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The current third-line (and beyond) treatment options for RAS-mutant metastatic colorectal cancer have yielded limited efficacy. At the time of study start, the combination of sotorasib, a KRAS (Kirsten rat sarcoma viral oncogene homolog)-G12C inhibitor, and panitumumab, an epidermal growth factor receptor (EGFR) inhibitor, was hypothesized to overcome treatment-induced resistance. This phase 1b substudy of the CodeBreaK 101 master protocol evaluated sotorasib plus panitumumab in patients with chemotherapy-refractory KRASG12C-mutated metastatic colorectal cancer. Here, we report the results in a dose-exploration cohort and a dose-expansion cohort. Patients received sotorasib (960 mg, once daily) plus panitumumab (6 mg kg-1, once every 2 weeks). The primary endpoints were safety and tolerability. Secondary endpoints included efficacy and pharmacokinetics. Exploratory biomarkers at baseline were assessed. Forty-eight patients (dose-exploration cohort, n = 8; dose-expansion cohort, n = 40) were treated. Treatment-related adverse events of any grade and grade ≥3 occurred in 45 (94%) and 13 (27%) patients, respectively. In the dose-expansion cohort, the confirmed objective response rate was 30.0% (95% confidence interval (CI) 16.6%, 46.5%). Median progression-free survival was 5.7 months (95% CI 4.2, 7.7 months). Median overall survival was 15.2 months (95% CI 12.5 months, not estimable). Prevalent genomic coalterations included APC (84%), TP53 (74%), SMAD4 (33%), PIK3CA (28%) and EGFR (26%). Sotorasib-panitumumab demonstrated acceptable safety with promising efficacy in chemotherapy-refractory KRASG12C-mutated metastatic colorectal cancer. ClinicalTrials.gov identifier: NCT04185883 .

DESTINY-CRC01 (NCT03384940) was a multicenter, open-label, phase 2 trial assessing the efficacy and safety of trastuzumab deruxtecan (T-DXd) in patients with HER2-expressing metastatic colorectal cancer (mCRC) that progressed after ≥2 prior regimens; results of the primary analysis are published. Patients received T-DXd 6.4 mg/kg every 3 weeks and were assigned to either: cohort A (HER2-positive, immunohistochemistry [IHC] 3+ or IHC 2+/in situ hybridization [ISH]+), cohort B (IHC 2+/ISH-), or cohort C (IHC 1+). Primary endpoint was objective response rate (ORR) by independent central review in cohort A. Secondary endpoints included ORR (cohorts B and C), duration of response, disease control rate, progression-free survival, overall survival, pharmacokinetics, and safety of T-DXd. 86 patients were enrolled (53 in cohort A, 15 in cohort B, and 18 in cohort C). Results of the primary analysis are published, reporting an ORR of 45.3% in cohort A. Here, we report the final results. No responses occurred in cohorts B or C. Median progression-free survival, overall survival, and duration of response were 6.9, 15.5, and 7.0 months, respectively. Overall serum exposure (cycle 1) of T-DXd, total anti-HER2 antibody, and DXd were similar regardless of HER2 status. Most common grade ≥3 treatment-emergent adverse events were decreased neutrophil count and anemia. Adjudicated drug-related interstitial lung disease/pneumonitis occurred in 8 patients (9.3%). These findings support the continued exploration of T-DXd in HER2-positive mCRC.

PurposeEntrectinib potently inhibits tropomyosin receptor kinases (TRKAs)/B/C and ROS1, and previously induced deep [objective response rate (ORR) 57.4%] and durable [median duration of response (DoR) 10.4 months] responses in adults with NTRK fusion-positive solid tumors from three phase I/II trials. This article expands prior reports with additional patients and longer follow-up.Patients and methodsPatients with locally advanced/metastatic NTRK fusion-positive solid tumors and ≥12 months' follow-up were included. Primary endpoints were ORR and DoR by blinded independent central review (BICR); secondary endpoints included progression-free survival (PFS), intracranial efficacy, and safety. The safety-evaluable populations included all patients who had received ≥1 entrectinib dose.ResultsAt clinical cut-off (August 31, 2020), the efficacy-evaluable population comprised 121 adults with 14 tumor types and ≥30 histologies. Median follow-up was 25.8 months; 61.2% of patients had a complete (n = 19) or partial response (n = 55). Median DoR was 20.0 months [95% confidence interval (CI), 13.0-38.2]; median PFS was 13.8 months (95% CI, 10.1-19.9). In 11 patients with BICR-assessed measurable central nervous system (CNS) disease, intracranial ORR was 63.6% (95% CI, 30.8-89.1) and median intracranial DoR was 22.1 (95% CI, 7.4-not estimable) months. The safety profile of entrectinib in adults and pediatric patients was aligned with previous reports. Most treatment-related adverse events (TRAEs) were grade 1/2 and manageable/reversible with dose modifications. TRAE-related discontinuations occurred in 8.3% of patients.ConclusionsWith additional clinical experience, entrectinib continues to demonstrate durable systemic and intracranial responses and can address the unmet need of a CNS-active treatment in patients with NTRK fusion-positive solid tumors.

