Drugs to watch at ASCO 2014

Below is my ASCO 2014 preview (better late than never…). I tried to make this recap as comprehensive as possible but it is practically impossible to cover all the interesting stuff (let me know if I missed anything dramatic). Unlike last year, I decided to group interesting abstracts based on mechanism of action rather than companies in order to provide a more holistic perspective. On top of attending the conference itself, I will try to attend as many analyst events as possible (this year I have Clovis, Roche, BMS and Incyte on my list) and include them in my post-ASCO write-up.

PD-1 antibodies – still promising but challenges start to emerge

PD-1 antibodies continue to dominate the scene and this ASCO will have clinical data sets for 6 antibodies from BMS, Merck, Roche, AstraZeneca, Merck-Serono and Curetech. So far, updated results in the abstracts for the 3 primary indications (lung, renal, melanoma) fell short of expectations and raise 4 significant issues:

1.       Most patients do not experience long term remissions

2.       Combination data with Yervoy in lung cancer suggest  limited to no added benefit  

3.       Combination with approved and investigational agents may be too toxic

4.       Contradicting results on the use of PD-L1 as a predictive marker

On a more positive note, PD-1 antibodies are still the most promising class of drugs in development for cancer and in some patients they lead to phenomenal long term remissions. In addition, there appears to be good activity across a wide variety of other tumor types including bladder, head and neck and ovarian cancer.

PD-1 for Lung cancer

BMS’ (BMY) Nivolumab + Yervoy results were uninspiring with a 17% response rate for nivo’s higher dose. This is lower than response rate seen to date with monotherapy PD-1 antibodies (20-30%) and there was no correlation between response and PD-L1 expression. The safety profile appears problematic with a discontinuation rate of 35% and 3 (6.5%) treatment-related deaths. If updated results are not materially different, it would be hard to justify advancing this combination in lung cancer, despite BMS’ intentions to do so and   promising activity in melanoma.

As 1st line treatment, nivolumab demonstrated a 30% response rate and a median PFS of 7 months. Response rate in PD-L1+ patients was 67% vs. 0% for PD-L1- patients. When Nivolumab was added to standard chemotherapy regimens, response rate was 33-50%, which appears numerically better than that expected with chemotherapy alone (30%+) but the increase in response rate is not dramatic and the small sample size makes it hard to interpret the data.

Updated results in pre-treated patients demonstrated median survival of 10 months, which is encouraging but not dramatically better than what is expected in this population with other salvage therapies. The 3 mg/kg arm had better overall survival (15 months) but it is unclear whether this effect is real or just a statistical fluke. Surprisingly, PD-L1+ patients had lower survival.

Merck (MRK) will present data for MK-3475 in 1st line (all PD-L1+) and pre-treated NSCLC patients. The trials demonstrated activity of 21%-36% but this includes also unconfirmed responses.  Interestingly, in pre-treated patients, PD-L1+ patients had a higher response rate than PD-L1- (24% vs. 8%).

PD-1 for Renal cancer

Nivolumab will have monotherapy and combination data. Interestingly, BMS issued a press release that included more updated data than what appears in the abstracts.

 The monotherapy response rate of 20-22% is lower than that of previous reports (30%). PFS of 4 months for the 2 higher doses implies the drug is active but again, the extent of benefit over standard of care is limited. The overall survival data (25 months) is encouraging and appears significantly higher than typical survival in this patient population (predominantly 3rd line).

BMS will also present results for combination with Yervoy and approved agents (Sutent, Votrient). In both cases, response rate climbs to 43%-52% . The nivo+ Yervoy abstract reports a PFS of 9 months, which appears higher than nivo monotherapy but can also be explained (at least partially) by the less pre-treated nature of the population (23% were 1st line). Combining Nivolumab with Sutent or Votrient had toxicity issues with 60-73% Gr 3/4 rate and a 20-24% discontinuation rate.

PD-1 for Melanoma

BMS will present updated 3-year survival rate for nivolumab monotherapy and the highly anticipated combination data with Yervoy. The abstract for the monotherapy study includes an impressive survival rate of 41% at 3 years vs. 48% at 2 years. This may represent a “tail” (flattening of the curve) driven by durable responses. PD-L1 expression was associated with better survival and PFS. The combination data will be disclosed at the conference and expectations are for a 50%+ response rate.

