background The epidermal growth factor receptor (EGFR), which participates in signaling pathways that are deregulated in cancer cells, commonly appears on colorectal-cancer cells. Cetuximab is a monoclonal antibody that specifically blocks the EGFR. We compared the efficacy of cetuximab in combination with irinotecan with that of cetuximab alone in metastatic colorectal cancer that was refractory to treatment with irinotecan. methods We randomly assigned 329 patients whose disease had progressed during or within three months after treatment with an irinotecan-based regimen to receive either cetuximab and irinotecan (at the same dose and schedule as in a prestudy regimen [218 patients]) or cetuximab monotherapy (111 patients). In cases of disease progression, the addition of irinotecan to cetuximab monotherapy was permitted. The patients were evaluated radiologically for tumor response and were also evaluated for the time to tumor progression, survival, and side effects of treatment. results The rate of response in the combination-therapy group was significantly higher than that in the monotherapy group (22.9 percent [95 percent confidence interval, 17.5 to 29.1 percent] vs. 10.8 percent [95 percent confidence interval, 5.7 to 18.1 percent], P=0.007). The median time to progression was significantly greater in the combination-therapy group (4.1 vs. 1.5 months, P<0.001 by the log-rank test). The median survival time was 8.6 months in the combination-therapy group and 6.9 months in the monotherapy group (P=0.48). Toxic effects were more frequent in the combinationtherapy group, but their severity and incidence were similar to those that would be expected with irinotecan alone. conclusions Cetuximab has clinically significant activity when given alone or in combination with irinotecan in patients with irinotecan-refractory colorectal cancer.

https://www.nejm.org/doi/pdf/10.1056/NEJMoa033025

Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer.

The accidental discovery of the anticancer properties of cisplatin and its clinical introduction in the 1970s represent a major landmark in the history of successful anticancer drugs. Although carboplatin--a second-generation analogue that is safer but shows a similar spectrum of activity to cisplatin--was introduced in the 1980s, the pace of further improvements slowed for many years. However, in the past several years interest in platinum drugs has increased. Key developments include the elucidation of mechanisms of tumour resistance to these drugs, the introduction of new platinum-based agents (oxaliplatin, satraplatin and picoplatin), and clinical combination studies using platinum drugs with resistance modulators or new molecularly targeted drugs.

The resurgence of platinum-based cancer chemotherapy

background The standard adjuvant treatment of colon cancer is fluorouracil plus leucovorin (FL). Oxaliplatin improves the efficacy of this combination in patients with metastatic colorectal cancer. We evaluated the efficacy of treatment with FL plus oxaliplatin in the postoperative adjuvant setting. methods We randomly assigned 2246 patients who had undergone curative resection for stage II or III colon cancer to receive FL alone or with oxaliplatin for six months. The primary end point was disease-free survival. results A total of 1123 patients were randomly assigned to each group. After a median followup of 37.9 months, 237 patients in the group given FL plus oxaliplatin had had a cancer-related event, as compared with 293 patients in the FL group (21.1 percent vs. 26.1 percent; hazard ratio for recurrence, 0.77; P=0.002). The rate of disease-free survival at three years was 78.2 percent (95 percent confidence interval, 75.6 to 80.7) in the group given FL plus oxaliplatin and 72.9 percent (95 percent confidence interval, 70.2 to 75.7) in the FL group (P=0.002 by the stratified log-rank test). In the group given FL plus oxaliplatin, the incidence of febrile neutropenia was 1.8 percent, the incidence of gastrointestinal adverse effects was low, and the incidence of grade 3 sensory neuropathy was 12.4 percent during treatment, decreasing to 1.1 percent at one year of follow-up. Six patients in each group died during treatment (death rate, 0.5 percent). conclusions Adding oxaliplatin to a regimen of fluorouracil and leucovorin improves the adjuvant treatment of colon cancer.

/pdf/oxaliplatin-fluorouracil-and-leucovorin-as-adjuvant-guj6w6mmk0.pdf

Oxaliplatin, Fluorouracil, and Leucovorin as Adjuvant Treatment for Colon Cancer

Purpose In metastatic colorectal cancer, phase III studies have demonstrated the superiority of fluorouracil (FU) with leucovorin (LV) in combination with irinotecan or oxaliplatin over FU LV alone. This phase III study investigated two sequences: folinic acid, FU, and irinotecan (FOLFIRI) followed by folinic acid, FU, and oxaliplatin (FOLFOX6; arm A), and FOLFOX6 followed by FOLFIRI (arm B). Patients and Methods Previously untreated patients with assessable disease were randomly assigned to receive a 2-hour infusion of l-LV 200 mg/m 2 or dl-LV 400 mg/m 2 followed by a FU bolus 400 mg/m 2 and 46-hour infusion 2,400 to 3,000 mg/m 2 every 46 hours every 2 weeks, either with irinotecan 180 mg/m 2 or with oxaliplatin 100 mg/m 2 as a 2-hour infusion on day 1. At progression, irinotecan was replaced by oxaliplatin (arm A), or oxaliplatin by irinotecan (arm B).

