Lung cancer is the leading cause of cancer-related death worldwide. The majority of these cancers are non-small-cell lung cancer, of which adenocarcinoma is the most common histologic subtype. Most patients are diagnosed at advanced stages when systemic treatment is needed. Whereas prognosis has improved for patients with targetable driver mutations, the majority of patients do not possess tumors with such molecular mutations. Platinum-based chemotherapy has traditionally been the mainstay of treatment, although in recent years immunotherapy has emerged as a treatment option and can result in robust and durable treatment responses in a subset of patients. Recent clinical trials on novel immunotherapy combinations and immunochemotherapy combinations may broaden the number of patients that may benefit from checkpoint inhibitors and elicit responses in those who otherwise may not have experienced a response to monotherapy with an immunotherapy drug. This review will outline the currently available therapies for the first-line treatment of metastatic adenocarcinoma that do not possess a driver mutation and provide a recommended approach and algorithm by which to select the best first-line therapy.

Immune checkpoint blockade (ICB) is an approved therapy for advanced metastatic mismatch repair (MMR)‐deficient cancer regardless of tissue of origin. Although therapy is effective initially, recurrence rates are significant, and long‐term outcomes remain poor for most patients. It is not currently recommended to give sequential ICB for advanced MMR‐deficient colorectal cancer (CRC) or for patients with metastatic cancer from Lynch syndrome. The need for subsequent therapy options in advanced MMR‐deficient cancer beyond the first ICB regimen arises in clinical practice, and there are often no effective standard chemotherapies or other targeted therapies. We report the case of a Lynch syndrome patient with metastatic CRC and urothelial cancer who was treated sequentially with pembrolizumab (targeting PD1), atezolizumab (targeting PD‐L1), brief rechallenge with pembrolizumab, and finally the combination of ipilimumab (targeting CTLA‐4) and nivolumab (targeting PD1). Over a 28‐month period the patient experienced prolonged disease control with each different regimen the first time it was given, including metabolic response by positron emission tomography and computed tomography scanning and tumor marker reductions. The case suggests that some patients with advanced MMR‐deficient CRC may experience meaningful clinical benefit from multiple sequential ICB regimens, a strategy that can be further tested in clinical trials. Key Points The case exemplifies clinical benefit from sequential immune checkpoint blockade in a patient with Lynch syndrome with advanced metastatic colorectal cancer and urothelial cancer. Metabolic response, with decreased fluorodeoxyglucose avidity on positron emission tomography and computed tomography, and reductions in tumor markers, such as carcinoembryonic antigen, were helpful in this case to monitor disease status over a 28‐month period of therapy. The concept of sequential immune checkpoint blockade in patients with advanced mismatch repair‐deficient cancer merits further study to determine which patients are most likely to benefit.

Background: Liquid biopsy (LB) captures dynamic genomic alterations (alts) across metastatic colorectal cancer (mCRC) therapy and may complement tissue biopsy (TB). We sought to describe the utility of LB and better understand mCRC biology during therapy.Methods: Thirty-three patients (pts) with mCRC underwent LB. We used permutation-based t-tests to assess associations between alts, and clinical variables and used Kendall's tau to measure correlations.Results: Of 33 pts, 15 were women; 22 had colon, and the rest rectal cancer. Pts received a median of two lines of therapy before LB. Nineteen pts had limited testing on TB (RAS/RAF/TP53/APC), 11 extended NGS, and 3 no TB. Maxpct and alts correlated with CEA (p < 0.001, respectively). In 3/5 pts with serial LB, CEA correlated with maxpct trend, and CT tumor burden. In 6 pts, mutant RAS was seen in LB and not TB; 5/6 had received anti-EGFR therapy prior to LB, suggesting RAS alts developed post-therapy. In two pts RAS-mutated by TB, no RAS alts were detected on LB; these pts had low disease burden on CT at time of LB that also did not reveal APC or TP53 alts. In six patients who were KRAS wt based on TB, post anti-EGFR LB revealed subclonal KRAS mutations, likely a treatment effect. The median number of alts was higher post anti-EGFR LB (n = 12) vs. anti-EGFR naïve LB (n = 22) (9.5 vs. 5.5, p = 0.059) but not statistically significant. More alts were also noted in post anti-EGFR therapy LB vs. KRAS wt anti-EGFR-naïve LB (n = 6) (9.5 vs. 5) among patients with KRAS wild-type tumors, although the difference was not significant (p = 0.182).Conclusions: LB across mCRC therapy detects driver mutations, monitors disease burden, and identifies sub-clonal alts that reflect drug resistance, tumor evolution, and heterogeneity. Interpretation of LB results is impacted by clinical context.

Tyrosine kinase inhibitors (TKIs) have transformed the treatment landscape for patients with gastrointestinal stromal tumors (GIST). Unfortunately, resistance to the currently approved TKIs poses a huge challenge, and patients are in need of additional therapeutic options. Fortunately, many novel therapeutic approaches are being tested in treatment of GIST to overcome resistance to the approved TKIs Areas covered: We performed an extensive literature (PUBMED) search to identify emerging drugs being tested in treatment of GIST in early phase clinical trials. We discuss recent ongoing research and emerging novel inhibitors of KIT and PDGFRA receptors, inhibitors in downstream signaling pathways (mTOR and PIK3 inhibitors), inhibitors of other potential targets including ETV1/MEK, MET, FGFR, IGF1R, histone deacetylase inhibitors, heat shock protein 90 inhibitors, cyclin-dependent kinase inhibitors and immune checkpoint inhibitors in treatment of GIST Expert opinion: Multiple agents are under evaluation; those that benefit GIST patients with imatinib resistant mutations, or those with benefit in patients refractory to approved agents are most likely to be developed in this disease. The role of immunotherapy for GIST is still investigational.

Gallbladder (GB) carcinoma is a rare carcinoma with a poor prognosis. The prevalence is 0.7-21/100,000 worldwide and 1-2/100,000 in the United States. Adenosquamous cell carcinoma is composed of glandular and squamous components. The overall five-year survival rate is less than 5%, with a median survival of fewer than six months. We are presenting a case of adenosquamous carcinoma of the GB in a 76-year-old female who presented with right upper quadrant abdominal pain and was found to have an enlarged GB, with thickened irregular wall likely inflammatory or malignant and mildly dilated common bile duct on ultrasound imaging of the abdomen. Core needle biopsy of GB showed findings compatible with adenosquamous carcinoma and immunohistochemistry was positive for P40, CK5,6. She was diagnosed with stage T4 N0 M0. She was started on chemotherapy with cisplatin and gemcitabine (25 mg/m2 and 1000 mg/m2), respectively, every three weeks but her condition worsened after the fifth cycle of chemotherapy and she decided to move forward with hospice care given her bad prognosis. Unfortunately, she passed away one week after being discharged home.