5-fluorouracil, leucovorin, irinotecan and oxaliplatin (FOLFIRINOX) is superior to gemcitabine in patients with metastatic pancreatic cancer who have a good performance status. We investigated this combination as neoadjuvant therapy for locally advanced pancreatic cancer (LAPC).

Objective: nab-Paclitaxel has been shown to disrupt pancreatic cancer stroma and was effective in combination with gemcitabine in a phase I/II trial. This study was designed to determine the efficacy of nab-paclitaxel monotherapy in previously treated pancreatic cancer patients. Methods: In this phase II trial, patients with advanced pancreatic cancer who progressed on gemcitabine-based therapy, received nab-paclitaxel 100 mg/m² over 30 minutes on days 1, 8, and 15 of a 28-day cycle. The primary endpoint was 6-month overall survival (OS). Secondary endpoints were response rate (by Response Evaluation Criteria In Solid Tumors), progression-free survival, safety, and toxicity profile. Results: Among 19 patients treated, the median age was 61 years, 9 (47%) were male patients and 18 (95%) had stage-IV disease. The primary endpoint of the study was reached with a 6-month OS of 58% [95% confidence interval (95% CI), 33%-76%] and an estimated median OS of 7.3 months (95% CI, 2.8-15.8 mo). The median progression-free survival was 1.7 months (95% CI, 1.5-3.5 mo). One patient had a confirmed partial response and 6 (32%) had stable disease as their best response. Nonhematological toxicities were generally mild with grades 1-2 nausea, anorexia, hypocalcemia, and vomiting occurring in 63%, 47%, 37%, and 26% of patients, respectively. Grades 3-4 neutropenia, neutropenic fever, and anemia occurred in 32%, 11%, and 11% of patients, respectively. Only 2 of 15 available tumors stained positive for secreted protein acid rich in cysteine, and neither of these patients benefited from the therapy. Conclusions: nab-Paclitaxel was well tolerated, and it demonstrated preliminary evidence of activity in a subset of patients who progressed on gemcitabine-based therapy.

Approximately 3% to 10% of patients with pancreatic ductal adenocarcinoma (PDAC) have pathogenic germline variants (PGVs) leading to homologous recombination deficiency (HRD), and approximately 15% to 17% have similar somatic alterations.¹ These patients have increased sensitivity to platinum-containing chemotherapy and PARP inhibitors.^1,2 There is increased genomic instability in this subgroup of patients; in a pan-cancer analysis, PDACs with biallelic loss of BRCA1 and BRCA2 (BRCA1/2) had a higher median tumor mutation burden (4.3 vs 1.7 mutations/Mb) and higher genomic loss of heterozygosity than wild-type tumors.³ Similar genomic instability leading to tumor-inflamed phenotype has been described in BRCA1/2-variant breast, ovarian, and prostate cancers.⁴ Immune checkpoint inhibitors (ICIs) have been ineffective in unselected patients with PDAC.⁵ Given the molecular rationale for increased susceptibility to ICIs in patients with PDAC associated with HRD PGVs, we investigated whether this subgroup may be sensitive to immunotherapy strategies.

Patients with pathogenic germline and somatic variants in DNA damage repair (DDR) genes may derive greater benefit with platinum-based chemotherapy in metastatic pancreatic ductal adenocarcinoma (PDAC). This study investigates the role of DDR genes as a predictive biomarker for response to first-line platinum chemotherapy with FOLFIRINOX in metastatic PDAC patients. Demographic, clinical, and pathologic variables were collected for patients with metastatic PDAC who received FOLFIRINOX as frontline treatment and who had germline and somatic genetic testing. Kaplan-Meier analysis of overall survival (OS) and progression free survival (PFS) were correlated to the presence of DDR pathogenic variants. Forty patients with metastatic PDAC met inclusion criteria. Germline genetic testing revealed germline pathogenic variants in DDR genes in 5 patients (12%), and somatic pathogenic variants in DDR genes in 4 patients (10%). Median PFS was significantly longer in patients with any (germline or somatic) pathogenic variant in DDR genes than in those without alterations 18.5 vs. 6.9 months (log-rank P=0.003). When restricted to the presence or absence of germline pathogenic variants in DDR genes, the median PFS was 18.5 vs. 7.4 months (log-rank P=0.005). The median OS for the entire cohort was 11.5 months was not statistically different between the two groups, however there were no deaths in the subgroup with germline pathogenic variants in DDR genes treated with frontline FOLFIRINOX. A subset of patients with metastatic PDAC and germline or somatic pathogenic variants in DDR genes have a statistically superior PFS when treated with the platinum containing regimen FOLFIRINOX. The role of DDR gene alterations as a predictive biomarker for FOLFIRINOX benefit should be further evaluated in prospective trials.

Background Immune checkpoint inhibitors (CPIs) have shown promising results in many solid tumors. There are limited data on the safety and efficacy of these drugs in HIV infected patients as they have traditionally been excluded from CPIs clinical trials. Case presentation We present a case of an HIV-positive patient with extensive extrapulmonary high-grade small cell carcinoma who was treated with dual CPIs (nivolumab and ipilimumab) with a complete response to therapy and with a manageable safety profile. We performed a comprehensive literature review identifying 62 total HIV positive cases treated with CPIs showing this to be a potentially safe option in HIV-positive patients. Conclusion HIV infection is not an absolute contraindication to CPI therapy. Our case and others provide justification for ongoing trials of CPI therapy in patients with HIV infection, a group that has traditionally been excluded from clinical trials.