Real-World Efficacy and Safety of Amivantamab for EGFR-Mutant NSCLC.

INTRODUCTION: Amivantamab-vmjw (amivantamab) is a bispecific EGFR/MET antibody approved for patients with advanced NSCLC with EGFR exon 20 insertion mutations, after prior therapy. Nevertheless, the benefits and safety of amivantamab in other EGFR-mutant lung cancer, with or without osimertinib, and with concurrent radiation therapy, are less known. METHODS: We queried the MD Anderson Lung Cancer GEMINI, Fred Hutchinson Cancer Research Center, University of California Davis Comprehensive Cancer Center, and Stanford Cancer Center's database for patients with EGFR-mutant NSCLC treated with amivantamab, not on a clinical trial. The data analyzed included initial response, duration of treatment, and concomitant radiation safety in overall population and prespecified subgroups. RESULTS: A total of 61 patients received amivantamab. Median age was 65 (31-81) years old; 72.1% were female; and 77% were patients with never smoking history. Median number of prior lines of therapies was four. On the basis of tumor's EGFR mutation, 39 patients were in the classical mutation cohort, 15 patients in the exon 20 cohort, and seven patients in the atypical cohort. There were 37 patients (58.7%) who received amivantamab concomitantly with osimertinib and 25 patients (39.1%) who received concomitant radiation. Furthermore, 54 patients were assessable for response in the overall population; 19 patients (45.2%) had clinical response and disease control rate (DCR) was 64.3%. In the classical mutation cohort of the 33 assessable patients, 12 (36.4%) had clinical response and DCR was 48.5%. In the atypical mutation cohort, six of the seven patients (85.7%) had clinical response and DCR was 100%. Of the 13 assessable patients in the exon 20 cohort, five patients (35.7%) had clinical response and DCR was 64.3%. Adverse events reported with amivantamab use were similar as previously described in product labeling. No additional toxicities were noted when amivantamab was given with radiation with or without osimertinib. CONCLUSIONS: Our real-world multicenter analysis revealed that amivantamab is a potentially effective treatment option for patients with EGFR mutations outside of exon 20 insertion mutations. The combination of osimertinib with amivantamab is safe and feasible. Radiation therapy also seems safe when administered sequentially or concurrently with amivantamab.

Predicting benefit from immune checkpoint inhibitors in patients with non-small-cell lung cancer by CT-based ensemble deep learning: a retrospective study.

BACKGROUND: Only around 20-30% of patients with non-small-cell lung cancer (NCSLC) have durable benefit from immune-checkpoint inhibitors. Although tissue-based biomarkers (eg, PD-L1) are limited by suboptimal performance, tissue availability, and tumour heterogeneity, radiographic images might holistically capture the underlying cancer biology. We aimed to investigate the application of deep learning on chest CT scans to derive an imaging signature of response to immune checkpoint inhibitors and evaluate its added value in the clinical context. METHODS: In this retrospective modelling study, 976 patients with metastatic, EGFR/ALK negative NSCLC treated with immune checkpoint inhibitors at MD Anderson and Stanford were enrolled from Jan 1, 2014, to Feb 29, 2020. We built and tested an ensemble deep learning model on pretreatment CTs (Deep-CT) to predict overall survival and progression-free survival after treatment with immune checkpoint inhibitors. We also evaluated the added predictive value of the Deep-CT model in the context of existing clinicopathological and radiological metrics. FINDINGS: Our Deep-CT model demonstrated robust stratification of patient survival of the MD Anderson testing set, which was validated in the external Stanford set. The performance of the Deep-CT model remained significant on subgroup analyses stratified by PD-L1, histology, age, sex, and race. In univariate analysis, Deep-CT outperformed the conventional risk factors, including histology, smoking status, and PD-L1 expression, and remained an independent predictor after multivariate adjustment. Integrating the Deep-CT model with conventional risk factors demonstrated significantly improved prediction performance, with overall survival C-index increases from 0·70 (clinical model) to 0·75 (composite model) during testing. On the other hand, the deep learning risk scores correlated with some radiomics features, but radiomics alone could not reach the performance level of deep learning, indicating that the deep learning model effectively captured additional imaging patterns beyond known radiomics features. INTERPRETATION: This proof-of-concept study shows that automated profiling of radiographic scans through deep learning can provide orthogonal information independent of existing clinicopathological biomarkers, bringing the goal of precision immunotherapy for patients with NSCLC closer. FUNDING: National Institutes of Health, Mark Foundation Damon Runyon Foundation Physician Scientist Award, MD Anderson Strategic Initiative Development Program, MD Anderson Lung Moon Shot Program, Andrea Mugnaini, and Edward L C Smith.

