Safety, tolerability, and clinical activity of selinexor in combination with pembrolizumab in treatment of metastatic non-small cell lung cancer.

BACKGROUND: In lung cancer, overexpression of nuclear export proteins can result in inactivation of critical tumor suppressor proteins and cell-cycle regulators. Selective suppression of nuclear export proteins has immunomodulatory activities. Here, clinical safety and early efficacy data are presented on the combination of pembrolizumab and an oral selective nuclear export inhibitor, selinexor, for the treatment of metastatic non-small cell lung cancer (mNSCLC). METHODS: The primary objective of this prospective investigator-initiated study was to determine the safety and tolerability of selinexor in combination with pembrolizumab in patients with mNSCLC. Secondary objectives included determination of objective tumor response rate, disease control rate, and progression-free survival duration. RESULTS: A total of 17 patients were included in the final analysis. Fifteen (88%) received more than two lines of prior systemic therapy and 10 (59%) had prior exposure to anti-PD-1/programmed death-ligand 1 (PD-L1) therapy. The median age was 67.5 years. Ten patients had grade ≥3 adverse events related to selinexor treatment. Responses to treatment occurred in patients who did and did not undergo previous anti-PD-1/PD-L1 therapy and in patients with activating driver mutations. The median overall survival and progression-free survival were 11.4 months (95% CI, 3.4-19.8 months) and 3.0 months (95% CI, 1.7-5.7 months), respectively. The overall response rate was 18% and the 6-month disease control rate was 24%. CONCLUSIONS: Selinexor in combination with pembrolizumab demonstrated promising antitumor activity in patients with mNSCLC, including those who had previously received anti-PD-1/PD-L1 therapy. The therapy-related toxic effects were consistent with the prior safety data for both drugs, and no overlapping toxic effects were observed. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02419495. PLAIN LANGUAGE SUMMARY: New strategies to prevent or reverse resistance to immune checkpoint inhibitors are under investigation. Selective inhibitors of nuclear export proteins, such as selinexor, can induce restoration of tumor-suppressing pathways and induce potent immunomodulatory activities. This article contains the clinical safety and early efficacy data on the combination of pembrolizumab and selinexor in treatment of metastatic non-small cell lung cancer.

Outcomes of patients with oropharyngeal squamous cell carcinoma treated with induction chemotherapy followed by concurrent chemoradiation compared with those treated with concurrent chemoradiation.

BACKGROUND: Induction chemotherapy (IC) has been associated with a decreased risk of distant metastasis in locally advanced head and neck squamous cell carcinoma. However, its role in the treatment of oropharyngeal squamous cell carcinoma (OPSCC) is not well established. METHODS: The outcomes of patients with OPSCC treated with IC followed by concurrent chemoradiation (CRT) were compared with the outcomes of those treated with CRT alone. The primary outcome was overall survival (OS), and the secondary end points were the times to locoregional and distant recurrence. RESULTS: In an existing database, 585 patients met the inclusion criteria: 137 received IC plus CRT, and 448 received CRT. Most patients were positive for human papillomavirus (HPV; 90.9%). Patients receiving IC were more likely to present with a higher T stage, a higher N stage, and low neck disease. The 3-year OS rate was significantly lower in patients receiving IC (75.7%) versus CRT alone (92.9%). In a multicovariate analysis, receipt of IC (adjusted hazard ratio [aHR], 3.4; P < .001), HPV tumor status (aHR, 0.36; P = .002), and receipt of concurrent cetuximab (aHR, 2.7; P = .002) were independently associated with OS. The risk of distant metastasis was also significantly higher in IC patients (aHR, 2.8; P = .001), whereas an HPV-positive tumor status (aHR, 0.44; P = .032) and completion of therapy (aHR, 0.51; P = .034) were associated with a lower risk of distant metastasis. In HPV-positive patients, IC remained associated with distant metastatic progression (aHR, 2.6; P = .004) but not OS. CONCLUSIONS: In contrast to prior studies, IC was independently associated with worse OS and a higher risk of distant metastasis in patients with OPSCC. Future studies are needed to validate these findings.

