/m2, is the recommended phase 2 dose for patients with HNSCC.
In a phase 1b trial, the safety of adavosertib in combination with definitive chemoradiotherapy is evaluated in patients with newly diagnosed, intermediate‐risk/high‐risk, locally advanced head and neck squamous cell carcinoma. The maximum tolerated dose and the recommended phase 2 dose of adavosertib for these patients is 100 mg in combination with 70 grays of intensity‐modulated radiation and cisplatin 30 mg/m2.
Patients with locally advanced head and neck squamous cell cancer (HNSCC) are treated with surgery followed by adjuvant (chemo) radiotherapy or definitive chemoradiation, but recurrence rates are ...high. Immune checkpoint blockade improves survival in patients with recurrent/metastatic HNSCC; however, the role of chemo-immunotherapy in the curative setting is not established.
This phase 2, single-arm, multicenter study evaluated neoadjuvant chemo-immunotherapy with carboplatin, nab-paclitaxel, and durvalumab in patients with resectable locally advanced HNSCC. The primary end point was a hypothesized pathologic complete response rate of 50%. After chemo-immunotherapy and surgical resection, patients received study-defined, pathologic risk adapted adjuvant therapy consisting of either durvalumab alone (low risk), involved field radiation plus weekly cisplatin and durvalumab (intermediate risk), or standard chemoradiation plus durvalumab (high risk).
Between December 2017 and November 2021, 39 subjects were enrolled at three centers. Oral cavity was the most common primary site (69%). A total of 35 of 39 subjects underwent planned surgical resection; one subject had a delay in surgery due to treatment-related toxicity. The most common treatment-related adverse events were cytopenias, fatigue, and nausea. Post treatment imaging demonstrated an objective response rate of 57%. Pathologic complete response and major pathologic response were achieved in 29% and 49% of subjects who underwent planned surgery, respectively. The 1-year progression-free survival was 83.8% (95% confidence interval, 67.4%-92.4%).
Neoadjuvant carboplatin, nab-paclitaxel, and durvalumab before surgical resection of HNSCC were safe and feasible. Although the primary end point was not met, encouraging rates of pathologic complete response and clinical to pathologic downstaging were observed.
Objective
To compare oncologic outcomes in sinonasal squamous cell carcinoma (SNSCC) treated with standard of care (SOC) definitive therapy, consisting of surgery or chemoradiotherapy, vs induction ...therapy followed by definitive therapy.
Study Design
Retrospective review.
Setting
Academic tertiary care hospital.
Methods
The medical records of patients with biopsy-proven SNSCC treated between 2000 and 2020 were reviewed for demographics, tumor characteristics, staging, treatment details, and oncologic outcomes. Patients were matched 1-to-1 by age, sex, and cancer stage according to treatment received. Time-to-event analyses were conducted.
Results
The analysis included 26 patients with locally advanced SNSCC who received either induction therapy (n = 13) or SOC (n = 13). Baseline demographics, Charlson Comorbidity Index, and median follow-up time were well balanced. Weekly cetuximab, carboplatin, and paclitaxel were the most common induction regimen utilized. Tolerance and safety to induction were excellent. Objective responses were observed in 11 of 13 patients receiving induction. No difference in disease-free survival was found between the induction and SOC groups at 1 or 3 years. However, when compared with SOC, induction therapy resulted in significant improvement in overall survival at 2 years (100% vs 65.3%, P = .043) and 3 years (100% vs 48.4%, P = .016) following completion of definitive therapy. Two patients in the SOC group developed metastatic disease, as compared with none in the induction group.
Conclusions
Induction therapy was safe and effective. When compared with SOC, induction therapy improved 3-year overall survival.
Induction with four cycles of platinum-based chemotherapy was the standard of care for metastatic non-small cell lung cancer (NSCLC) until the approval of immune checkpoint blockade (ICB) in the ...first-line setting. Switch maintenance therapy has shown promise in improving survival by exposing patients to novel, non-cross-resistant agents earlier in their treatment course.
We performed this open-label, three-arm, randomized phase II study (NCT02684461) to evaluate three sequences of consolidation with pembrolizumab and nab-paclitaxel in patients without progressive disease post induction chemotherapy. Consolidation was either sequential with pembrolizumab for four cycles followed by nab-paclitaxel for four cycles (P→A), nab-paclitaxel followed by pembrolizumab (A→P), or concurrent nab-paclitaxel and pembrolizumab for four cycles (AP).
Twenty patients were randomized before the study was closed early due to the approval of first-line checkpoint inhibitors. We found that consolidation is feasible and well tolerated, with 30% of patients experiencing grade 3 toxicity. The median progression-free survival and OS in months (95% CI) in P→A were 10.1 (1.5-NR), 27.6 (1.7-NR); 8.4 (1.2-9.0), 12.7 (4.4-NR) in A→P; and 10.2 (5.1-NR), NR. Quality of life as measured by FACT-L improved in the majority of patients during the course of the study.
Sequential and concurrent consolidation regimens are well tolerated and have encouraging overall survival in patients with metastatic NSCLC.
Background
NUT carcinoma is an aggressive malignancy characterized by translocations in the NUTM1 gene. There are currently no consensus treatment recommendations for NUT carcinomas.
Methods
Here, we ...describe the case of a previously healthy male diagnosed with NUT carcinoma after presenting with sinus pressure, found to have a sinonasal mass and distant metastatic disease in the lungs. While pathologic evaluation and immunohistochemistry were consistent with NUT carcinoma, initial genomic profiling did not demonstrate a NUTM1 translocation.
Results
Whole transcriptomic RNA sequencing of the tumor revealed a YAP1‐NUTM1 fusion. Based on an in vitro drug sensitivity screen, the patient was treated with gemcitabine and nab‐paclitaxel, achieving a partial response that persisted for 9 months.
Conclusions
Unbiased transcriptomic sequencing may identify previously uncharacterized NUTM1 fusion partners. Gemcitabine and nab‐paclitaxel is a well‐tolerated combination chemotherapy regimen and could offer a novel treatment approach for NUT carcinoma.
Unbiased transcriptome sequencing may identify previously uncharacterized NUTM1 fusion partners. Gemcitabine and nab‐paclitaxel is a well‐tolerated combination chemotherapy regimen and could offer a novel treatment approach for NUT carcinoma.
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