Esophageal adenocarcinoma with any component of signet ring cells portends poor prognosis and response to neoadjuvant therapy.

BACKGROUND: Multiple investigations have shown inferior outcomes for esophageal cancer patients with signet ring cell (SRC) histology. Traditionally, SRC adenocarcinoma has been defined by ≥50% of the tumor composed of SRC. We hypothesized that patients with SRC even <50% would show resistance to standard multimodality therapy with poorer long-term outcomes. METHODS: Patients treated with trimodality therapy for adenocarcinoma from 2006 to 2018 were evaluated for SRC on pretreatment biopsy specimens. Available hematoxylin and eosin slides containing SRC tumors were re-reviewed by an esophageal pathologist to quantify the percent composition of SRC. RESULTS: SRC histology was identified on at least 1 pathologic specimen in 106 of 819 (13%) patients. Rates of pathologic complete response (pCR) among usual-type and SRC tumors were 25% (177/713) and 10% (11/106), respectively (P = .006). The pretreatment SRC components did not independently affect the rate of pCR (1%-10% SRC: 4% [2/46] pCR; 11%-49% SRC: 25% [7/28] pCR; 50%-100% SRC: 7% [2/30] pCR). Kaplan-Meier analysis demonstrated worse survival among patients with any degree of SRC present on pretreatment biopsy, as compared with usual-type esophageal adenocarcinoma (P < .0001). Cox multivariable analysis failed to identify a relationship between increasing SRC component and poorer survival. CONCLUSIONS: We present the only known evaluation of the percentage of SRC component in esophageal carcinoma. Our data support the hypothesis that esophageal adenocarcinoma with any component of SRC are more resistant to chemoradiation with poorer survival. Pathologic reporting of esophageal adenocarcinoma should include any component of SRC. Alternative therapies in patients with any SRC component may be indicated.

Preoperative chemotherapy prior to pulmonary metastasectomy in surgically resected primary colorectal carcinoma.

BACKGROUND: The benefit of preoperative chemotherapy prior to pulmonary metastasectomy for patients with colorectal carcinoma (CRC) is unknown. Here, we identify outcomes of preoperative chemotherapy in patients with resected primary CRC who then underwent pulmonary metastasectomy. METHODS: We queried a prospective database to identify treatment characteristics. Multivariate analyses identified predictors of overall survival (OS) and progression-free survival (PFS). RESULTS: 229 patients underwent lung metastasectomy, of whom 115 proceeded to surgery without chemotherapy while 114 received preoperative regimen based on oxaliplatin (32%), irinotecan (46%), capecitabine (16%), or other (6%). Median PFS in preoperative chemotherapy vs. surgery alone arms were comparable (p=0.004). Patients on oxaliplatin-based therapy had an improved OS vs. an irinotecan, capecitabine, or alternate regimen (p=.019). On multivariate analysis, the irinotecan subset had a worse OS (HR 1.846; 95% CI 1.070, 3.185) vs. surgery alone arm (p=0.028). The OS of an oxaliplatin-based regimen vs. no chemotherapy was inconclusive (HR 0.57; 95% CI 0.237 to 1.389, p=0.218). Multivariate analysis demonstrated a worse PFS and OS for the male gender and an incomplete resection (R2). CONCLUSION: Prospective trials on specific preoperative regimens and criteria for patient selection may identify a role for preoperative chemotherapy prior to a curative pulmonary metastasectomy.