Determinants of patient-reported xerostomia among long-term oropharyngeal cancer survivors.

BACKGROUND: This study was conducted to identify clinicodemographic risk factors for xerostomia among long-term oropharyngeal cancer (OPC) survivors. METHODS: This cross-sectional study included 906 disease-free, adult OPC survivors with a median survival duration at the time of survey of 6 years (range, 1-16 years); self-reported xerostomia scores were available for 877 participants. Study participants had completed curative treatment between January 2000 and December 2013 and responded to a survey administered from September 2015 to July 2016. The primary outcome variable was cancer patient-reported xerostomia measured with the MD Anderson Symptom Inventory Head and Neck Cancer Module. Clinicodemographic risk factors for moderate to severe xerostomia were identified via multivariable logistic regression. RESULTS: Moderate to severe xerostomia was reported by 343 of the respondents (39.1%). Female sex (odds ratio [OR], 1.82; 95% CI, 1.22-2.71; P = .003; Bayesian false-discovery probability [BFDP] = 0.568), high school or lower education (OR, 1.73; 95% CI, 1.19-2.52; P = .004; BFDP = 0.636), and current cigarette smoking at the time of survey (OR, 2.56; 95% CI, 1.19-5.47; P = .016; BFDP = 0.800) were risk factors for moderate to severe xerostomia, and bilateral intensity-modulated radiotherapy (IMRT) combined with proton therapy and ipsilateral IMRT were protective. CONCLUSIONS: In this large xerostomia study, modern radiotherapy was a protective factor, and continued cigarette smoking at the time of survey, female sex, and high school or lower education were identified as other contributing risk factors associated with moderate to severe xerostomia. Importantly, these findings need to be confirmed in prospective studies. These results can inform future research and targeted patient-centered interventions to monitor and manage radiation therapy-associated xerostomia and preserve quality of life among patients with OPC.

Self-Reported Trismus: prevalence, severity and impact on quality of life in oropharyngeal cancer survivorship: a cross-sectional survey report from a comprehensive cancer center.

OBJECTIVE: The purpose of this study was to estimate prevalence/severity of self-reported trismus, determine association with quality of life (QOL), and examine clinical risk factors in a large population of patients treated for oropharyngeal cancer. MATERIALS AND METHODS: A cross-sectional survivorship survey was conducted among patients who completed definitive treatment for oropharyngeal carcinoma, disease-free ≥ 1-year post-treatment (median survival, 7 years among 892 survivors). Associations between trismus and QOL were also analyzed using MDASI-HN, EQ-5D, and MDADI. Dietary and feeding tube status were also correlated to trismus status. RESULTS: Trismus was self-reported in 31%. Severity of trismus positively correlated (r = 0.29) with higher mean interference scores reflecting a moderate association with quality of life (p < 0.0001). There was a negative correlation for MDADI composite scores (r = - 0.33) indicating increased perceived dysphagia related to trismus severity (p < 0.0001). EQ-5D VAS scores were also negatively correlated with trismus severity (r = - 0.26, p < 0.0001). Larger T-stage (p ≤ 0.001), larger nodal stage (p = 0.03), tumor sub-site (p = 0.05), and concurrent chemoradiation (p = 0.01) associated with increased prevalence of trismus. Diet negatively correlated (r = - 0.27) with trismus severity (p = < 0.0001), and survivors with severe trismus were also more likely to be feeding tube-dependent. CONCLUSION: Severity of trismus appears to negatively impact quality of life and associate with various adverse functional outcomes in long-term oropharyngeal cancer survivorship. Trismus remains associated with advanced disease stages, tumor sub-site (tonsil), and addition of chemotherapy. Further investigation is merited for the dose-effect relationship to the muscles of mastication.

Sarcoidosis and Airway Disease After Immune Checkpoint Inhibitor Therapy: Case Study and Review of the Literature.

