Dual CTLA-4 and PD-1 checkpoint blockade using CS1002 and CS1003 (nofazinlimab) in patients with advanced solid tumors: A first-in-human, dose-escalation, and dose-expansion study.

BACKGROUND: This study investigated the safety and efficacy of an anti-CTLA-4 monoclonal antibody (CS1002) as monotherapy and in combination with an anti-PD-1 monoclonal antibody (CS1003) in patients with advanced/metastatic solid tumors. METHODS: The phase 1 study involved phase 1a monotherapy dose-escalation (part 1) and phase 1b combination therapy dose escalation (part 2) and expansion (part 3). Various dosing schedules of CS1002 (0.3, 1, or 3 mg/kg every 3 weeks, or 3 mg/kg every 9 weeks) were evaluated with 200 mg CS1003 every 3 weeks in part 3. RESULTS: Parts 1, 2, and 3 included a total of 13, 18, and 61 patients, respectively. No dose-limiting toxicities or maximum tolerated doses were observed. Treatment-related adverse events (TRAEs) were reported in 30.8%, 83.3%, and 75.0% of patients in parts 1, 2, and 3, respectively. Grade ≥3 TRAEs were experienced by 15.4%, 50.0%, and 18.3% of patients in each part. Of 61 patients evaluable for efficacy, 23 (37.7%) achieved objective responses in multiple tumor types. Higher objective response rates were observed with conventional and high-dose CS1002 regimens (1 mg/kg every 3 weeks or 3 mg/kg every 9 weeks) compared to low-dose CS1002 (0.3 mg/kg every 3 weeks) in microsatellite instability-high/mismatch repair-deficient tumors, melanoma, and hepatocellular carcinoma (50.0% vs. 58.8%, 14.3% vs. 42.9%, and 0% vs. 16.7%). CONCLUSION: CS1002, as monotherapy, and in combination with CS1003, had a manageable safety profile across a broad dosing range. Promising antitumor activities were observed in patients with immune oncology (IO)-naive and IO-refractory tumors across CS1002 dose levels when combined with CS1003, supporting further evaluation of this treatment combination for solid tumors. PLAIN LANGUAGE SUMMARY: CS1002 is a human immunoglobulin (Ig) G1 monoclonal antibody that blocks the interaction of CTLA-4 with its ligands and increases T-cell activation/proliferation. CS1003, now named nofazinlimab, is a humanized, recombinant IgG4 monoclonal antibody that blocks the interaction between human PD-1 and its ligands. In this original article, we determined the safety profile of CS1002 as monotherapy and in combination with CS1003. Furthermore, we explored the antitumor activity of the combination in anti-programmed cell death protein (ligand)-1 (PD-[L]1)-naive microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) pan tumors, and anti-PD-(L)1-refractory melanoma and hepatocellular carcinoma (HCC). CS1002 in combination with CS1003 had manageable safety profile across a broad dosing range and showed promising antitumor activities across CS1002 dose levels when combined with CS1003. This supports further assessment of CS1002 in combination with CS1003 for the treatment of solid tumors.

A first-in-human phase 1 study of nofazinlimab, an anti-PD-1 antibody, in advanced solid tumors and in combination with regorafenib in metastatic colorectal cancer.

BACKGROUND: We assessed nofazinlimab, an anti-PD-1 antibody, in solid tumors and combined with regorafenib in metastatic colorectal cancer (mCRC). METHODS: This phase 1 study comprised nofazinlimab dose escalation (phase 1a) and expansion (phase 1b), and regorafenib dose escalation (80 or 120 mg QD, days 1-21 of 28-day cycles) combined with 300-mg nofazinlimab Q4W (part 2a) to determine safety, efficacy, and RP2D. RESULTS: In phase 1a (N = 21), no dose-limiting toxicity occurred from 1 to 10 mg/kg Q3W, with 200 mg Q3W determined as the monotherapy RP2D. In phase 1b (N = 87), 400-mg Q6W and 200-mg Q3W regimens were found comparable. In part 2a (N = 14), both regimens were deemed plausible RP2Ds. Fatigue was the most frequent treatment-emergent adverse event (AE) in this study. Any-grade and grade 3/4 nofazinlimab-related AEs were 71.4% and 14.3%, 56.3% and 5.7%, and 57.1% and 21.4% in phases 1a, 1b, and part 2a, respectively. ORRs were 14.3% and 25.3% in phases 1a and 1b, respectively. In part 2a, no patients had radiological responses. CONCLUSIONS: Nofazinlimab monotherapy was well tolerated and demonstrated preliminary anti-tumor activity in multiple tumor types. Regorafenib plus nofazinlimab had a manageable safety profile but was not associated with any response in mCRC. CLINICAL TRIAL REGISTR ATION: Clinicaltrials.gov (NCT03475251).

Colorectal cancer survival: An analysis of patients with metastatic disease synchronous and metachronous with the primary tumor.

