SITC abstract title referenced on call today...

P520 Natural killer (NK) cells orchestrate the antitumor activities of Listeria monocytogenes (Lm)-based immunotherapy

https://sitc.sitcancer.org/2018/abstracts/titles/poster/index.php?category=Poster+Accept&filter=listeria

Full abstract will post Tuesday, Nov. 6th, at 8AM.

NTGN...scientific co-founder....Jim Allison.

New patent app for use of biomarker to select for benefit in AXAL-HPV (AIM2CERV)...

from the patent app:
"Therefore, employing a baseline AA T cut-off at 3.5 mg/ml would screen out patients who are not likely to experience a survival benefit on AXAL. Baseline AAT <3.5 mg/ml can be used as biomarker for clinical benefit in AXAL treatment. Additionally, AAT <3.5 mg/ml as an eligibility criteria would eliminate the risk of exposing patients to AXAL treatment when they are not likely to obtain clinical benefit.
12 month survival is a good surrogate for overall survival. AXAL monotherapy compares favorably with 127C series for 12 Mo. and overall survival. Setting an eligibility criteria for AXAL treatment of AA T <3.5 may increase 12 month survival from 38% to 49% and median survival from 6.2 months to 10.3 months in advanced cervical cancer".


https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2018170313&recNum=2&office=&queryString=FP%3A%28advaxis%29&prevFilter=&sortOption=Pub+Date+Desc&maxRec=193

Abstract out for WCLC.....


P2.09-24 - MERS67 is a Novel anti-NaPi2b Antibody and Demonstrates Differential Expression Patterns in Lung Cancer Histologic Subtypes
16:45 - 18:00 | Presenting Author(s): Rebecca Mosher | Author(s): Hui Yu, Kim Ellison, Pamela Shaw, Rafal Dziadziuszko, Eric Hailman, Christopher J. Rivard, Fred R. Hirsch

Abstract
Background
NaPi2b is a sodium-dependent phosphate transporter expressed in lung, ovarian, and thyroid cancers. Prior studies have suggested an enrichment of expression in lung adenocarcinoma (ACA).

XMT-1536 is a NaPi2b targeting ADC (Antibody Drug Conjugate) comprised of a humanized antibody (XMT-1535) conjugated with 10-15 auristatin F-HPA (AF-HPA) payload molecules via the Dolaflexin platform. AF-HPA is capable of controlled bystander-effect killing, resulting in efficacy in models with heterogeneous antigen expression, and is metabolized intra-tumorally to an active non-permeable metabolite to enable greater systemic tolerability. Previously, we demonstrated pre-clinical activity of XMT-1536 in human primary xenograft models of non-small cell lung cancer (NSCLC).

MERS67 is a human-rabbit chimeric antibody derived from XMT-1535. MERS67 has been formatted for use as an immunohistochemical reagent by multiple methods and expression has been shown to correlate with response in an unselected series of primary ovarian cancer xenografts. (AACR-EORTC, 2017)

We evaluated MERS67 to see if it would preferentially stain lung adenocarcinoma (ACA), as has been demonstrated using other NaPi2b antibodies.

Method
An immunohistochemical assay for MERS67 was established on a Leica BondRx Instrument. The assay was performed on tissue microarrays (TMA), including NSCLC and small cell lung cancer (SCLC) cell line arrays, and a NSCLC human tumor array. Tumors in the NSCLC array had previously been classified based on morphologic features only. All arrays were scored based on the H-score method.

To characterize the primary tumors further, the tumor TMA was stained with TTF-1 and p40, markers of ACA and squamous cell carcinoma (SqCC), respectively. Results of this staining were compared to MERS67 staining patterns.