Pulmonary toxicity from immune checkpoint inhibitor therapy is typically a severe and potentially fatal complication, but these observations are driven by the most common toxicity, pneumonitis. Rarer pulmonary immune related adverse events, like airway disease and sarcoidosis, may have a more benign course. In this case report, we present a patient in whom therapy with the PD-1 inhibitor pembrolizumab resulted in severe eosinophilic asthma and sarcoidosis. This is the first case showing that anti-IL-5 inhibition may be safe in patients who develop eosinophilic asthma after ICI therapy. We further show that sarcoidosis does not necessarily require treatment cessation. This case highlights relevant nuances when clinicians face pulmonary toxicities other than pneumonitis.

Association of hearing loss and tinnitus symptoms with health-related quality of life among long-term oropharyngeal cancer survivors.

BACKGROUND: This study investigated the association of hearing loss and tinnitus with overall health-related quality of life (HRQoL) among long-term oropharyngeal cancer (OPC) survivors. METHODS: This study included OPC survivors treated between 2000 and 2013 and surveyed from September 2015 to July 2016. Hearing loss and tinnitus were measured by asking survivors to rate their "difficulty with hearing loss and/or ringing in the ears" from 0 (not present) to 10 (as bad as you can imagine). Hearing loss and tinnitus scores were categorized as follows: 0 for none, 1-4 for mild, and 5-10 for moderate to severe. The primary outcome was the mean score of MD nderson Symptom Inventory Head & Neck module interference component as a HRQoL surrogate dichotomized as follows: 0 to 4 for none to mild and 5 to 10 for moderate to severe interference. RESULTS: Among 880 OPC survivors, 35.6% (314), reported none, 39.3% (347) reported mild, and 25.1% (221) reported moderate to severe hearing loss and tinnitus. On multivariable analysis, mild (OR, 5.83; 95% CI; 1.48-22.88; p = 0.012) and moderate (OR, 30.01; 95% CI; 7.96-113.10; p < 0.001) hearing loss and tinnitus were associated with higher odds of reporting moderate to severe symptom interference scores in comparison to no hearing loss and tinnitus. This association of hearing dysfunction was consistent with all domains of HRQoL. CONCLUSIONS: Our findings provide preliminary evidence to support the need for continued audiological evaluations and surveillance to detect hearing dysfunction, to allow for early management and to alleviate the long-term impact on QoL.

Risk factors associated with patient-reported fatigue among long-term oropharyngeal carcinoma survivors.

BACKGROUND: The study objective is to identify risk factors associated with fatigue among long-term OPC survivors. METHODS: This cross-sectional study included disease-free OPC survivors treated curatively between 2000 and 2013 who were surveyed from September 2015 to July 2016. The outcome variable was patient-reported fatigue. Multivariable logistic regression was used to identify factors associated with moderate to severe fatigue. RESULTS: Among 863 OPC survivors, 17.4% reported moderate to severe fatigue. Self-reported thyroid problems (OR: 2.01; p = 0.003), current cigarette smoking at time of survey (OR: 3.85; p = 0.001), late lower cranial neuropathy (OR: 3.44; p = 0.002), and female sex (OR: 1.91; p = 0.010) were concurrent risk factors of reporting moderate to severe fatigue. Ipsilateral intensity-modulated radiotherapy (OR: 0.18; p = 0.014) was associated with lower risk of reporting moderate to severe fatigue. CONCLUSIONS: Our study identified thyroid problems, smoking, and late lower cranial neuropathy as associated with moderate to severe fatigue. These findings should be further validated in prospective studies to address fatigue among OPC survivors.

Poziotinib for Patients With HER2 Exon 20 Mutant Non-Small-Cell Lung Cancer: Results From a Phase II Trial.