Colorectal cancer (CRC) is a leading cause of cancer mortality. Creatine metabolism was previously shown to critically regulate colon cancer progression. We report that RGX-202, an oral small-molecule SLC6A8 transporter inhibitor, robustly inhibits creatine import in vitro and in vivo, reduces intracellular phosphocreatine and ATP levels, and induces tumor apoptosis. RGX-202 suppressed CRC growth across KRAS wild-type and KRAS mutant xenograft, syngeneic, and patient-derived xenograft (PDX) tumors. Antitumor efficacy correlated with tumoral expression of creatine kinase B. Combining RGX-202 with 5-fluorouracil or the DHODH inhibitor leflunomide caused regressions of multiple colorectal xenograft and PDX tumors of distinct mutational backgrounds. RGX-202 also perturbed creatine metabolism in patients with metastatic CRC in a phase 1 trial, mirroring pharmacodynamic effects on creatine metabolism observed in mice. This is, to our knowledge, the first demonstration of preclinical and human pharmacodynamic activity for creatine metabolism targeting in oncology, thus revealing a critical therapeutic target.

BackgroundNo therapies for targeting KRAS mutations in cancer have been approved. The KRAS p.G12C mutation occurs in 13% of non-small-cell lung cancers (NSCLCs) and in 1 to 3% of colorectal cancers and other cancers. Sotorasib is a small molecule that selectively and irreversibly targets KRASG12C.MethodsWe conducted a phase 1 trial of sotorasib in patients with advanced solid tumors harboring the KRAS p.G12C mutation. Patients received sotorasib orally once daily. The primary end point was safety. Key secondary end points were pharmacokinetics and objective response, as assessed according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1.ResultsA total of 129 patients (59 with NSCLC, 42 with colorectal cancer, and 28 with other tumors) were included in dose escalation and expansion cohorts. Patients had received a median of 3 (range, 0 to 11) previous lines of anticancer therapies for metastatic disease. No dose-limiting toxic effects or treatment-related deaths were observed. A total of 73 patients (56.6%) had treatment-related adverse events; 15 patients (11.6%) had grade 3 or 4 events. In the subgroup with NSCLC, 32.2% (19 patients) had a confirmed objective response (complete or partial response) and 88.1% (52 patients) had disease control (objective response or stable disease); the median progression-free survival was 6.3 months (range, 0.0+ to 14.9 [with + indicating that the value includes patient data that were censored at data cutoff]). In the subgroup with colorectal cancer, 7.1% (3 patients) had a confirmed response, and 73.8% (31 patients) had disease control; the median progression-free survival was 4.0 months (range, 0.0+ to 11.1+). Responses were also observed in patients with pancreatic, endometrial, and appendiceal cancers and melanoma.ConclusionsSotorasib showed encouraging anticancer activity in patients with heavily pretreated advanced solid tumors harboring the KRAS p.G12C mutation. Grade 3 or 4 treatment-related toxic effects occurred in 11.6% of the patients. (Funded by Amgen and others; CodeBreaK100 ClinicalTrials.gov number, NCT03600883.).