Trimodality therapy without a platinum compound for localized carcinoma of the esophagus and gastroesophageal junction.

BACKGROUND: : The use of platinum-based chemoradiation for esophageal cancer is routine, but it is unclear which class of cytotoxic are optimum. It was hypothesized that chemoradiotherapy with fluoropyrimidine, taxane, and camptothecin would have preserved or improved efficacy with no compromise in safety. METHODS: : Patients with histologically confirmed, resectable esophageal carcinoma were eligible. In addition to other tests, a baseline endoscopic ultrasonography (EUS) was obtained. Patients were medically fit and had near-normal organ functions. Patients received docetaxel and irinotecan, plus 5-fluorouracil as induction therapy and then the same cytotoxics with 50.4 grays of radiotherapy followed by an attempted surgery. Pathologic complete response (pathCR) at a rate of > or =20% was the primary endpoint. The pathCR and R0 resection were correlated with overall survival (OS). Safety was documented. RESULTS: : Fifty-five patients were enrolled. Seven were women, and the median age was 56 years. Fifty-three (96%) patients had EUST3, and 41 (75%) had EUSN1 disease. Forty-three (78%) patients underwent surgery, 20% achieved a pathCR, and 76.4% underwent an R0 resection. The median survival (n = 55 patients) was 43.3 months (range, 19-75 months). Baseline clinical parameters were not found to be predictive of OS; however, patients with a pathCR (P = .005) and who underwent R0 resection (P < or = .0001) had an improved OS. There was 1 treatment-related postsurgical death reported. Grade 3 or 4 toxicity (graded according to the National Cancer Institute Common Toxicity Criteria [version 2.0]) was observed in 62% of patients. CONCLUSIONS: : The results of the current study documented that this 3-drug, noncisplatin-based chemoradiotherapy was feasible, safe, and active but not better than the published cisplatin-based chemoradiotherapy. A fluoropyrimidine and another cytotoxic (from any class) may be adequate to establish a baseline chemoradiotherapy regimen to combine biologics. Cancer 2010. (c) 2010 American Cancer Society.

Antiseptic effect of a novel alcohol-free mouthwash: a convenient prophylactic alternative for high-risk patients.

We developed an efficacious and non-irritant mouthwash that is alcohol-free and that has a low concentration of chlorhexidine, in order to be used for preventing oral cavity infections in immunocompromised and cancer patients. The novel mouthwash solution was tested for its antimicrobial efficacy against both free floating (planktonic) and the biofilm forms of Candida albicans. The solution was also tested against Klebsiella pneumoniae, Pseudomonas aeruginosa, and methicillin-resistant Staphylococcus aureus (MRSA), using a modification of a previously published method. The activity of the novel mouthwash was also compared with that of three commercially available mouthwashes. The experimental mouthwash showed efficacy against C. albicans, both in free-floating form and in biofilm. With higher concentration of chlorhexidine, the solution was also efficacious in inhibiting the growth of K. pneumoniae, P. aeruginosa, and MRSA. The antiseptic activity of the alcohol-free mouthwash against other bacterial organisms and C. albicans was comparable to other commercially available alcohol-based mouthwash solutions. A novel alcohol-free mouthwash solution, that has low concentration of chlorhexidine, showed antiseptic effect against planktonic and biofilm forms of C. albicans and against K. pneumoniae, P. aeruginosa, and MRSA.

Utility of PET, CT, and EUS to identify pathologic responders in esophageal cancer.