PURPOSE: Targeted therapies against non-small-cell lung cancer (NSCLC) harboring HER2 mutations remain an unmet need. In this study, we assessed the efficacy and safety of poziotinib in patients with HER2 exon 20 mutant advanced NSCLC in a single-arm, open-label, phase II study. PATIENTS AND METHODS: Patients with advanced HER2 exon 20 mutant NSCLC were enrolled to receive poziotinib at a dose of 16 mg/d for 28-day cycles. The primary end point was objective response rate per RECIST version 1.1. Confirmatory scans were performed at least 28 days from initial radiologic response. RESULTS: Thirty patients received poziotinib treatment. At baseline, 90% of patients received prior platinum-based chemotherapy and 53% had two lines or more prior systemic therapies. As of data cutoff on March 1, 2021, the confirmed objective response rate was 27% (95% CI, 12 to 46). Responses were observed across HER2 exon 20 mutation subtypes. The median duration of response was 5.0 months (95% CI, 4.0 to not estimable). The median progression-free survival was 5.5 months (95% CI, 4.0 to 7.0). The median overall survival was 15 months (95% CI, 9.0 to not estimable). The most common grade 3 treatment-related adverse events were skin rash (47%) and diarrhea (20%). There was one possible treatment-related death because of pneumonitis. CONCLUSION: Poziotinib showed promising antitumor activity in patients with HER2 exon 20 mutant NSCLC including patients who had previously received platinum-based chemotherapy.

Genetic susceptibility to patient-reported xerostomia among long-term oropharyngeal cancer survivors.

Genetic susceptibility for xerostomia, a common sequela of radiotherapy and chemoradiotherapy for head and neck cancer, is unknown. Therefore, to identify genetic variants associated with moderate to severe xerostomia, we conducted a GWAS of 359 long-term oropharyngeal cancer (OPC) survivors using 579,956 autosomal SNPs. Patient-reported cancer treatment-related xerostomia was assessed using the MD Anderson Symptom Inventory. Patient response was dichotomized as moderate to severe or none to mild symptoms. In our study, 39.2% of OPC survivors reported moderate to severe xerostomia. Our GWAS identified eight SNPs suggestively associated with higher risk of moderate to severe xerostomia in six genomic regions (2p13.3, rs6546481, Minor Allele (MA) = A, ANTXR1, P = 4.3 × 10-7; 5p13.2-p13.1, rs16903936, MA = G, EGFLAM, P = 5.1 × 10-6; 4q21.1, rs10518156, MA = G, SHROOM3, P = 7.1 × 10-6; 19q13.42, rs11882068, MA = G, NLRP9, P = 1.7 × 10-5; 12q24.33, rs4760542, MA = G, GLT1D1, P = 1.8 × 10-5; and 3q27.3, rs11714564, MA = G, RTP1, P = 2.9 × 10-5. Seven SNPs were associated with lower risk of moderate to severe xerostomia, of which only one mapped to specific genomic region (15q21.3, rs4776140, MA = G, LOC105370826, a ncRNA class RNA gene, P = 1.5 × 10-5). Although our small exploratory study did not reach genome-wide statistical significance, our study provides, for the first time, preliminary evidence of genetic susceptibility to xerostomia. Further studies are needed to elucidate the role of genetic susceptibility to xerostomia.

Clinical Effectiveness and Safety of Anti-PD-(L)1 Therapy Among Older Adults With Advanced Non-Small Cell Lung Cancer.

INTRODUCTION: As a result of the approval of several immune checkpoint inhibitors (ICIs) for the treatment of non-small cell lung cancer (NSCLC), many older adults are being treated with ICIs. Older adults are underrepresented in most pharmaceutical clinical trials. Therapy outcomes in this population with ICIs is particularly important since, age related factors may have an influence on the immune system. METHODS: We utilized the MD Anderson Cancer Center Gemini Team's Lung Cancer Database to retrospectively study patients ≥70 years of age with advanced NSCLC treated with anti-PD-(L)1 monotherapy to look at the clinical outcomes. RESULTS: 179 patients met the inclusion criteria for this retrospective analysis. There were 106 men and 73 women. The median age of the cohort was 74.9 years, and overall survival was 20.6 months. 27.6% of all patients had an objective response to therapy. In 33 patients who had radiological progression, treatment continued beyond progression due to clinical benefit. In this group, 6 patients had subsequent improvement in radiologic assessment. Age groups were not significantly associated with differences in clinical outcomes. CONCLUSIONS: This study suggests that anti-PD-(L)1 monotherapy is effective and well tolerated among older adults with advanced NSCLC. While pseudoprogression is rare, treatment beyond progression may provide clinical benefit in a subset of patients and warrants further investigation.

