Avid Bioservices Inc (CDMO): 6-2011 WJCO Article lists 2ndLine NSCLC...

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cjgaddy

Re: cjgaddy post# 77308

Sunday, 03/18/2012 5:12:07 PM

Sunday, March 18, 2012 5:12:07 PM

6-2011 WJCO Article lists 2ndLine NSCLC hist. trial results (Docetaxel/Tarceva/Pemetrexed) and gives a wealth on info. on the current status of the War on NSCLC…

“Review of the Treatment of Metastatic NSCLC: a Practical Approach”
World J Clin Oncol, June 2011, Vera Hirsh
10-pg PDF: http://www.wjgnet.com/2218-4333/pdf/v2/i6/262.pdf

CP=Carboplatin+Paclitaxel
CG=Cisplatin+Gemcitabine
Bevacizumab=Avastin
Erlotinib=Tarceva (an “EGFR-TKI”)
Gefitinib=Iressa (an “EGFR-TKI”)
Zoledronic Acid = Novartis’ Zometa/Zomera/Aclasta/Reclast (a bisphosphonate)

Article excerpts:
INTRO: …Historically, the treatment of NSCLC has involved a finite number of cycles of 1st-Line chemotherapy, the most commonly-used regimens being platinum doublets for patients with a good performance status (PS) and no significant comorbidities, after which patients with tumor response or stable disease were observed for evidence of disease progression; at this point, suitable patients would start 2nd-Line therapy. We learned that the introduction of a 3rd chemotherapeutic agent only increased toxicity, but not efficacy. We also realized that only about 50%-60% of patients go on to receive 2nd-Line therapy and of those, only 50%-60% will receive third-line therapy. It is therefore important to ensure that patients receive the best therapeutic option in each line of therapy[2]… The goal of the treatments of advanced NSCLC is only palliative for now, thus QOL remains a very important factor. Early control of symptoms such as nausea, diarrhea, constipation, pain, or prevention of cytopaenias and bone metastases enables patients to maintain good PS and QOL, enabling them to receive now available numerous lines of treatments.

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Ref #41/Tarceva: Fossella FV, “2ndLine Chemo for NSCLC” Curr Oncol Rep 2000 http://www.ncbi.nlm.nih.gov/pubmed/11122830
Ref #38/Docetaxel/Pemetrexed: Rosen LS…Seaman JJ, “Zoledronic Acid [Novartis’ Zometa, Zomera, Aclasta, Reclast] vs. Placebo in the Treatment of Skeletal Metastases in Patients with Lung Cancer and Other Solid Tumors: A Phase III, Double-Blind, Randomized Trial”, J Clin Oncol 2003 http://jco.ascopubs.org/content/21/16/3150.full.pdf
Ref #39/Docetaxel, Henry D…Dansey RA, “Double-Blind, Randomized Study of Denosumab Vs. Zoledronic Acid for the Treatment Of Bone Metastases In Patients With Advanced Cancer”, Eur J Can Suppl 2009 http://jco.ascopubs.org/content/early/2011/02/16/JCO.2010.31.3304.full.pdf
Ref #40/Docetaxel; Shepherd FA…Berille J, “Prospective Randomized Trial of Docetaxel vs. Best Supportive Care in Patients with NSCLC Prev. Treated With Platinum-Based Chemo”, J Clin Oncol 2000 http://www.ncbi.nlm.nih.gov/pubmed/10811675
Ref #46/Docetaxel: Bezjak A… Shepherd FA, “Symptom Improvement in Lung Cancer Patients Treated with Erlotinib [TARCEVA]: Quality Of Life Analysis of them NCI/Canada Clinic” http://jco.ascopubs.org/content/24/24/3831.full.pdf