PurposeKEYNOTE-158 (ClinicalTrials.gov identifier: NCT02628067) investigated the efficacy and safety of pembrolizumab across multiple cancers. We present results from patients with previously treated advanced well-differentiated neuroendocrine tumors (NET).Patients and methodsPembrolizumab 200 mg was administered every 3 weeks for 2 years or until progression, intolerable toxicity, or physician/patient decision. Tumor imaging was performed every 9 weeks for the first year and then every 12 weeks. Endpoints included objective response rate (ORR) per RECIST v1.1 by independent central radiologic review (primary) and duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety (secondary).ResultsA total of 107 patients with NETs of the lung, appendix, small intestine, colon, rectum, or pancreas were treated. Median age was 59.0 years (range, 29-80), 44.9% had ECOG performance status 1, 40.2% had received ≥3 prior therapies for advanced disease, and 15.9% had PD-L1-positive tumors (combined positive score ≥1). Median follow-up was 24.2 months (range, 0.6-33.4). ORR was 3.7% (95% CI, 1.0-9.3), with zero complete responses and four partial responses (three pancreatic and one rectal) all in patients with PD-L1-negative tumors. Median DOR was not reached, with one of four responses ongoing after ≥21 months follow-up. Median PFS was 4.1 months (95% CI, 3.5-5.4); the 6-month PFS rate was 39.3%. Median OS was 24.2 months (95% CI, 15.8-32.5). Treatment-related adverse events (AE) occurred in 75.7% of patients, 21.5% of whom had grade 3-5 AEs.ConclusionsPembrolizumab monotherapy showed limited antitumor activity and manageable safety in patients with previously treated advanced well-differentiated NETs.

BackgroundEntrectinib is a potent inhibitor of tropomyosin receptor kinase (TRK) A, B, and C, which has been shown to have anti-tumour activity against NTRK gene fusion-positive solid tumours, including CNS activity due to its ability to penetrate the blood-brain barrier. We present an integrated efficacy and safety analysis of patients with metastatic or locally advanced solid tumours harbouring oncogenic NTRK1, NTRK2, and NTRK3 gene fusions treated in three ongoing, early-phase trials.MethodsAn integrated database comprised the pivotal datasets of three, ongoing phase 1 or 2 clinical trials (ALKA-372-001, STARTRK-1, and STARTRK-2), which enrolled patients aged 18 years or older with metastatic or locally advanced NTRK fusion-positive solid tumours who received entrectinib orally at a dose of at least 600 mg once per day in a capsule. All patients had an Eastern Cooperative Oncology Group performance status of 0-2 and could have received previous anti-cancer therapy (except previous TRK inhibitors). The primary endpoints, the proportion of patients with an objective response and median duration of response, were evaluated by blinded independent central review in the efficacy-evaluable population (ie, patients with NTRK fusion-positive solid tumours who were TRK inhibitor-naive and had received at least one dose of entrectinib). Overall safety evaluable population included patients from STARTRK-1, STARTRK-2, ALKA-372-001, and STARTRK-NG (NCT02650401; treating young adult and paediatric patients [aged ≤21 years]), who received at least one dose of entrectinib, regardless of tumour type or gene rearrangement. NTRK fusion-positive safety evaluable population comprised all patients who have received at least one dose of entrectinib regardless of dose or follow-up. These ongoing studies are registered with ClinicalTrials.gov, NCT02097810 (STARTRK-1) and NCT02568267 (STARTRK-2), and EudraCT, 2012-000148-88 (ALKA-372-001).FindingsPatients were enrolled in ALKA-372-001 from Oct 26, 2012, to March 27, 2018; in STARTRK-1 from Aug 7, 2014, to May 10, 2018; and in STARTRK-2 from Nov 19, 2015 (enrolment is ongoing). At the data cutoff date for this analysis (May 31, 2018) the efficacy-evaluable population comprised 54 adults with advanced or metastatic NTRK fusion-positive solid tumours comprising ten different tumour types and 19 different histologies. Median follow-up was 12.9 months (IQR 8·77-18·76). 31 (57%; 95% CI 43·2-70·8) of 54 patients had an objective response, of which four (7%) were complete responses and 27 (50%) partial reponses. Median duration of response was 10 months (95% CI 7·1 to not estimable). The most common grade 3 or 4 treatment-related adverse events in both safety populations were increased weight (seven [10%] of 68 patients in the NTRK fusion-positive safety population and in 18 [5%] of 355 patients in the overall safety-evaluable population) and anaemia (8 [12%] and 16 [5%]). The most common serious treatment-related adverse events were nervous system disorders (three [4%] of 68 patients and ten [3%] of 355 patients). No treatment-related deaths occurred.InterpretationEntrectinib induced durable and clinically meaningful responses in patients with NTRK fusion-positive solid tumours, and was well tolerated with a manageable safety profile. These results show that entrectinib is a safe and active treatment option for patients with NTRK fusion-positive solid tumours. These data highlight the need to routinely test for NTRK fusions to broaden the therapeutic options available for patients with NTRK fusion-positive solid tumours.FundingIgnyta/F Hoffmann-La Roche.