Association of Risk Factors With Patient-Reported Voice and Speech Symptoms Among Long-term Survivors of Oropharyngeal Cancer.

Importance: Voice and speech production are critical physiological functions that affect quality of life and may deteriorate substantially after oropharyngeal cancer (OPC) treatment. There is limited knowledge about risk factors associated with voice and speech outcomes among survivors of OPC. Objective: To identify the risk factors of voice and speech symptoms among long-term survivors of OPC. Design, Setting, and Participants: This retrospective cohort study with cross-sectional survivorship survey administration includes cancer-free survivors of OPC who were treated curatively between January 2000 and December 2013 at MD Anderson Cancer Center (Houston, Texas) who participated in a survey from September 2015 to July 2016. Of 906 survivors of OPC with a median survival duration at time of survey of 6 years (range, 1-16 years), patient-rated voice and speech outcomes for 881 were available and analyzed. The data were analyzed from June 30, 2020, to February 28, 2021. Main Outcomes and Measures: The primary outcome variable was patient-reported voice and speech scores that were measured using the MD Anderson Symptom Inventory-Head and Neck Cancer Module. Voice and speech scores of 0 to 4 were categorized as none to mild symptoms, and scores of 5 to 10 were categorized as moderate to severe symptoms. Risk factors for moderate to severe voice and speech symptoms were identified by multivariable logistic regression. Results: Among 881 survivors of OPC (median [range] age, 56 [32-84] years; 140 women [15.5%]; 837 White [92.4%], 17 Black [1.9%], and 35 Hispanic individuals [3.8%]), 113 (12.8%) reported moderate to severe voice and speech scores. Increasing survival time (odds ratio [OR], 1.17; 95% CI, 1.06-1.30) and increasing total radiation dose (OR, 1.16; 95% CI, 1.00-1.34), Black race (OR, 3.90; 95% CI, 1.02-14.89), Hispanic ethnicity (OR, 3.74; 95% CI, 1.50-9.35), current cigarette smoking at the time of survey (OR, 3.98; 95% CI, 1.56-10.18), treatment with induction and concurrent chemotherapy (OR, 1.94; 95% CI, 1.06-3.57), and late (OR, 7.11; 95% CI, 3.08-16.41) and baseline lower cranial neuropathy (OR, 8.70; 95% CI, 3.01-25.13) were risk factors associated with moderate to severe voice and speech symptoms. Intensity-modulated radiotherapy split-field regimen (OR, 0.31; 95% CI, 0.12-0.80; P = .01) was associated with lower likelihood of moderate to severe voice and speech symptoms. Conclusions and Relevance: This large OPC survivorship cohort study identified many treatment-related factors, including increasing total radiotherapy dose, multimodality induction and concurrent chemotherapy regimens, and continued smoking, as well as clinical and demographic factors, as risk factors that were associated with moderate to severe voice and speech symptoms. The key findings in this study were the protective associations of split-field radiation and that longer-term survivors, and those who continued to smoke, had worse voice and speech symptoms. These findings may inform research and effective targeted clinical voice and speech preservation interventions and smoking cessation interventions to maximize voice and speech function and address quality of life among patients with OPC.

Efficacy of Targeted Inhibitors in Metastatic Lung Squamous Cell Carcinoma With EGFR or ALK Alterations.

INTRODUCTION: The efficacy of targeted therapies in oncogene-driven lung adenocarcinomas (LUADs) has been well established; however, the benefit for EGFR-mutant or ALK-rearranged lung squamous cell carcinomas (LUSCs) is less known, partially owing to the rarity of the incidence. METHODS: We reviewed the database of the MD Anderson Cancer Center and identified metastatic LUSC with classic EGFR or ALK alterations. RESULTS: There were eight patients with EGFR-mutant LUSC (median age = 58 y) and six patients with EML4-ALK LUSC (median age = 50 y) who received tyrosine kinase inhibitors (TKIs) that were identified. Of the 14 patients, 11 (79%) were females and 12 (86%) were never smokers, similar to the demographics of EGFR or ALK LUAD. With TKI treatment, seven of eight cases of EGFR LUSC and four of six cases of ALK LUSC achieved partial response or stable disease, but the progression-free survival was 4.9 months and 2.9 months for EGFR-mutant and ALK-rearranged LUSC, respectively. In addition, we compared comutation profile of EGFR-mutant LUAD (The Cancer Genome Atlas, n = 46) versus LUSC (n = 19) and found that the comutation patterns are more consistent with squamous disease with a higher incidence of PIK3CA (p = 0.02) and KRAS or BRAF (p = 0.04) alterations. CONCLUSIONS: EGFR or ALK alterations occur in patients with LUSC, especially never-smoker females. TKI treatments render clinical benefit in disease control, but the duration was considerably truncated compared with those historically observed in LUAD.