BACKGROUND: This study evaluates the utility of positron emission tomography (PET), endoscopic ultrasonography (EUS), and computed tomographic (CT) scans to predict pathologic response and survival following preoperative chemoradiation (CRT) in esophageal cancer. METHODS: One hundred three sequential patients with locoregionally advanced esophageal cancer, who were treated with CRT and esophageal resection between May 2001 and November 2003 at the University of Texas M.D. Anderson Cancer Center, were retrospectively reviewed. PET, EUS, and CT were performed before (pre) or after (post) CRT and before surgical resection. PET standardized uptake value (SUV) was defined as maximal uptake in primary tumor. RESULTS: Most patients were male (91 [88%]) with adenocarcinoma (90 [87%]). Pretreatment clinical stages were: IIA (42 [41%]), IIB (5 [5%]), III (50 [49%]), and IVA (6 [6%]). At the time of surgery, 58 patients (56%) had a pathologic response to CRT (< or =10% viable cells). Post-CRT measurements that correlated with pathologic response were: CT esophageal wall thickness (13.3 vs 15.3 mm, p = 0.04), EUS mass size (0.7 vs 1.7 cm, p = 0.01) and PET SUV (3.1 vs 5.8, p = 0.01). Post-CRT PET SUV equal to or greater than 4 had the highest accuracy for pathologic response (76%). Univariate and multivariate Cox regression analysis demonstrated that a post-CRT PET SUV equal to or greater than 4 was an independent predictor of survival (HR, 3.5, p = 0.04). CONCLUSIONS: The FDG-PET SUV is the most accurate noninvasive test to predict long-term survival after preoperative CRT and before surgical resection. Post-CRT FDG-PET cannot, however, rule out residual microscopic disease so esophagectomy should remain a therapeutic option even if the post-CRT imaging modalities are normal.

Induction chemotherapy improved outcomes of patients with resectable esophageal cancer who received chemoradiotherapy followed by surgery.

PURPOSE: To investigate the effect of induction chemotherapy (CHT) before trimodality therapy on the outcome of patients with resectable cancer of the esophagus. METHODS AND MATERIALS: This retrospective study included 81 consecutive patients with resectable cancer of the esophagus who received neoadjuvant chemoradiotherapy followed by esophagectomy between January 1990 and December 1998 (inclusive). Thirty-nine patients underwent chemoradiotherapy followed by esophagectomy (CHT/RT+S), 42 received additional induction CHT followed by CHT/RT+S (CHT+CHT/RT+S). Of the 81 patients, 47 were entered in institutional or national prospective trials (6 in the CHT/RT+S and 41 in the CHT+CHT/RT+S group). Induction CHT consisted of three courses of 5-fluorouracil (5-FU), cisplatin, and paclitaxel given in 28-day cycles in 37 patients (88.1%). Concurrent CHT was 5-FU and platinum based. The median radiation dose for patients treated with CHT/RT+S was 30 Gy (range, 30-50.4 Gy) delivered in a median of 10 fractions (range, 10-28 fractions) and 45 Gy (range, 30-45 Gy) in a median of 25 fractions (range, 10-25 fractions) for patients treated with CHT+CHT/RT+S. Esophagectomy was performed 6-8 weeks after completion of concurrent chemoradiotherapy. Most patients underwent transthoracic esophagectomy (n = 66, 82.5%). RESULTS: The pretreatment characteristics were well balanced between the two groups except for age. The median follow-up time was 29 months (22 months for the CHT/RT+S group and 38.5 months for the CHT+CHT/RT+S group) for all patients and 49 months for living patients. The actuarial overall survival (OS), disease-free survival (DFS), locoregional control (LRC), and distant metastasis-free survival (DMFS) rate at 5 years for the entire group was 46%, 36.6%, 70.7%, and 53.2%, respectively. Statistically significant differences in the OS, DFS, and LRC rates between the two groups were detected. Specifically, the 5-year OS rate was 22.8% and 71.1% in the CHT/RT+S and CHT+CHT/RT+S group (p = 0.0001), respectively. The 5-year DFS rate was 27.6% and 56.6% in the CHT/RT+S and CHT+CHT/RT+S group (p = 0.003), respectively. The 5-year LRC rate was 64.2% and 85.6% in the CHT/RT+S and CHT+CHT/RT+S group (p = 0.007), respectively. The difference in the DMFS rate between the two groups was statistically significant, with a 2- and 5-year actuarial rate of 63.9% and 51.9%, respectively, in the CHT/RT+S group and 76.9% and 74.1%, respectively, in the CHT+CHT/RT+S group (p = 0.04). The statistically significant differences persisted when patients who received >/=45 Gy in each group were compared. Among those patients, the 5-year OS, DFS, LRC, and DMFS rates were 23.1%, 15.4%, 58.6%, and 39.2%, respectively, for those receiving CHT/RT+S, and 71.4% (p = 0.001), 55.8% (p = 0.0008), 84.6% (p = 0.005), and 77.3% (p = 0.009), respectively, for those receiving CHT+CHT/RT+S. The pathologic complete response (pCR) rate was greater in the CHT+CHT/RT+S group compared with in the CHT/RT+S group (p = 0.008). In univariate analysis, young age, good Karnofsky performance status, Stage II disease, total radiation dose, multiple drug regimen for concurrent CHT, pCR, R0 resection, distant disease progression, and CHT+CHT/RT+S treatment proved to be prognostic factors for OS. Lower esophageal/gastroesophageal junction tumor location, pCR, R0 resection, and CHT+CHT/RT+S treatment were favorable prognostic factors for LRC. Neither the total radiation dose nor multiple drugs for concurrent CHT were negative prognostic factors for LRC. In multivariate analysis, pCR, R0 resection, and treatment with CHT+CHT/RT+S were independent positive predictive factors for OS, and distant recurrences were negative predictive factors for OS. R0 resection, CHT+CHT/RT+S treatment, and lower esophageal/gastroesophageal junction tumor location were positive predictive factors for LRC. The radiation dose was not identified as an independent prognostic factor for either OS or LRC in the multivariate analysis. Meaningful multivariate analysis could not be performed when the multiple drug vperformed when the multiple drug variable was included in the model because of the small number of patients. CONCLUSION: Significantly greater LRC, DFS, OS, and DMFS were found in patients treated with CHT+CHT/RT+S compared with those treated with CHT/RT+S. The pCR rate was significantly higher in the CHT+CHT/RT+S group. Induction CHT was an independent favorable prognostic factor for both LRC and OS for the population included in this study. Our data suggest that a randomized trial comparing CHT+CHT/RT+S and CHT/RT+S is warranted to assess further the merits of this treatment in patients with this currently very lethal cancer.