Result
H-Scores in the NSCLC cell line TMA ranged from 0-260, and from 0-100 in the SCLC TMA. Within the tissue microarray, 99 individual cases were evaluable. By morphologic classification 63 cases were SqCC, and 23 cases were ACA. Using an arbitrary cut point of H=50, there was a statistically significant difference in the number of NaPi2b positive ACA cases (19/23) vs SqCC (3/63). Among 43 cases where p40 and TTF-1 were evaluable and were in agreement with morphologic diagnosis, 7/7 cases of ACA were positive for NaPi2b, while 0/36 SqCC were positive.

Conclusion
MERS67 is an anti-NaPi2b antibody that frequently demonstrates immunoreactivity in lung ACA. MERS67 is a chimeric antibody related to XMT-1536, a proprietary anti-NaPi2b ADC. Target expression using MERS67 is being evaluated in an ongoing XMT-1536 Phase 1 clinical trial enrolling non-squamous NSCLC patients.

I would add here if I hadn't loaded up on ADXS last week.

I trust Ana to handle this carefully and professionally and to resolve the hold in less than a month. I assume they are already on dose level 9, since ASCO data cut in May nearly completed DL7 and its a 4-week cycle to assess DLT prior to moving to next dose. Dose level 7 patients have been on drug for three months, with one DLT and one Grade 3 event, AST elevation (reported at ASCO). So far about ~50 patients have been dosed with this payload, including 1522 & 1536, and this is the first Grade 4 or 5 event. All patients are very sick, with average of 4 prior regimens.

Definitely a risk-raising event, but given the established MOA and safety reported to date, I think this will turn out to be a monitorable and manageable event for investigators. Of course this is not good news, but likely outcome will force early reporting of additional safety data around time of Q2 call, pencilled for August 10th.

Mersana...after ASCO...

Looks like a long summer for Mersana. The ASCO data was a real cliff-hanger, responses trending in the right direction, but AEs showing up to, so woefully inconclusive. Doses 8-10 will take ~6-8 weeks each so any meaningful update will be at ENA'18 in mid-November, which is also likely the venue for unveiling the 3rd candidate. Patent app for 3rd drug should publish by end of summer.

In other news, DS-8201 continues to crush the competition and raise the bar for XMT-1522. ASCO data showed 50% ORR for Her-2 low MBC patients. Mersana will need to approach this number with some differentiation in order to compete.

Hopefully XMT-1536 will also reach MTD this year, but readout would be AACR in April at earliest.

New patent app published for new linker/scaffold...

Fairly comprehensive new platform published on WIPO today. Addresses use of new linker/scaffold to achieve higher DAR and greater control of released drug for numerous combinations of antibodies and payloads.

Shows order of magnitude higher potency for conjugates using same XMT-1535 (NaPi2b) against cancer cell lines compared to XMT-1536. Similar results for trastuzumab ADCs in Her2 models.

Looking forward to see how it improves potential of next ADC for colorectal cancer.

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2018098269&recNum=1&office=&queryString=FP%3A%28mersana%29&prevFilter=&sortOption=Pub+Date+Desc&maxRec=113

Good read on CEO Protopapas's path to Mersana...


page 26...

http://www.qgdigitalpublishing.com/publication/?i=492965&p=4#{%22page%22:26,%22issue_id%22:492965}

Exactly. Looking forward to pre-clinical on next ADC in November at ENA18.

Also should see next-gen platform (payload/linker) presentation at same conference.

Takeda selected ADC will move more slowly, wouldn't be surprised if we don't see data until next year at AACR19.

All eyes on Wednesday 5PM...first clinical data for XMT-1536, sets the table for all science.

DS-8201 showing 60% ORR in Her2+ and 30% ORR in Her-low, those are the benchmarks for a competitive next-gen ADC in MBC.

Another Her2 ADC competitor down for the count....

ADCT-502 was terminated today for safety, joining MEDI4276 as another potent next-gen ADC with potential in Her2-low expressing breast cancer that failed to live up to expectations this year. ADCT-502 was trastuzamab conjugated to a PBD payload at a DAR of 1.7.