Cytotoxic and targeted systemic therapy in patients with advanced cutaneous squamous cell carcinoma in the head and neck.

BACKGROUND: The outcomes of patients treated with cytotoxic or targeted systemic therapy is not well defined for cutaneous squamous cell carcinoma of the head and neck (cSCCHN). METHODS: Patients with cSCCHN treated with cytotoxic or targeted systemic therapy were included. Patients were divided into two groups based on the presence of distant metastasis (M1 vs. M0) at presentation. A proportional hazards model was used to assess for independent predictors of overall survival. RESULTS: Of 129 patients with cSCCHN, 20 (16%) were M1 and 109 (84%) were M0. Independent predictors of improved survival were M0 status, treatment of locally advanced disease with radiotherapy, and lower Eastern Cooperative Oncology Group (ECOG) score. CONCLUSIONS: Survival was worse in M1 patients treated with cytotoxic or targeted systemic therapy and poor baseline performance status but improved in those receiving radiotherapy. These data can serve as historical controls for future systemic therapy trials, including immunotherapy.

Outcomes after salvage for HPV-positive recurrent oropharyngeal cancer treated with primary radiation.

PURPOSE: HPV-positive oropharyngeal squamous cell carcinoma (OPSCC) carries a favorable prognosis for patients, yet nearly 30% of patients will experience disease relapse. We sought to detail patterns of failure, associated salvage therapy, and outcomes for patients with recurrent HPV-positive OPSCC. METHODS AND MATERIALS: This is a single institution retrospective study of patients with recurrent HPV-positive OPSCC irradiated from 2002 to 2014. The primary study outcome was overall survival (OS, calculated using the Kaplan-Meier method). Secondary aims included patterns of first failure with descriptive details of salvage therapy. Solitary recurrences were defined as initial presentation of recurrence in a single site (primary, neck or oligometastatic), and multi-site was defined as local and regional and/or multiple sites of distant recurrence. Survival outcomes were compared using the log-rank test. RESULTS: The cohort consisted of 132 patients. The median follow-up was 59 months for surviving patients. Estimated 2-year and 5-year OS rates were 47% and 32%, respectively. Comparative 2-year and 5-year OS rates were 65% and 46% versus 19% and 9% for the solitary group and multi-site group, respectively (p < .001). CONCLUSIONS: Patients with recurrent HPV-positive OPSCC experience 5-year survival of approximately 32%. However, patients with a "solitary" recurrence including disease at the primary site, neck or oligometastatic site have more favorable long-term outcomes.

Pilot Phase II Trial of Neoadjuvant Immunotherapy in Locoregionally Advanced, Resectable Cutaneous Squamous Cell Carcinoma of the Head and Neck.

