AI
Monday, January 23, 2012 12:29:59 PM
Excellent 6-2011 article summarizing current NSCLC treatment options (and trial data) for 1stLine & 2ndLine (and 3rdLine) settings…
“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
Extracts…
CP=Carboplatin+Paclitaxel
CG=Cisplatin+Gemcitabine
Bevacizumab=Avastin
INTRO
…Historically, the treatment of NSCLC has involved a finite number of cycles of first-line chemotherapy, the most commonly-used regimens being platinum doublets[1] 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 second-line therapy. We learned that the introduction of a third chemotherapeutic agent only increased toxicity, but not efficacy. We also realized that only about 50%-60% of patients go on to receive second-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, diarrhoea, 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.
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]…
SECOND-LINE THERAPY - CHEMOTHERAPY IN SECOND-LINE
Several chemotherapy agents, including docetaxel and pemetrexed, have demonstrated efficacy in the second-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]…
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…
.
.
.
.
.
.
NOTES ON 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
= = = = = = = = = = = = = = = = = = = = = = = = = =
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
...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. Refractory 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)
...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."
K. 3rd IST Trial: Bavi+PemCarbo (Pemetrexed+Carboplatin) vs. Frontline NSCLC, open-label Ph.1B
Protocol: http://clinicaltrials.gov/ct2/show/NCT01323062
...3-8-11: IST (NSCLC) initiated at UNC (PI= J.Grilley-Olson), ~25 patients - http://tinyurl.com/6b926ku
"We are encouraged by the prior lung cancer data on bavituximab in combination with chemotherapy and look forward to evaluating the safety and potential efficacy of bavituximab in combination with pemetrexed and carboplatin as an additional therapeutic option in the Front-line treatment setting," said Juneko E. Grilley-Olson, M.D., lead investigator of this trial and assistant professor of hematology and oncology at the Univ. of North Carolina at Chapel Hill. "Chemotherapy has been shown to increase the exposure of phosphatidylserine (PS) on tumor blood vessel cells, upregulating the exposure of bavituximab's PS target. We are eager to evaluate this new combination therapy regimen for the treatment of this deadly form of cancer."
= = = = = = = = COMPLETED SINGLE-ARM BAVI+PC FRONTLINE NSCLC TRIAL:
5. PH.2 BAVI+PC/FRONTLINE NSCLC (Single-Arm, INDIA N=49, 6/2008-10/2009):
FINAL BAVI+PC DATA: ORR=43%, PFS=6.1MOS, MOS=12.4MOS#
**Results for the completed Ph.2 Bavi+PC Frontline NSCLC signal-seeking trial (dosed 6/2008-10/2009 n=49 http://clinicaltrials.gov/ct2/show/NCT00687817 ) were released 6-6-10 at ASCO’10 (ORR=43% PFS=6.1mos – see http://tinyurl.com/2g5cqof - also of note, see the TWO “100% max. reductions in tumor size” bars in the Fig1 waterfall plot), with a MOS=12.4mos followup in a 6-15-11 PR ( http://tinyurl.com/3fcz5ok ).
The 6-15-11 PR compared the Bavi+PC results “versus historic control [PC-only] data of ORR=15%, PFS=4.5mos, and MOS=10.3mos”, taken from the E4599 Avastin+PC Frontline NSCLC Ph.3 trial reported 12-2006 in NEJM (Sandler et al http://www.nejm.org/doi/pdf/10.1056/NEJMoa061884 ).
[“PC” = Paclitaxel+Carboplatin]
#NOTE: Compare #MOS=12.4mos to P+C/alone=10.3mos, 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 .
“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
Extracts…
CP=Carboplatin+Paclitaxel
CG=Cisplatin+Gemcitabine
Bevacizumab=Avastin
INTRO
…Historically, the treatment of NSCLC has involved a finite number of cycles of first-line chemotherapy, the most commonly-used regimens being platinum doublets[1] 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 second-line therapy. We learned that the introduction of a third chemotherapeutic agent only increased toxicity, but not efficacy. We also realized that only about 50%-60% of patients go on to receive second-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, diarrhoea, 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.
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]…
SECOND-LINE THERAPY - CHEMOTHERAPY IN SECOND-LINE
Several chemotherapy agents, including docetaxel and pemetrexed, have demonstrated efficacy in the second-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]…
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…
.
.
.
.
.
.
NOTES ON 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
= = = = = = = = = = = = = = = = = = = = = = = = = =
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
...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. Refractory 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)
...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."
K. 3rd IST Trial: Bavi+PemCarbo (Pemetrexed+Carboplatin) vs. Frontline NSCLC, open-label Ph.1B
Protocol: http://clinicaltrials.gov/ct2/show/NCT01323062
...3-8-11: IST (NSCLC) initiated at UNC (PI= J.Grilley-Olson), ~25 patients - http://tinyurl.com/6b926ku
"We are encouraged by the prior lung cancer data on bavituximab in combination with chemotherapy and look forward to evaluating the safety and potential efficacy of bavituximab in combination with pemetrexed and carboplatin as an additional therapeutic option in the Front-line treatment setting," said Juneko E. Grilley-Olson, M.D., lead investigator of this trial and assistant professor of hematology and oncology at the Univ. of North Carolina at Chapel Hill. "Chemotherapy has been shown to increase the exposure of phosphatidylserine (PS) on tumor blood vessel cells, upregulating the exposure of bavituximab's PS target. We are eager to evaluate this new combination therapy regimen for the treatment of this deadly form of cancer."
= = = = = = = = COMPLETED SINGLE-ARM BAVI+PC FRONTLINE NSCLC TRIAL:
5. PH.2 BAVI+PC/FRONTLINE NSCLC (Single-Arm, INDIA N=49, 6/2008-10/2009):
FINAL BAVI+PC DATA: ORR=43%, PFS=6.1MOS, MOS=12.4MOS#
**Results for the completed Ph.2 Bavi+PC Frontline NSCLC signal-seeking trial (dosed 6/2008-10/2009 n=49 http://clinicaltrials.gov/ct2/show/NCT00687817 ) were released 6-6-10 at ASCO’10 (ORR=43% PFS=6.1mos – see http://tinyurl.com/2g5cqof - also of note, see the TWO “100% max. reductions in tumor size” bars in the Fig1 waterfall plot), with a MOS=12.4mos followup in a 6-15-11 PR ( http://tinyurl.com/3fcz5ok ).
The 6-15-11 PR compared the Bavi+PC results “versus historic control [PC-only] data of ORR=15%, PFS=4.5mos, and MOS=10.3mos”, taken from the E4599 Avastin+PC Frontline NSCLC Ph.3 trial reported 12-2006 in NEJM (Sandler et al http://www.nejm.org/doi/pdf/10.1056/NEJMoa061884 ).
[“PC” = Paclitaxel+Carboplatin]
#NOTE: Compare #MOS=12.4mos to P+C/alone=10.3mos, 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 .