DS-8201 remains the only real ADC competitor for XMT-1522 in Her2-low expressing MBC.

https://clinicaltrials.gov/ct2/show/NCT03125200

Potential competitor SD-101 does not impress at AACR...

Combo of SD-101 plus pembrolizumab shows only 15% ORR in PD-1 R/R patients.

Presentation CT139 / 22 Durability of responses to the combination of SD-101 and pembrolizumab in advanced metastatic melanoma: Results of a phase Ib, multicenter study

Results: Of the 22 patients, 9 were naïve to anti-PD-1/L1 therapy at baseline and 13 had progressive disease while receiving prior anti-PD-1/L1 therapy. Treatment was well tolerated with no Grade 3 or higher treatment-related AEs in longer term follow up. Among the 9 patients who were anti-PD-1/L1 naïve, best objective responses were CR: 2, PR: 5, PD: 1, not evaluated [NE]: 1. Median PFS, duration of response, and OS have not been reached. Estimated 12 month PFS was 88% and OS was 89%. After a median of 18 months of follow-up, 86% of responses were ongoing. One patient with a PR developed progressive disease after 20 months of treatment. Among patients who had received prior anti-PD-1/L1 therapy, best objective responses were PR: 2, SD: 5, PD: 5, NE: 1.

http://www.abstractsonline.com/pp8/#!/4562/presentation/11261

Mersana ex-CMO lands at Relay Therapeutics....

https://www.firstwordpharma.com/node/1554191?tsid=1

XMT-1522 Late-breaker at AACR in April...

LB-294 / 16 - Synergy of an anti-HER2 ADC TAK-522 (XMT-1522) in combination with anti-PD1 monoclonal antibody (mAb) in a syngeneic breast cancer model expressing human HER2
http://www.abstractsonline.com/pp8/#!/4562/presentation/10611


Also poster on differentiation of ADC platform...
754 / 21 - Unique pharmacologic properties of Dolaflexin-based ADCs—a controlled bystander effect
http://www.abstractsonline.com/pp8/#!/4562/presentation/3082

Potential competitor MEDI4276 flames out...

The wait is over for long overdue clinical data on AZD's "next-gen" Her-2 ADC MEDI4276. Published Phase 1 results this week at TAT demonstrated an ORR of 5% with DLTs and MTD at higher doses. This result most likely signals the end for this candidate as competitors such as DS-8201 already show ORR's over 50% in a similar population (3L), with 31% ORR for Her2-low.

XMT-1522 will need to clear 50% Her2+ and 30% Her2-low hurdles, with differentiating benefits, to be competitive. In the near term only DS-8201, SYD985, and PF-06804103 are "best-in-class" ADC competitors to keep an eye on.

https://academic.oup.com/annonc/article/29/suppl_3/mdy048.005/4917517?searchresult=1

Phase 3...now recruiting...

https://clinicaltrials.gov/ct2/results?term=idera&Search=Search

AACR titles posted online today...

4704 / 7 - Triple combination of IMO-2125, epacadostat and anti-PD-1 antibody demonstrates maximal antitumor efficacy and eradicates large established tumors in preclinical models

Evren Kocabas Argon1, Fugang Zhu1, Sudhir Agrawal1, Jonathan Yingling2, Daqing Wang1. 1Idera Pharmaceuticals, Inc., Cambridge, MA; 2Idera Pharmaceuticals, Inc., Exton, PA

http://www.abstractsonline.com/pp8/#!/4562/presentation/8178

Article in ADC Review notes Mersana's progress...

Pretty much a recap of JPM updates, potentially five abstracts at AACR in April:

1. Phase 1 data for XMT-1522, safety, efficacy, and RDP2.
2. Pre-clinical on XMT-1536 in IO combo.
3. Pre-clinical on next ADC, IND in 2018.
4. Pre-clinical on Takeda-ADC, IND in mid-2018.
5. Pre-clinical on new platform - new linker and PBD payload.