PURPOSE: In locoregionally advanced, resectable cutaneous squamous cell carcinoma of the head and neck (CSCC-HN), surgery followed by radiotherapy is standard but can be cosmetically and functionally devastating, and many patients will have recurrence. PATIENTS AND METHODS: Newly diagnosed or recurrent stage III-IVA CSCC-HN patients amenable to curative-intent surgery received two cycles of neoadjuvant PD-1 inhibition. The primary endpoint was ORR per RECIST 1.1. Secondary endpoints included pathologic response [pathologic complete response (pCR) or major pathologic response (MPR; ≤10% viable tumor)], safety, DSS, DFS, and OS. Exploratory endpoints included immune biomarkers of response. RESULTS: Of 20 patients enrolled, 7 had recurrent disease. While only 6 patients [30%; 95% confidence interval (CI), 11.9-54.3] had partial responses by RECIST, 14 patients (70%; 95% CI, 45.7-88.1) had a pCR (n = 11) or MPR (n = 3). No SAEs ocurred during or after the neoadjuvant treatment. At a median follow-up of 22.6 months (95% CI, 21.7-26.1), one patient progressed and died, one died without disease, and two developed recurrence. The 12-month DSS, DFS, and OS rates were 95% (95% CI, 85.9-100), 89.5% (95% CI, 76.7-100), and 95% (95% CI, 85.9-100), respectively. Gene expression studies revealed an inflamed tumor microenvironment in patients with pCR or MPR, and CyTOF analyses demonstrated a memory CD8+ T-cell cluster enriched in patients with pCR. CONCLUSIONS: Neoadjuvant immunotherapy in locoregionally advanced, resectable CSCC-HN is safe and induces a high pathologic response rate. Pathologic responses were associated with an inflamed tumor microenvironment.

Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial.

Ipilimumab improves clinical outcomes when combined with nivolumab in metastatic non-small cell lung cancer (NSCLC), but its efficacy and impact on the immune microenvironment in operable NSCLC remain unclear. We report the results of the phase 2 randomized NEOSTAR trial (NCT03158129) of neoadjuvant nivolumab or nivolumab + ipilimumab followed by surgery in 44 patients with operable NSCLC, using major pathologic response (MPR) as the primary endpoint. The MPR rate for each treatment arm was tested against historical controls of neoadjuvant chemotherapy. The nivolumab + ipilimumab arm met the prespecified primary endpoint threshold of 6 MPRs in 21 patients, achieving a 38% MPR rate (8/21). We observed a 22% MPR rate (5/23) in the nivolumab arm. In 37 patients resected on trial, nivolumab and nivolumab + ipilimumab produced MPR rates of 24% (5/21) and 50% (8/16), respectively. Compared with nivolumab, nivolumab + ipilimumab resulted in higher pathologic complete response rates (10% versus 38%), less viable tumor (median 50% versus 9%), and greater frequencies of effector, tissue-resident memory and effector memory T cells. Increased abundance of gut Ruminococcus and Akkermansia spp. was associated with MPR to dual therapy. Our data indicate that neoadjuvant nivolumab + ipilimumab-based therapy enhances pathologic responses, tumor immune infiltrates and immunologic memory, and merits further investigation in operable NSCLC.

Subjective functional outcomes in oropharyngeal cancer treated with induction chemotherapy using the MD Anderson Symptom Inventory (MDASI).

OBJECTIVES: Evaluate the use of induction chemotherapy (IC) in oropharyngeal cancer (OPC) and its impact on subjective functional outcomes using a validated MD Anderson Symptom Inventory-Head and Neck (MDASI-HN) survey tool. METHODS: A single institution retrospective review of OPC patients who received IC, including reasons given for using IC, regimens employed, responses, and patient-reported outcomes (PRO). The latter included pain, distress, dysphagia, xerostomia, and feeding tube placement and dependency. PRO's were assessed using the validated MD Anderson Symptom Inventory-Head and Neck (MDASI-HN) conducted at baseline, during treatment, and at six-month follow up. RESULTS: One hundred and twenty-five patients were evaluable. They were more likely to have large primary and/or bulky or low neck nodal disease as a reason for IC. A taxane-containing regimen was most common. Primary tumor response was seen in 83.2% and the nodal response in 81.6%. Pain and xerostomia improved with IC, dysphagia was not adversely affected with IC. These symptoms all increased with consolidation chemoradiotherapy (CRT) but returned to baseline by 6 months post treatment. Feeding tube placement did not increase with IC but did with CRT, most patients were no longer feeding tube dependent at 6 months. CONCLUSION: This retrospective review of subjective functional outcomes, especially swallowing and feeding tube dependency, using the MDASI survey tool in 125 oropharyngeal cancer patients with large primary tumors and/or bulky adenopathy treated predominantly with platinum-taxane based induction chemotherapy showed that such outcomes were not adversely impacted. While not standard, such approach may be beneficial in such patients. LEVEL OF EVIDENCE: 2.