BACKGROUND: Whether metastatic colorectal cancer (mCRC) that presents synchronously with the primary lesion behaves differently from mCRC that appears metachronously to the primary disease is not clear. PATIENTS AND METHODS: The South Australian Clinical Registry for mCRC collects data for patients diagnosed after February 2006. Data from 2502 patients, available on October 22, 2012, were analyzed according to stage at initial diagnosis (SAID) to compare outcomes between metachronous tumors (MTs) (stages I, II, III) and synchronous tumors (STs) (stage IV). Overall survival (OS) was calculated from the date of mCRC diagnosis. RESULTS: Patients with ST had more liver-only metastases, and patients with MT had more lung-only, non-lung and non-liver, and non-lung metastases. The median time to recurrence differed significantly according to SAID: stage I, 49.3 mo (n = 29), stage II, 25.2 mo (n = 346) and stage III, 18.4 mo (n = 497). The median OS was longer for patients with MT than for those with ST (19.0 vs.14.9 mo, P = .003). For patients who received any treatment for mCRC, the OS was longer for patients with MT than for those with ST (19.2 vs. 15.3 mo, P = .005). In patients who received only chemotherapy for mCRC, the median OS was longer for patients with MT than for those with ST (15.2 vs. 9.9 mo, P < .0001). No difference in OS between the MT and ST groups for patients who did not receive treatment for mCRC (1.6 vs. 2.6 mo; P = .95). CONCLUSION: Patients with MT have a longer OS than those with ST, independent of treatment. Classification of patients according to whether they have metachronous or synchronous presentation of mCRC is prognostic. These results may add further support for population screening with the aim to reduce de novo metastatic disease.

Liver only metastatic disease in patients with metastatic colorectal cancer: impact of surgery and chemotherapy.

BACKGROUND: Metastatectomy in colorectal cancer (CRC) is now a standard of care with improved survival reported. Conversion chemotherapy has increased the population who are suitable for surgery. Here we assess patterns of care and treatment outcome in liver only metastases in South Australia using the clinical registry for advanced CRC. METHODS: We analysed the outcomes for patients with liver only metastatic involvement from the SA Metastatic CRC Database with the aim to investigate the role of chemotherapy on liver resection and outcome in comparison to liver resection only and chemotherapy without liver resection. Patients who had no therapy or non-surgical liver interventions were excluded for this analysis. RESULTS: One thousand nine hundred and eight patients were available for analysis, 687 (36%) had liver only metastatic disease and 455 (24%) had active therapy as defined. In total 54.2% (247/455) had chemotherapy alone, 19.1% (87/455) had liver resection alone, and 26.6% (121/455) had combined treatment. The three-year survival for chemotherapy, resection and combined treatment subgroups is 19.5%, 73.8% and 73.7%, respectively. The addition of chemotherapy to surgery did not improve survival. Switching chemotherapy was associated with a poorer outcome; three-year overall survival for chemotherapy switch was 62.5%, compared with same regimen pre- and post-74%, and chemo post-resection 80%. CONCLUSION: Liver only metastatic disease is common in CRC and patients undergoing liver resection have improved long-term survival. Survival for a combined approach of chemotherapy and hepatic resection is similar to surgery alone. Patients not suitable for surgery with liver only disease have a poorer prognosis highlighting the need for improved liver-directed therapies and attempts to covert non-resectable to resectable disease if possible.

Rechallenge with oxaliplatin and fluoropyrimidine for metastatic colorectal carcinoma after prior therapy.

OBJECTIVES: Patients with advanced colorectal cancer (CRC) who have received oxaliplatin, 5-fluoropyrimidine, and irinotecan chemotherapy (with or without bevacizumab) and antiepidermal growth factor receptor therapy (if KRAS is wild type) have no further standard treatment options. Although repeating a prior chemotherapy [in particular, oxaliplatin and fluoropyrimidine (FOX)] is an option, there is very little evidence in the literature for this approach; thus, we reviewed our registry to assess the frequency and outcome of rechallenging with FOX. METHODS: Patients who had been rechallenged with FOX were identified from the South Australian metastatic CRC database. Patient characteristics were analyzed, and tumor response was retrospectively assessed using Response Evaluation Criteria in Solid Tumors criteria. RESULTS: Twenty patients were eligible for inclusion in this analysis. The number of prior lines of therapy received for metastatic CRC was 4 lines for 2 patients, 3 lines for 6 patients, 2 lines for 7 patients, and 1 line for 3 patients, with 3 patients having received oxaliplatin as adjuvant therapy. Four patients had received bevacizumab previously, 7 patients had undergone antiepidermal growth factor receptor treatment, and 4 patients had undergone liver resection earlier. Response rate was 18%, and 47% had stable disease. The median progression-free survival was 3.7 months, median overall survival was 7.8 months, and 1-year survival was 37%. CONCLUSIONS: In this selected population, there is evidence of modest activity of rechallenge with FOX chemotherapy, although radiologic response is uncommon.