/pdf/folfiri-followed-by-folfox6-or-the-reverse-sequence-in-d2yr6xn6ub.pdf

FOLFIRI Followed by FOLFOX6 or the Reverse Sequence in Advanced Colorectal Cancer: A Randomized GERCOR Study

Purpose To evaluate the efficacy and safety of bevacizumab when added to first-line oxaliplatin-based chemotherapy (either capecitabine plus oxaliplatin [XELOX] or fluorouracil/folinic acid plus oxaliplatin [FOLFOX-4]) in patients with metastatic colorectal cancer (MCRC).

/pdf/bevacizumab-in-combination-with-oxaliplatin-based-1muhwz838g.pdf

Bevacizumab in Combination With Oxaliplatin-Based Chemotherapy As First-Line Therapy in Metastatic Colorectal Cancer: A Randomized Phase III Study

PURPOSE: In a previous study of treatment for advanced colorectal cancer, the LV5FU2 regimen, comprising leucovorin (LV) plus bolus and infusional fluorouracil (5FU) every 2 weeks, was superior to the standard North Central Cancer Treatment Group/Mayo Clinic 5-day bolus 5FU/LV regimen. This phase III study investigated the effect of combining oxaliplatin with LV5FU2, with progression-free survival as the primary end point. PATIENTS AND METHODS: Four hundred twenty previously untreated patients with measurable disease were randomized to receive a 2-hour infusion of LV (200 mg/m2/d) followed by a 5FU bolus (400 mg/m2/d) and 22-hour infusion (600 mg/m2/d) for 2 consecutive days every 2 weeks, either alone or together with oxaliplatin 85 mg/m2 as a 2-hour infusion on day 1. RESULTS: Patients allocated to oxaliplatin plus LV5FU2 had significantly longer progression-free survival (median, 9.0 v 6.2 months; P = .0003) and better response rate (50.7% v 22.3%; P = .0001) when compared with the control arm. The imp...

Leucovorin and Fluorouracil With or Without Oxaliplatin as First-Line Treatment in Advanced Colorectal Cancer

PURPOSE
Tilsotolimod is an investigational synthetic Toll-like receptor 9 (TLR9) agonist that has demonstrated anti-tumor activity in preclinical models. The ILLUMINATE-101 phase 1 study explored the safety, dose, efficacy, and immune effects of intra-tumoral (it) tilsotolimod monotherapy in multiple solid tumors.


METHODS
Patients with a diagnosis of refractory cancer not amenable to curative therapies received tilsotolimod in doses escalating from 8 to 32 mg into a single lesion at weeks 1, 2, 3, 5, 8, and 11. Additional patients with advanced malignant melanoma (MM) were enrolled into an expansion cohort at the 8 mg dose. Objectives included characterizing the safety, establishing the dose, efficacy, and immunological assessment. Blood samples and tumor biopsies of injected and non-injected lesions were obtained at baseline and 24 hours post treatment for immune analyses.


RESULTS
38 & 16 patients were enrolled into the dose escalation and melanoma expansion cohorts, respectively. Deep visceral injections were conducted in 91% of patients. No dose-limiting toxicities (DLTs) or Grade 4 treatment-related adverse events were observed. Biopsies 24 hours after treatment demonstrated an increased IFN pathway signature and dendritic cell maturation. Immunologic profiling revealed upregulation of IFN-signaling genes and modulation of genes for checkpoint proteins. In the dose escalation cohort, 12 (34%) of 35 evaluable patients achieved a best overall response rate (ORR) of stable disease (SD) while 3 (19%) of 16 evaluable patients in the melanoma cohort achieved stable disease.


CONCLUSION
Overall, tilsotolimod monotherapy was generally well tolerated and induced rapid, robust alterations in the tumor microenvironment.

Tilsotolimod exploits the TLR9 pathway to promote antigen presentation and Type 1 IFN signaling in solid tumors: A Multicenter International Phase I/II trial (ILLUMINATE-101).