A Phase I/II Study of Neoadjuvant Cisplatin, Docetaxel, and Nintedanib for Resectable Non-Small Cell Lung Cancer.

PURPOSE: Nintedanib enhances the activity of chemotherapy in metastatic non-small cell lung cancer (NSCLC). In this phase I/II study, we assessed safety and efficacy of nintedanib plus neoadjuvant chemotherapy, using major pathologic response (MPR) as primary endpoint. PATIENTS AND METHODS: Eligible patients had stage IB (≥4 cm)-IIIA resectable NSCLC. A safety run-in phase was followed by an expansion phase with nintedanib 200 mg orally twice a day (28 days), followed by three cycles of cisplatin (75 mg/m2), docetaxel (75 mg/m2) every 21 days plus nintedanib, followed by surgery. With 33 planned patients, the study had 90% power to detect an MPR increase from 15% to 35%. RESULTS: Twenty-one patients (stages I/II/III, N = 1/8/12) were treated. One of 15 patients treated with nintedanib 200 mg achieved MPR [7%, 95% confidence interval (CI), 0.2%-32%]. Best ORR in 20 evaluable patients was 30% (6/20, 95% CI, 12%-54%). Twelve-month recurrence-free survival and overall survival were 66% (95% CI, 47%-93%) and 91% (95% CI, 79%-100%), respectively. Most frequent treatment-related grade 3-4 toxicities were transaminitis and electrolyte abnormalities. On the basis of an interim analysis the study was discontinued for futility. Higher levels of CD3+ and cytotoxic CD3+CD8+ T cells were found in treated tumors of patients who were alive than in those who died (652.8 vs. 213.4 cells/mm2, P = 0.048; 142.3 vs. 35.6 cells/mm2, P = 0.018). CONCLUSIONS: Although tolerated, neoadjuvant nintedanib plus chemotherapy did not increase MPR rate compared with chemotherapy historical controls. Additional studies of the combination in this setting are not recommended. Posttreatment levels of tumor-infiltrating T cells were associated with patient survival. Use of MPR facilitates the rapid evaluation of neoadjuvant therapies.See related commentary by Blakely and McCoach, p. 3499.

Programmed Death-Ligand 1 Heterogeneity and Its Impact on Benefit From Immune Checkpoint Inhibitors in NSCLC.

INTRODUCTION: Programmed death-ligand 1 (PD-L1) expression may vary in different disease sites and at different time points of the disease course. We aimed to investigate PD-L1 heterogeneity and its usefulness as a predictive value for immune checkpoint inhibitor (ICI) therapy in patients with NSCLC. METHODS: PD-L1 expression was analyzed in 1398 patients with NSCLC. The predictive value of PD-L1 for ICIs in 398 patients with metastatic NSCLC was assessed. RESULTS: PD-L1 was significantly associated with biopsy sites (p = 0.004). Adrenal, liver, and lymph node (LN) metastases had the highest PD-L1 expression as a continuous variable and at 1% or 50% cutoff. PD-L1 expression was lower in bone and brain metastases. Among 112 patients with two specimens tested, 55 (49%) had major changes in PD-L1 falling into different clinically relevant categories (<1%, 1%-49%, ≥50%) at different time points. Previous ICI therapy was associated with significant decrease in PD-L1 compared with treatment-naive counterparts (p = 0.015). Patients with metastatic NSCLC treated with ICI (n = 398) were divided into three cohorts on the basis of biopsy sites: lung (n = 252), LN (n = 85), and distant metastasis (n = 61). Higher PD-L1 in lung or distant metastasis specimens was associated with higher response rate, longer progression-free survival, and overall survival. However, PD-L1 in LN biopsies was not associated with either response or survival. CONCLUSIONS: PD-L1 varies substantially across different anatomical sites and changes during the clinical course. PD-L1 from different biopsy sites may have different predictive values for benefit from ICIs in NSCLC.