Likely at least 3 of the above, importantly #1 sets the table for all others. Abstracts posted online March 14.

https://adcreview.com/news/expanding-field-antibody-drug-conjugates/

Article on TLR-9 eradicating tumors getting attention....


Good exposure for potential of TLR-9s in checkpoint combo immunotherapy. Study used Dynavax's SD-101 in combo with OX-40 mAb. Limited comparative data with IMO-2125, but in PD-1 R/R melanoma so far, IMO+ipi showing 50% ORR (5/10) versus 17% (2/12) for SD-101+pembro (100% ORR 7/7 for SD-101+pembro in PD-1 naive). Should see IMO+pembro data in PD-1 R/R soon to make meaningful comparison.

No pre-clinical of IMO+OX-40 to date, but proven synergy with other checkpoints, notably IDO1.


http://stm.sciencemag.org/content/10/426/eaan4488

Notes from JPM: Moving forward on all fronts...

XMT-1522 - 6th dose cohort enrolling, more than needed for efficacy but will dose to MTD. Likely first data at AACR, abstracts publish March 14. Still presenting all 4 cohorts as accelerated opportunities, increased target population for NSCLC to 90K. Takeda to fund 50% of developement post Phase 1.

XMT-1536 - starting 3rd dose cohort - identified addl. indications in basket cohort, enrolling faster than 1522 (likely due to CRO) so will establish MTD by YE.

New platform - new payload, customized linker - likely a PDB per recent patent apps, DAR of 24 is unprecedented, likely presentation at AACR.

XMT-XXXX - New ADC TBA in 2018, colorectal identified in study, likely presentation at AACR.

Takeda ADC - advanced to pre-IND, eligible for milestones in 2018 of $1-2M.

So 4 drugs in clinic by end of 2018.

Evaluate Pharma says IMO+ipi is one to watch in 2018...

New 3GA patent app published yesterday...

This one specifically covers compounds that inhibit single point mutations BRAF 600VE (melanoma) and MyD88 L265P (Waldenstr6m's macroglobulinemia) while sparing wild type.

3GA patent app for compounds modulating essentially all immune checkpoints (PDl, PDLl, IDOl, LAG3, TIM3, CTLA4, ID02, CEACAMl, OX40) was published in February.

I suspect patent app supporting IDRA-008 in a liver target will be published in the next month or so, hence the timing of the disclosure.


https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2017205384&recNum=1&office=&queryString=FP%3A%28idera+pharmaceuticals%29&prevFilter=&sortOption=Pub+Date+Desc&maxRec=369

Poster from today's presentation at AACR-EORTC available here...

http://www.mersana.com/our-technology#scientific_publications

Essentially 83% ORR in NaPi2b+ ovarian cancer (n mice).

60% (NapI2b +) of ovarian cancer is ~$4B market opportunity (all lines).

That’s $2B in bio-bucks right? This will be spent over several years on expanded R&D and SGA for US commercial effort. I don’t assume much of these milestones will flow through to earnings for PE. Are you thinking about M&A value? I saw something on IPO about no sale for 3 years...unless of course the offer is exceptional.

PE’s are all over the map, I mean PPS.. as in $150 pps in 2022.

Mersana picks up 'Best New Drug Developer' at World ADC 2017...

Not a huge pool of candidates here, but in 2016 Mersana was 'Best ADC Platform Technology' and runner-up for 'Best New Drug Developer'.

http://worldadc-awards.com/about/2017-winners/

Should see analyst coverage Monday...expiration of quiet period..

JP Morgan, Cowen, Leerink, and/or Wedbush

MRSN...all green lights for me...

Award-winning platform, outstanding pre-clinical with proven MOAs and targets, strong team, multi-billion dollar markets for both lead compounds consisting of several potential indications.

Will have 3-4 candidates in clinic by end of 2018, 2 internal and 1-2 with partners (Merck KgaA and/or Takeda). Recent IPO (June) with steady flow of milestones (up to $2B) from partnerships.

Looking at a 5-year 10-bagger here...good luck to all.