The role of palliative surgery in the management of acute complications in patients with disseminated malignancy remains controversial given the complexity of assessing acute surgical risk and long-term oncologic outcome. With the emergence of checkpoint blockade immunotherapy, there appears to be an increasing role for historically palliative procedures as a bridge to systemic immunotherapy. This is especially evident in advanced microsatellite instability-high (MSI-H) colorectal cancer where malignant obstruction and fistula formation are more common and where immunotherapy with checkpoint blockade (anti-PD-1/PD-L1, anti-CTLA-4) has a high response rate with potential for favorable oncologic outcomes. We present a series of three patients with MSI-H metastatic colorectal cancer complicated by malignant bowel obstruction and fistula formation, who having progressed on standard chemotherapy, underwent palliative intervention as a bridge to immune checkpoint blockade with durable and clinically meaningful anti-cancer responses. These cases highlight the need to re-evaluate the role of historically palliative operations in the setting of disease progression for immunotherapy-responsive tumors.

RET fusions are oncogenic drivers of various tumors, including non-small cell lung cancers (NSCLC). The safety and antitumor activity of the multikinase RET inhibitor RXDX-105 were explored in a phase I/Ib trial. A recommended phase II dose of 275 mg fed daily was identified. The most common treatment-related adverse events were fatigue (25%), diarrhea (24%), hypophosphatemia (18%), maculopapular rash (18%), and nonmaculopapular rash (17%). In the phase Ib cohort of RET inhibitor-naïve patients with RET fusion-positive NSCLCs, the objective response rate (ORR) was 19% (95% CI, 8%-38%, n = 6/31). Interestingly, the ORR varied significantly by the gene fusion partner (P < 0.001, Fisher exact test): 0% (95% CI, 0%-17%, n = 0/20) with KIF5B (the most common upstream partner for RET fusion-positive NSCLC), and 67% (95% CI, 30%-93%, n = 6/9) with non-KIF5B partners. The median duration of response in all RET fusion-positive NSCLCs was not reached (range, 5 to 18+ months). SIGNIFICANCE: Although KIF5B-RET is the most common RET fusion in NSCLCs, RET inhibition with RXDX-105 resulted in responses only in non-KIF5B-RET-containing cancers. Novel approaches to targeting KIF5B-RET-containing tumors are needed, along with a deeper understanding of the biology that underlies the differential responses observed.This article is highlighted in the In This Issue feature, p. 305.

Peritoneal metastasis (PM) from appendiceal cancer or colorectal cancer (CRC) has significant morbidity and limited survival. Pressurized intraperitoneal aerosolized chemotherapy (PIPAC) is a minimally invasive approach to treat PM. We aim to conduct a dose-escalation trial of mitomycin C (MMC)-PIPAC combined with systemic chemotherapy (FOLFIRI) in patients with PM from appendiceal cancer or CRC.

What is this summary about? This is a summary describing the results from a phase 3 clinical trial called SUNLIGHT. The study looked at treatment with orally administered trifluridine/tipiracil plus intravenously administered bevacizumab in people with metastatic colorectal cancer (mCRC) that is refractory to treatment. This study included people whose cancer had grown or spread beyond its original location after no more than two previous treatments. People in the study received either the combination of trifluridine/tipiracil plus bevacizumab or they received trifluridine/tipiracil alone. The aims of the study were to see how long people lived after treatment with trifluridine/tipiracil plus bevacizumab compared with trifluridine/tipiracil alone and to find out how well the combination of trifluridine/tipiracil plus bevacizumab worked at slowing down the spread of the cancer. Researchers also looked at side effects from taking the medicines and at how treatment affected people's physical functioning. What are the key takeaways? People in the combination group lived longer (a median of 10.8 months) than people who received trifluridine/tipiracil alone (7.5 months). In addition, the time it took for the cancer to worsen was longer for those who received the combination treatment (a median of 5.6 months) compared with those who received trifluridine/tipiracil alone (2.4 months). People's physical functioning took longer to worsen with combination therapy (a median of 9.3 months) than it did with trifluridine/tipiracil alone (6.3 months), as measured by the impact of treatment on people's ability to carry out daily living activities. The most common side effects in both treatment groups were low levels of white blood cells, known as neutrophils (neutropenia), nausea, and low levels of healthy red blood cells (anemia). What were the main conclusions reported by the researchers? The results from the study suggest that treatment with oral trifluridine/tipiracil plus intravenous (IV) bevacizumab could help people with refractory mCRC live longer and maintain good physical functioning, and it could slow the worsening of their cancer. Clinical Trial Registration:NCT04737187 (SUNLIGHT) (ClinicalTrials.gov) [ABSTRACT FROM AUTHOR]