Objective Cutaneous squamous cell carcinoma (cSCC) is the second most common non-melanoma skin cancer worldwide. It is usually treated surgically, with very high cure rates. However, in 3%-7% of cases, cSCC metastasizes to lymph nodes or distant organs. Many of the affected patients are elderly with comorbidities who are not candidates for standard-of-care curative-intent treatment with surgery and/or radio-/chemotherapy. Immune checkpoint inhibitors, which target programmed cell death protein 1 (PD-1) pathways, have recently emerged as a potent therapeutic option. The present report presents the Israeli experience with PD-1 inhibitors for the treatment of loco-regionally advanced or metastatic cSCC in a diverse and elderly population, with or without the addition of radiotherapy. Material and methods The databases of two university medical centers were retrospectively searched for patients with cSCC treated with the PD-1 inhibitors cemiplimab or pembrolizumab between January 2019 and May 2022. Data on baseline, disease-related, treatment-related, and outcome parameters were collected and analyzed. Results The cohort included 102 patients of a median age 78.5 years. Evaluable response data were available for 93. The overall response rate was 80.6%: complete response in 42 patients (45.2%) and partial response in 33 (35.5%). Stable disease was recorded in 7 (7.5%) and progressive disease in 11 (11.8%). Median progression-free survival was 29.5 months. Radiotherapy was administered to the target lesion during PD-1 treatment in 22.5% of patients. mPFS was not significantly different in patients who treated with RT than patients how did not (NR vs 18.4 months, HR=0.93, 95%CI: 0.39 - 2.17, p<0.859). Any-grade toxicity was recorded in 57 patients (55%), including grade ‗3 in 25, of whom 5 (5% of cohort) died. Compared to toxicity-free patients, patients with drug toxicity had better progression-free survival (18.4 months vs not reached, HR=0.33, 95% CI: 0.13-0.82, p=0.012) and higher overall response rate (87% vs 71.8%, p=0.06). Conclusion This retrospective real-world study showed that PD-1 inhibitors were effective in the treatment of locally advanced or metastatic cSCC and appeared to be amenable for use in elderly or fragile patients with comorbidities. However, the high toxicity warrants consideration against other modalities. Induction or consolidation radiotherapy may improve the results. These findings need to be corroborated in a prospective trial.

/pdf/first-line-programmed-death-1-inhibitor-treatment-for-2de18pmf.pdf

First-line programmed death-1 inhibitor treatment for locoregionally advanced or metastatic cutaneous squamous cell carcinoma – A real-world experience from Israel

Purpose: In a previous study of treatment for advanced colorectal cancer, the LV5FU2 regimen, comprising leucovorin (LV) plus bolus and infusional fluorouracil (5FU) every 2 weeks, was superior to the standard North Central Cancer Treatment Group/Mayo Clinic 5-day bolus 5FU/LV regimen. This phase III study investigated the effect of combining oxaliplatin with LV5FU2, with progression-free survival as the primary end point. Patients and Methods: Four hundred twenty previously untreated patients with measurable disease were randomized to receive a 2-hour infusion of LV (200 mg/m 2 /d) followed by a 5FU bolus (400 mg/m 2 /d) and 22-hour infusion (600 mg/m 2 /d) for 2 consecutive days every 2 weeks, either alone or together with oxaliplatin 85 mg/m 2 as a 2-hour infusion on day 1. Results: Patients allocated to oxaliplatin plus LV5FU2 had significantly longer progression-free survival (median, 9.0 v 6.2 months; P 5 .0003) and better response rate (50.7% v 22.3%; P 5 .0001) when compared with the control arm. The improvement in overall survival did not reach significance (median, 16.2 v 14.7 months; P 5 .12). LV5FU2 plus oxaliplatin gave higher frequencies of National Cancer Institute common toxicity criteria grade 3/4 neutropenia (41.7% v 5.3% of patients), grade 3/4 diarrhea (11.9% v 5.3%), and grade 3 neurosensory toxicity (18.2% v 0%), but this did not result in impairment of quality of life (QoL). Survival without disease progression or deterioration in global health status was longer in patients allocated to oxaliplatin treatment (P 5 .004). Conclusion: The LV5FU2-oxaliplatin combination seems beneficial as first-line therapy in advanced colorectal cancer, demonstrating a prolonged progressionfree survival with acceptable tolerability and maintenance of QoL. J Clin Oncol 18:2938-2947. © 2000 by American Society of Clinical Oncology.

D. Hendler

Papers

Leucovorin and Fluorouracil With or Without Oxaliplatin as First-Line Treatment in Advanced Colorectal Cancer

Tilsotolimod exploits the TLR9 pathway to promote antigen presentation and Type 1 IFN signaling in solid tumors: A Multicenter International Phase I/II trial (ILLUMINATE-101).

First-line programmed death-1 inhibitor treatment for locoregionally advanced or metastatic cutaneous squamous cell carcinoma – A real-world experience from Israel

Leucovorin a nd F luorouracil W ith o r W ithout O xaliplatin as F irst-Line T reatment i n A dvanced C olorectal C ancer