"Watchful waiting" for metastatic colorectal cancer, antediluvian or an option to be considered again?

AIM: The role of chemotherapy in metastatic colorectal cancer (mCRC) is firmly established and the option of watchful waiting (WW) has become an alternative rarely considered. However, there may be a group of patients who are diagnosed with low volume and asymptomatic disease and who may be suitable for a WW plan. METHODS: From the South Australian Cancer Registry for mCRC we examined cancer characteristics and outcomes of patients who were suitable for chemotherapy but had their treatment delayed by more than 3 months from diagnosis of metastatic disease. RESULTS: Data from 417 mCRC patients who received chemotherapy as first intervention have been entered in the Registry to date and 38 (9.1%) had chemotherapy commencement delayed by more than 3 months from diagnosis. Their median age was 76.7 years (range 38-85). Overall 87% of patients had metachronous metastatic cancer with a median time to recurrence of 2.1 years (range 0.53-7.71) and 65.5% had single organ metastasis. Median delay from the diagnosis of metastatic disease to chemotherapy was 5.03 months (range 3-28). The median survival has yet to be reached. The 2-year overall survival is 65%. CONCLUSION: We found that almost 10% of all patients with mCRC had a delay in the initiation of chemotherapy, with most due to a WW approach based on case note review. Patients with a delay in chemotherapy initiation are more likely to have a single organ site of metastatic disease and are older than those who do not. Despite the treatment delay, there is no evidence of a negative impact on survival.

Small cell lung cancer: patterns of care and their influence on survival - 25 years experience of a single Australian oncology unit.

AIM: Evidence supporting improved outcomes for small cell lung cancer (SCLC) in recent decades is limited. This study aimed to identify patterns of care and survival over two time periods; 1 January 1987 to 31 December 1996 (cohort A) and 1 January 1997 to 31 December 2006 9 (cohort B). METHODS: Patients' characteristics, management and outcome data were extracted from the Hospital Cancer Registry and clinical records. Survival analysis was determined using the Kaplan-Meier method and the log-rank test. Factors influencing survival outcome were assessed using Cox proportional hazards regression. RESULTS: The total number of patients was 392 (224 in cohort A, 168 in cohort B). Overall 38% patients in cohort A and 24% in cohort B had limited stage (LS) disease at diagnosis. Combined chemoradiotherapy for LS increased from 5% in cohort A to 65% in cohort B. Overall 19% of patients in cohort A and 24% in cohort B received symptomatic treatment alone (STA). Median survival for LS in cohort B was significantly higher (19.5 months), than in cohort A (11.8 months) (P = 0.03). In extensive stage (ES) disease, median survival was 6.2 months in cohort A and 4.3 months in cohort B (P = 0.7). Variables for poorer outcome were STA, male gender, poor performance status, ES and whether the diagnosis was made in the earlier time period in cohort A. CONCLUSION: Outcomes for LS SCLC have improved with combined chemoradiotherapy, in keeping with worldwide data. The trends may also reflect recent improvements in staging and standardization of treatment. The outcome for ES-SCLC remains poor.

Very high GFR in cancer patients undergoing chemotherapy: prevalence, carboplatin dosing patterns and chemotherapy toxicity.

AIM: Carboplatin dosing depends on accurate glomerular filtration rate (GFR) estimation. There is a lack of clinical agreement about carboplatin dosing when the GFR measurement is very high (>110 mL/min). METHODS: A retrospective audit of pre-chemotherapy 99m technetium (Tc) diethylenetriamene pentaacetate (DTPA) radionuclide GFR estimations and patients' chart review were performed from January 2006 to May 2009. The primary objective was to determine the prevalence of patients with a high GFR and the incidence of myelotoxicity in this group. RESULTS: Overall 18 of 148 treated patients (14%) measured GFR >110mL/min. The GFR values of six of the 18 patients were capped for dose calculation. In eight patients a measured GFR corrected for body surface area was used and in four the actual measured GFR was used for dose calculation. In total, 63 cycles of chemotherapy were delivered. Grade III or IV myelotoxicity accounted for 37% (15/41) of all myelotoxicities. Neutropenia accounted for almost 39% of all myelotoxicities (16/41). Two patients (11%) were hospitalized due to febrile neutropenia. Eight patients (40%) had dose reduction and four (20%) had treatment delays due to myelotoxicity. The frequency of myelotoxicity was high irrespective of the GFR used (corrected or uncorrected) in calculating the chemotherapy dose. CONCLUSION: High values of GFR, by 99mTc DTPA radionuclide measurement, are a common finding in pre-chemotherapy patients irrespective of age. Carboplatin dosing patterns in this group of patients vary among treating oncologists and a standardized approach is needed.