SECOND-LINE NSCLC CHEMOTHERAPY
Several chemotherapy agents, including docetaxel & pemetrexed, have demonstrated efficacy in the 2nd-Line treatment of NSCLC patients[40-43]. Pemetrexed is approved for non-squamous histology only. Both drugs offer similar efficacy in randomized, phase III trials[42], with median OS of 8.3 mo for docetaxel and 7.9 mo for pemetrexed, however, pemetrexed has a milder toxicity profile than docetaxel[41]…

SECOND-LINE TARGETED THERAPIES
Erlotinib [”TARCEVA”, co-dev. Genentech & OSI] is an EGFR-TKI that suppresses intracellular signalling pathways, which promote cell growth and proliferation[44,45]. Unlike chemotherapy, it causes no cumulative hematologic toxicities, allowing for a longer treatment duration. The toxicities associated with chemotherapy allow for only a limited number of cycles, median of approximately 4 cycles. Table 2 compares clinical data for erlotinib (Tarceva), docetaxel, and pemetrexed.

In a randomized, placebo-controlled study (NCIC BR.21), erlotinib (Tarceva) [an “EGFR-TKI”] demonstrated improvement in median OS (6.7 mo vs 4.7 mo) and QOL across all subgroups[43,46]. 50% of patients were treated in 2nd-Line, and 50% in third-line; some patients even had PS of 3. The safety & efficacy of erlotinib were confirmed in the phase IV trial, TRUST (TarRceva LUng Cancer Survival Treatment), in a broad patient population[47], where median OS was 8.1 mo, and 1-year survival was 38.6%.

Gefitinib (Iressa), another EGFR-TKI, failed to demonstrate a survival advantage in the overall population of the phase III trial, ISEL (Iressa Survival Evaluation in Lung Cancer), where patients had to be refractory to previous chemotherapy. A phase II study of a single-agent, sorafenib (targeting mainly angiogenesis), in 2nd-Line suggests only modest benefits and some specific toxicity, such as hand-foot syndrome[48].

Vandetanib (Zactima), targeting VEGF receptor and EGFR, has demonstrated only a modest benefit [49-51] in phase III 2nd-Line trials alone or in combination with pemetrexed or docetaxel; and was withdrawn from the market for NSCLC treatment.

A PRACTICAL APPROACH IN 2ND-LINE
A good response to 1st-Line chemotherapy may warrant further chemotherapy in 2nd-Line. A meta-analysis of single agents vs doublet chemotherapy demonstrated improvement in response rate, but it did not translate into a PFS or OS benefit, only being associated with an increased toxicity[52]. If patients tolerated 1st-Line chemotherapy poorly, an EGFR inhibitor may be the preferred choice for 2nd-Line.

Non-inferiority in terms of OS for gefitinib (Iressa) compared with docetaxel, was demonstrated in the phase III trial INTEREST (Iressa NSCLC Trial Evaluating Response and Survival versus Taxotere)[53]. Non-inferiority was shown regardless of a patient’s EGFR protein expression, EGFR gene mutation, or K-RAS gene mutation status. The only advantage for OS was for patients who received docetaxel in third-line treatment. Given the lack of difference in clinical benefit relating to the sequence of chemotherapy vs EGFR-TKI in the 2nd & 3rd lines (INTEREST), as well as reduced toxicity & easy, convenient oral administration (sometimes for longer periods of time), EGFR-TKIs [like Tarceva & Iressa) are preferred 2nd-Line agents for NSCLC. Obtaining EGFR (exon 19 and 21) mutation status of the tumor for 2nd-line treatment of NSCLC is not a necessity.

Numerous randomized trials for 2nd-Line treatments of NSCLC are ongoing with different targeted agents. . .