Background There have been conflicting reports on the predictive impact of metastatic disease sites on the response to checkpoint inhibitors (CPI) in microsatellite instability (MSI) metastatic colorectal cancers (mCRC). Recent studies have highlighted peritoneal metastases, ascites, and liver metastases as possible indicators of resistance to CPI. Methods We performed a detailed analysis of high microsatellite instability (MSI-H) mCRC treated with programmed cell death (PD-1) or PD-1/cytotoxic T-lymphocyte-associated protein 4 CPI in a single center. Overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and stable disease but with complete pathological response upon resection (SDcPR) were analyzed by the presence of liver metastases, peritoneal metastases, or absence of either. The impact of number and size of liver metastases on clinical outcomes were also interrogated. Results Thirty-five patients with MSI mCRC were included in the analysis. Patients with peritoneal metastatic disease had lower ORR and shorter PFS compared to patients without liver and peritoneal metastases. Contrary to recent reports, ORR and ORR + SDcPR rates were high in patients with liver metastases, at 58% and 66%, respectively. In the liver metastases category, a better response rate was noted for patients with<5 lesions compared to patients with more than 5 lesions. Patients who responded had a higher median tumor mutation burden than patients with progressive disease. Conclusions In MSI mCRC, no single clinical characteristic was sufficient to preclude CPI response. Peritoneal metastatic disease was associated with numerically lower ORR and shorter PFS. In contrast, liver metastases do not predict poor outcome. [ABSTRACT FROM AUTHOR]

Biliary tract cancers are a rare diagnosis with a rising incidence. Up to 20% of patients have peritoneal metastases, resulting in symptoms of ascites, abdominal pain and potential bowel obstruction. A standard of care systemic treatment comprises gemcitabine, cisplatin and durvalumab (gem/cis/durva). However, the clinical benefit among patients with peritoneal metastases remains unknown. Pressurized intraperitoneal aerosolized chemotherapy (PIPAC) delivers chemotherapy directly to the peritoneal space, which could potentially improve efficacy with minimal systemic toxicity. We describe the design of a Phase I study investigating PIPAC with nab-paclitaxel plus systemic gem/cis/durva among biliary tract cancer patients with peritoneal metastases who have not received prior systemic treatment. The primary end point is safety of PIPAC with nab-paclitaxel in combination with systemic gem/cis/durva. Clinical Trial Registration:NCT05285358 (ClinicalTrials.gov) Article highlights Biliary tract cancers Biliary tract cancers include cholangiocarcinoma (intra-hepatic and extra-hepatic) and gallbladder cancer. Up to 20% of patients will have peritoneal metastases, which can cause ascites, abdominal pain and potential bowel obstruction. Systemic treatment landscape Standard of care first-line systemic treatment comprises gemcitabine, cisplatin and anti-PD-1/L1 immunotherapy (e.g. durvalumab). The addition of nab-paclitaxel to the combination of gemcitabine plus cisplatin showed promising results in a Phase II single-arm study, but a Phase III randomized study showed no significant improvement in efficacy with the triplet combination compared with gemcitabine plus cisplatin alone, potentially due to increased toxicity. The benefit of systemic treatment among patients with peritoneal metastases has not been thoroughly investigated. Pressurized intraperitoneal aerosolized chemotherapy (PIPAC) PIPAC delivers chemotherapy in an aerosolized form directly to the intraperitoneal space, allowing for lower doses of chemotherapy to be used; this may increase peritoneal tumor uptake and reduce systemic uptake, potentially reducing toxicities. Multiple studies in Europe and one study in the United States have demonstrated the feasibility and safety of PIPAC with multiple chemotherapies (including nab-paclitaxel) among patients with a variety of cancer diagnoses and peritoneal metastases. Phase I study of PIPAC in patients with advanced biliary tract cancer NCT05285358 is a Phase I single-arm study investigating PIPAC with nab-paclitaxel in combination with systemic gemcitabine, cisplatin and durvalumab in patients with advanced biliary tract cancer and peritoneal metastases who have not previously received systemic therapy. The primary objective is safety of PIPAC with nab-paclitaxel in combination with systemic chemotherapy (gemcitabine plus cisplatin) and immunotherapy (durvalumab). [ABSTRACT FROM AUTHOR]