Irinotecan/cisplatin followed by 5-FU/paclitaxel/radiotherapy and surgery in esophageal cancer.

Local-regional carcinoma of the esophagus is often diagnosed in advanced stages because the diagnosis is established when symptoms are severe. The prognosis of patients with local-regional carcinoma of the esophagus continues to be grim. While preoperative chemoradiotherapy increases the fraction of patients who achieve pathologic complete response, that percentage is approximately 25%. In an attempt to increase the number of patients with either no cancer in the surgical specimen or only microscopic cancer, we adopted a three-step strategy. The current study utilized up to two 6-week cycles of induction chemotherapy with irinotecan (CPT-11, Camptosar) and cisplatin as step 1. This was followed by concurrent radiotherapy and chemotherapy with continuous infusion fluorouracil (5-FU) and paclitaxel as step 2. Once the patients recovered from chemoradiotherapy, a preoperative evaluation was performed and surgery was attempted. All patients signed an informed consent prior to their participation on the study. A total of 43 patients were enrolled. The baseline endoscopic ultrasonography revealed that 36 patients had a T3 tumor, five patients had a T2 tumor, and two had a T1 tumor. Twenty-seven patients had node-positive cancer (N1). Thirty-nine (91%) of the 43 patients underwent surgery; all had an R0 (curative) resection. A pathologic complete response was noted in 12 of the 39 patients. In addition, 17 patients had only microscopic (< 10%) viable cancer in the specimen. Therefore, a significant pathologic response was seen in 29 (74%) of 39 taken to surgery or 29 (67%) of all 43 patients enrolled on the study. With a median follow up beyond 25 months, 20 patients remain alive and 12 patients remain free of cancer. Our preliminary data suggest that the proportion of patients with significant pathologic response can be increased by using the three-step strategy.