TARGETED THERAPIES IN FIRST-LINE
The first targeted agent which when added to a platinum doublet in first-line metastatic NSCLC resulted in an improved efficacy, was the anti-VEGF monoclonal antibody, bevacizumab [Avastin]…

CONCLUSION
The main goal should be to provide the best possible treatment in terms of both efficacy and safety in each line of therapy. As compared with chemotherapeutic agents, targeted agents may offer reduced toxicity, especially with prolonged use. By increasing the agent’s specificity, and possibly combining different agents in order to target different pathways, we will increase the treatment efficacy[57]. New agents, such as PARP inhibitors for squamous cancers, and IGFR, HDAC, HSP 90 and C-MET inhibitors are being tested in clinical trials, especially in combination with the already established targeted agents or with chemotherapy…

= = = = = = = = = = = = = = = = = = = =
Another 2nd-Line NSCLC Results Summary (Tarceva.net):
http://www.tarceva.net/portal/eipf/pb/tarceva/erlotinib

http://www.tarceva.net/portal/eipf/pb/tarceva/erlotinib

= = = = FIRST-LINE NSCLC:

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NOTES ON AVASITIN 1sT-LINE SAIL TRIAL:
“The SAiL study reviewed clinical experience of 2212 chemo-naive patients (2166 with adequate safety tissue available to review) with stage IIIB or IV NSCLC who were enrolled from over 40 centers outside of the US and otherwise pretty widely around the world, to receive Avastin combined with platinum-based chemotherapy. With a median age of just 58.8 years, this was clearly a young and presumably somewhat cherry-picked lung cancer population than the broader population, since the median age of a new diagnosis of lung cancer in the US is now just over 70 years old… It’s important to realize that this “study” wasn’t really a rigorous study comparable to many others that we discuss here, since it was really a registry in which investigators were essentially paid to report on what they were inclined to do anyway, as long as it included Avastin.”
http://cancergrace.org/lung/2010/07/20/sail-study-crino

= = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = =
BAVITUXIMAB SOLID CANCERS PHASE1+2 TRIALS: (see http://PeregrineTrials.com)
==> PR=Partial-Resp(30-99% Red.), SD=Stable-Disease(29% Red.-19% Incr.), OR=Obj-Resp(PR+CR)
3-12-12: Peregrine's Ambitious Goal for Bavi: Accelerated Approval after Phase II: http://tinyurl.com/82p596r

G. Phase IIb Bavi+PC vs. Front-Line NSCLC (randomized, unblinded, 'confirmatory', n=86)
Protocol: http://clinicaltrials.gov/ct2/show/NCT01160601 (17 U.S. + 9 India + 2 RepGA + 7 RussianFED + 5 Ukraine = 40 as of 8-12-11)
...Also listed in: India's CTRI registry ctri.in#2190 and WHO's registry who.int#1402
...3-9-12: Topline ORR & PFS Data (Bavi+PC vs.PC-only) http://tinyurl.com/7m9r6ya
…...LOCAL reads: ORR/32%-31% PFS/5.8-4.6mos , CENTRAL reads: ORR/25%-23% PFS/6.7-6.4mos
...12-6-11 Prelim. Data (n=86, 100% Stage IV's) => ORR=39%, PC/alone=25%: http://tinyurl.com/7ph4tty
......Comp.. vs. Avastin+PC/Ph3/n=417(74% Stage IV's): ORR=35% (Sandler/E4599/2006 http://www.nejm.org/doi/pdf/10.1056/NEJMoa061884 )
...9-8-11: Enrollment complete. http://tinyurl.com/3vv9zfx
...7-14-11/CC: Enrollment was taking longer than expected; have amended protocol; expanding to 30+ sites, expect enroll. comp. "in coming weeks", interim data by Yr-end'11. http://tinyurl.com/6k6y2as
…7-14-10/CC, J.Shan (VP/Clin+RegAffairs): "This trial is intended to confirm in a randomized setting the results from our Ph.2 signal-seeking NSCLC trial which showed 43% ORR, more than double the generally accepted chemo ORR of under 20% in numerous publications. Favorable results could then lead to an end of Ph.2 meeting with the FDA, with possibly a pivotal Ph/3 trial for front-line lung cancer, our 2nd potential regulatory pathway for bavituximab."
...7-14-10: U.S. Ph.2b randomized trial initiated http://tinyurl.com/27kxksl
……up to 86 front-line patients at ~20 clinical sites; goal: enrollment comp. by mid'11.