Will post often here.

Key phrase is "we are increasingly encouraged with the data seen to date." Orphan status in itself is not a big deal, however with patent expiration in 2025, the 7-year exclusivity will be helpful. Of course assuming other TLR9's-CPI combos go after same indication.

Would be competitors for PD-1 refractory melanoma are:

Idera (IDRA) IMO-2125 plus ipi or pembro
Dynavax (DVAX) SD-101 + pembro
Checkpoint CMP-001 + pembro

All three combo trials will have data updates at AACR 1st week in April, DVAX is a late-breaker.

Feb 21st is release of abstract on SITC-ASCO website.

http://immunosym.org/

Slides from this weekend's DDHO Conference...

Lot's of good summaries here from KOL's for most major cancers.

See 'Downloadable Slides' tab

http://www.winshipcancerddho.com/#downloadable-slides

For those interested...'Cancer: The Emperor of All Maladies' on PBS next Mon, Tues, Wed at 9PM...

http://www.latimes.com/entertainment/la-et-st-ca-cancer-20150329-story.html#page=1

NVDA?

A little background on FDA's guidance for rescinding BTD's...

http://www.lexology.com/library/detail.aspx?g=5316130e-d527-42ea-89e4-b6063687e494

That likely refers to fact that smoking accounts for ~1/2 of KRASm lung cancer and frequency of KRASm in Asian population is half of frequency in whites.

I think it was the NHL data...low ORR of 37% together with safety signals...Grade 3/4 adverse events (>=5%) include thrombocytopenia (37%), neutropenia (22%), anemia (16%), fatigue (12%), leukopenia (10%) and hyponatremia (10%). The most common Grade 1/2 adverse events were: nausea (63%), anorexia (52%), fatigue (46%), and vomiting (36%) that tend to lessen in severity with supportive care and were seen less frequently following cycle 1.

Thanks, great topic, and very helpful framing of issues. Should add discussion of commercializing CAR-T with high COGS, setting price of CAR-T therapy at premium to BITE/DART, not a good thing if benefit/risk is similar. Also regarding MGNX, note this article from Blood makes case for potential DART superiority over BITE (blina). Article is from 2011, but worth revisiting in this context.

http://www.bloodjournal.org/content/117/17/4403.full?sso-checked=true

HALO publishes in Molecular Cancer Therapeutics...

"These results suggest that HAhigh matrix in vivo may form a barrier inhibiting access of both MAb and NK cells, and that PEGPH20 treatment in combination with anti-cancer MAbs may be an effective adjunctive therapy for HAhigh tumors."

http://mct.aacrjournals.org/content/early/2014/12/13/1535-7163.MCT-14-0580.abstract

I agree, at this point convincing case needs head-to-head trial.

There's an IST (Spirit3) enrolling in January at 30mg dose, 2nd line "early switch", head-to-head against nilotinib, 500 patients each arm. Of course this assumes early switch becomes standard practice, but NVS, BMS, and PFE are helping to make the case. http://spirit3.spirit-cml.org/

What do you think about another front line possibility, using Pona at 30mg to reach MMR as quickly as possible and then generic imatinib as maintenance? Avoids VTE issue and has to be most cost effective.

I don’t see how you can conclude earlier lines are dead from ASH. Clearly the VTEs are caused by the drug at all doses, with ATEs being most serious. But at ASH PACE shows ~135 patients took 45mg for at least two years and then lowered to either 30mg or 15mg for one year, and of those 12(9%) experienced their first ATE in year 3, so I would expect lower rate with continuous use of lower doses. In my opinion a VTE rate of ~10% is acceptable for 2nd line, especially with all other AE’s reduced. Note separate ASH abstract for nilotinib in UK found 10% VTEs across all lines. https://ash.confex.com/ash/2014/webprogram/Paper76310.html. The question for front line remains how soon can you reduce 30mg to 15mg and will efficacy compete with 2nd-gen drugs after doing so.