MK-3475 will have monotherapy data, which appears in-line with Nivolumab. One abstract reports a 41% response rate and a PFS of 7 months. PD-L1 expression correlated with improved response rate (51% vs. 6%) and PFS (12 vs. 3 months). Another presentation titled “Efficacy and safety of the anti-PD-1 monoclonal antibody MK-3475 in 411 patients with melanoma” will be presented at the conference.

Additional indications for PD-1 antibodies

This year’s meeting will shed light on applicability of PD-1 antibodies in additional tumors. The most promising data will be for Roche’s MPDL3280A (Anti-PD-L1) in bladder cancer, where 10 (50%) of 20 patients with PD-L1+ tumors achieved a response. Nivolumab will have preliminary data in ovarian cancer. The abstract reports a response rate of 23% in platinum-resistant patients. Merck will present results in head and neck cancer, where activity has been observed but the abstract does not disclose any efficacy readouts. On its ASCO press release, BMS announced nivolumab received breakthrough designation for Hodkin’s lymphoma which suggests there is good activity in this tumor type as well. 

New immuno-oncology programs

2 combination studies evaluating new immunotherapies with Yervoy in melanoma patients will be presented. The significance of the data is in establishing proof of concept for the synergy with an immune checkpoint. Going forward both programs will likely be pursued with PD-1 antibodies.  

After months of speculations, Incyte (INCY) will report combination data for its IDO inhibitor (INCB024360) with Yervoy in melanoma patients. The abstract included information for the 300mg dose (too toxic) and for 8 patients in the 25mg dose, where a 38% response rate is reported. This response rate is numerically higher than Yervoy’s typical response rate of 10-15% but durability of response appears short. At the conference, Incyte will provide updated results for the 25mg cohort and report response rate with a higher dose (50 mg). In order to maintain the positive sentiment around this program, response rate needs to stay above 30% with evidence of durable responses, a hallmark of effective immunotherapy.

Amgen (AMGN) will also present for the first time results from a study evaluating it cancer vaccine     Talimogene laherparepvec (T-VEC) with Yervoy in melanoma patients. The abstract reports 41% response rate including an impressive 24% CR rate. Similarly to the IDO data set, investor attention at the conference will be on durability of responses.

Additional programs include Celldex’s (CLDX) CD27 antibody and Pfizer’s (PFE) 4-1BB antibody, both are agonists of their respective targets. Abstracts for the two programs disclose limited efficacy.

Next-gen EGFR inhibitors – Clovis vs. AstraZeneca

Investors are closely watching the face-off between AstraZeneca (AZN) and Clovis (CLVS), which will present data for their respective EGFR inhibitors. According to the abstracts, both agents have promising efficacy in NSCLC patients who failed approved EGFR inhibitors (Tarceva, Iressa) and harbor the T790M EGFR mutation. Both drugs recently received breakthrough designation from the FDA.

AstraZeneca is expected to report improved activity for AZD9291, with a response rate of 64% in 89 patients with T790M+ tumors according to the abstract. Durability seems strong as 97% of patients who had confirmed responses were still on treatment as of the cutoff date. Clovis’ abstract for CO-1686 does not provide new meaningful data and includes the previously presented response rate of 67% in just 9 patients. At the conference, investigators will have efficacy data for more patients (40+), which are expected to be positive based on the breakthrough designation CO-1686 received last week.

The two drugs appear comparable in term of efficacy (with the caveats of cross-trial comparison) but their safety profiles are differentiated. AZD9291 leads to more classic EGFR toxicities (rash, GI) and more importantly, 5 cases of interstitial lung disease-like symptoms were noted. For CO-1686, investors’ primary concern is QTc prolongation and whether it becomes clinically meaningful with prolonged treatment. Going forward and given the similar efficacy profile, a favorable safety profile may become an important advantage in this patient population, especially if the drugs reach first line EGFR+ NSCLC.   

FGFR inhibitors – Clovis still in the lead

This year’s meeting will have several presentations of FGFR inhibitors. Despite strong scientific evidence for the implication of the FGF pathway in many tumor types, FGFR inhibitors have demonstrated limited activity as monotherapy. The only exception to date is Clovis’ lucitanib, a dual FGFR/VEGFR inhibitor that demonstrated the promising results in a small data set of breast cancer patients with “FGF-aberrant” tumors. Lucitanib’s efficacy is attributed to the parallel inhibition of the VEGF and FGF pathways.