F. Phase IIb Bavi+Doce vs. 2nd-Line NSCLC (randomized, double-blinded, placebo-controlled, n=120, 'registrational')
Protocol: http://clinicaltrials.gov/ct2/show/NCT01138163 (24 U.S. + 15 India + 2 RepGA + 7 RussianFED + 5 Ukraine = 53 as of 8-12-11)
...Also listed in: India's CTRI registry ctri.in#2191 (12 sites a/o 3-20-11)
6-2011 Article lists 2ndLine NSCLC hist. results (Doce/Tarceva/Pemetrexed) http://tinyurl.com/xxxxxxx
. . . . .see pg.266, 2ndLine comparator results: ORR=6.7-9.1%, PFS=2.2-6.0mo, MOS=5.7-8.3mo
...10-6-11: Enrollment complete. http://tinyurl.com/3m9re39
...7-14-11/CC: Enrollment was taking longer than expected; have amended protocol; expanding to ~45 sites, expect enroll. comp. "early in Q4/2011", data unblinding 1H'12. http://tinyurl.com/6k6y2as
…3-17-10/Roth, CEO S.King: "We refer to this trial as a Registrational Phase II Study, because we believe that if we have results anywhere near approaching what we saw in the earlier [India] study, it could be a conduit for Accelerated Approval."
...6-4-10: Ph.2b randomized reg. trial Open for enrollment: http://tinyurl.com/25v22qk
……"up to 120 refractory patients at ~30 clinical sites; goal: fully-enroll by mid'11, topline data by y/e'11."

COMPLETED BAVI CANCER TRIALS:
These 5 completed Ph.1 & Ph.2 Bavituximab Cancer Trials archived to: http://tinyurl.com/72dnkfg
1. Ph.1A Bavi/Mono vs. Solid Cancers (USA n=26, 6/2005-6/2009)
2. Ph.1B Bavi+Chemo vs. Solid Cancers (India n=12, 11/2006-5/2007)
3. Ph.2 Bavi+Doce/BREAST/Refractory (RepGA n=46, 1/2008-5/2009): ORR=61%(Her2+=86%), PFS=7.4mos, MOS=20.7mos *
4. Ph.2 Bavi+PC/BREAST/Frontline (India n=46, 8/2008-9/2009): ORR=74%(Her2+=100%), PFS=6.9mos, MOS=23.2mos %
5. Ph.2 Bavi+PC/NSCLC/Frontline (India n=49, 6/2008-10/2009): ORR=43%, PFS=6.1mos, MOS=12.4mos #
......* BAVI+DOCE/Refract-MBC N=46: Compare *MOS=20.7mos to 11.4mos for Doce/alone (Nabholtz/JCO1999 Ph3/n=203 http://tinyurl.com/3rxqqtk )
......% BAVI+PC/FrontLine-MBC N=46: Compare %MOS=23.2mos to 16.0mos for P+C/alone (Loesch/JCO2002 Ph2/n=95 http://tinyurl.com/6wazs9p )
......# BAVI+PC/Frontline-NSCLC N=49: Compare #MOS=12.4mos to P+C/alone=10.3, Avastin+PC=12.3 (E4599/n=434), achieved using less Chemo (175-v-200 & AUC5-v-AUC6), treating 16% (8/49) more-difficult Squamous in Bavi trial (excluded totally from E4599), and treating higher % of sicker ECOG1 patients than in E4599 (96%-v-60%). See 6-15-11/PR http://tinyurl.com/3fcz5ok , ASCO'10 http://tinyurl.com/2g5cqof , and a discussion of differentiating factors between patient demographics and baselines treated in the 2 trials: http://tinyurl.com/6k5uuf7 .