Replies to post #223648 on Innovation Pharmaceuticals Inc (IPIX)

[DaubersUP]

Thank you for your input and docs

[frrol]

Did the same calcs as you. This PR is a bit disappointing, because it shows that our trial results were actually pretty muddy.

The q-3wk seems to have strong signal, but the flip side of that coin is that the q-1wk is no signal at all, and together make little physiological sense. (You could even claim B made SOM worse in the q-1wk, which you can dismiss but then you compromise the sub-grouping itself.)

The company is putting a spin on this, but this is not really what you want to see. They're even fibbing a bit: the Q-3wk was not the "more effective" sub, it was the only effective sub. This is going to attract unfortunate accusations of data mining.

[slcimmuno]

21 Day vs Weekly Cisplatin - re today’s PR

More digging

Looks like the higher dose Cisplatin regimen still preferred as SOC

Interesting BRIs efficacy so much better in the Higher Dose... maybe the weekly Cisplatin patients were less compliant because their OM didn’t occur as fast, or get as severe? Or maybe BRI MOA just better at mitigating the severe/est cases

What the CSR is for - clarifying the data ins, Exploratory outcomes

Still liking our BTD odds (60%+) if not our share price - land a deal and that ought to rightsize to the upside real fast. First domino twd others falling...

http://ascopubs.org/doi/abs/10.1200/JCO.2017.74.9457?et_cid=40157473&et_rid=931327482&linkid=Once-a-Week+Versus+Once-Every-3+Weeks+Cisplatin+in+Head+and+Neck+Cancer

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Once-a-Week Versus Once-Every-3-Weeks Cisplatin Chemoradiation for Locally Advanced Head and Neck Cancer: A Phase III Randomized Noninferiority Trial

Vanita Noronha, Amit Joshi, Vijay Maruti Patil, Jaiprakash Agarwal, Sarbani Ghosh-Laskar, Ashwini Budrukkar...
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Abstract

Full Text

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F&T
Supplements
Purpose
Chemoradiation with cisplatin 100 mg/m2 given once every 3 weeks is the standard of care in locally advanced head and neck squamous cell cancer (LAHNSCC). Increasingly, low-dose once-a-week cisplatin is substituted because of perceived lower toxicity and convenience. However, there is no level 1 evidence of comparable efficacy to cisplatin once every 3 weeks.

Patients and Methods
In this phase III randomized trial, we assessed the noninferiority of cisplatin 30 mg/m2 given once a week compared with cisplatin 100 mg/m2 given once every 3 weeks, both administered concurrently with curative intent radiotherapy in patients with LAHNSCC. The primary end point was locoregional control (LRC); secondary end points included toxicity, compliance, response, progression-free survival, and overall survival.

Results
Between 2013 and 2017, we randomly assigned 300 patients, 150 to each arm. Two hundred seventy-nine patients (93%) received chemoradiotherapy in the adjuvant setting. At a median follow-up of 22 months, the estimated cumulative 2-year LRC rate was 58.5% in the once-a-week arm and 73.1% in the once-every-3-weeks arm, leading to an absolute difference of 14.6% (95% CI, 5.7% to 23.5%); P = .014; hazard ratio (HR), 1.76 (95% CI, 1.11 to 2.79). Acute toxicities of grade 3 or higher occurred in 71.6% of patients in the once-a-week arm and in 84.6% of patients in the once-every-3-weeks arm (P = .006). Estimated median progression-free survival in the once-a-week arm was 17.7 months (95% CI, 0.42 to 35.05 months) and in the once-every-3-weeks arm, 28.6 months (95% CI, 15.90 to 41.30 months); HR, 1.24 (95% CI, 0.89 to 1.73); P = .21. Estimated median overall survival in the once-a-week arm was 39.5 months and was not reached in the once-every-3-weeks arm (HR, 1.14 [95% CI, 0.79 to 1.65]; P = .48).

Conclusion
Once-every-3-weeks cisplatin at 100 mg/m2 resulted in superior LRC, albeit with more toxicity, than did once-a-week cisplatin at 30 mg/m2, and should remain the preferred chemoradiotherapy regimen for LAHNSCC in the adjuvant setting.

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https://www.ncbi.nlm.nih.gov/m/pubmed/28533474/

Weekly Low-Dose Versus Three-Weekly High-Dose Cisplatin for Concurrent Chemoradiation in Locoregionally Advanced Non-Nasopharyngeal Head and Neck Cancer: A Systematic Review and Meta-Analysis of Aggregate Data.
Review article
Szturz P, et al. Oncologist. 2017.
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Abstract
BACKGROUND: Three-weekly high-dose cisplatin (100 mg/m2) is considered the standard systemic regimen given concurrently with postoperative or definitive radiotherapy in locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN). However, due to unsatisfactory patient tolerance, various weekly low-dose schedules have been increasingly used in clinical practice. The aim of this meta-analysis was to compare the efficacy, safety, and compliance between these two approaches.

MATERIALS AND METHODS: We systematically searched literature for prospective trials of patients with LA-SCCHN who received postoperative or definitive conventionally fractionated concurrent chemoradiation. Radiation doses were usually 60-66 gray (Gy) in the postoperative setting and 66-70 Gy in the definitive setting. Standard, three-weekly high-dose cisplatin (100 mg/m2, 3 doses) was compared with the weekly low-dose protocol (≤50 mg/m2, ≥6 doses). The primary endpoint was overall survival. Secondary outcomes comprised response rate, acute and late adverse events, and treatment compliance.

RESULTS: Fifty-two studies with 4,209 patients were included in two separate meta-analyses according to the two clinical settings. There was no difference in treatment efficacy as measured by overall survival or response rate between the chemoradiation settings with low-dose weekly and high-dose three-weekly cisplatin regimens. In the definitive treatment setting, the weekly regimen was more compliant and significantly less toxic with respect to severe (grade 3-4) myelosuppression (leukopenia p?=?.0083; neutropenia p?=?.0024), severe nausea and/or vomiting (p?<?.0001), and severe nephrotoxicity (p?=?.0099). Although in the postoperative setting the two approaches were more equal in compliance and with clearly less differences in the cisplatin-induced toxicities, the weekly approach induced more grade 3-4 dysphagia (p?=?.0026) and weight loss (p?<?.0001).

CONCLUSION: In LA-SCCHN, current evidence is insufficient to demonstrate a meaningful survival difference between the two dosing regimens. Prior to its adoption into routine clinical practice, the low-dose weekly approach needs to be prospectively compared with the standard three-weekly high-dose schedule.

IMPLICATIONS FOR PRACTICE: Given concurrently with conventional radiotherapy in locally advanced head and neck cancer, high-dose three-weekly cisplatin has often been replaced with weekly low-dose infusions to increase compliance and decrease toxicity. The present meta-analysis suggests that both approaches might be equal in efficacy, both in the definitive and postoperative settings, but differ in toxicity. However, some toxicity data can be influenced by unbalanced representation, and the conclusions are not based on adequately sized prospective randomized studies. Therefore, low-dose weekly cisplatin should not be used outside clinical trials but first prospectively studied in adequately sized phase III trials versus the high-dose three-weekly approach.

[To infinity and beyond!]

critical reading for all of us. conclusions hard but likely simple- numbers too small to support reliable evidence. Thanks.