At ASCO, Clovis will present updated results which may corroborate the initial efficacy signal in breast cancer and potentially other tumor types. The abstract discloses the previously reported 50% response rate in 12 heavily pre-treated breast cancer patients.

Other companies will have data for their selective FGFR programs. AstraZeneca will report data for AZD4547 in 2 trials (gastric cancer and solid tumors). The drug generated responses in 1/38 and 1/7 patients with FGF aberrations, respectively. Novartis (NVS) will report phase I data for BGJ398 in squamous NSCLC patients with FGFR1 amplification. The abstract reports encouraging preliminary signs of activity with 4 responses among 21 patients. J&J (JNJ) will present phase I data for JNJ-42756493, including a subset of FGF pathway aberrations. According to the abstract, of 8 biomarker positive patients, two urothelial cancer patients achieved a response.

Hutchison MediPharma will report data for its dual FGFR/VEGFR inhibitor, which should be viewed as a direct competitor to lucitanib. Of 17 patients who received an improved formulation of the drug, 4 achieved a response. It is not disclosed whether these patients had FGF aberrations so it is unclear whether their responses are mediated by FGFR inhibition.

CD38 antibodies – Sanofi emerges as a worthy opponent

This year’s meeting will hae updated results for the 2 leading CD38 antibodies for multiple myeloma.

Genamb’s (GEN)/J&J’s daratumumab will have 2 oral presentations as monotherapy and in combination with Revlimid. The abstract for the monotherapy study reports mixed efficacy data for 2 expansion cohorts (8 and 16 mg/kg). The combined response rate for the two cohorts was only 19% (compared to 33% for ≥4 mg/kg at ASH 2012). Nevertheless, the 16 mg/kg arm had a response rate of 46%, which suggests a dose dependent response but sample size is small (13 patients). The daratumumab+Revlimid combination continues to look active with responses in 8 (72%) of 11 patients.

Sanofi’s (SNY) /Immunogen (IMGN) SAR650984 will also have data as monotherapy or in combination with Revlimid. The abstract for the monotherapy study reports a 24% response rate including a 33% response rate for doses ≥ 10mg/kg. Of note, 2 patients achieved a complete response whereas in daratumumab’s data set there were none. Efficacy in combination with Revlimid was 58% (7/12 patients).  This is numerically lower than daratumumab+Revlimid but the small sample size makes it hard to compare the 2 drugs. In addition, patients in the SAR650984 trials appear more heavily pre-treated.

Although both agents are active in multiple myeloma, daratumumab has a clear development lead with 2 phase III trials (still not active) and a pivotal phase II trial in relapsed/refractory patients.

Of note, there are still no published data for Celgene/Morphosys’ (MOR.DE) anti-CD38 antibody. The antibody was licensed by Celgene in a huge licensing deal last year.  

Antibody-drug conjugates- strong data in lymphoma and ovarian cancer

This year’s ASCO will have a record number of ADC presentations, predominantly from Roche. Most of the ADCs to be presented this year are powered by Seattle Genetics’ (SGEN) and Immunogen’s technologies.

Roche will present results from the ROMULUS trial, which compares its CD22 ADC (pinotuzumab) vs. its CD79b ADC (polatuzumab) when added to Rituxan in 2 subtypes of non-hodgkin’s lymphoma (DLBCL and follicular lymphoma). Both regimens demonstrated strong response rate of 54%/51% in DLBCL and 67%/60% in FL. However, both agents have tolerability issues with 36% of patients experiencing serious side effects and a high discontinuation rate. There were also 2 deaths related to pinotuzumab. Before pursuing phase III, Roche will probably explore regimens to minimize toxicity, especially peripheral neuropathy.

2 ADCs targeting CD19 will report data in NHL, both are expected to report a 40+% response rate. Sanofi’s SAR3419 (utilizes Immunogen’s technology) will have phase II data in DLBCL, which appears surprisingly good based on the abstract. Of 41 patients, 18 (43.9%) achieved a response including a CR rate of 12.2%. Although patients were relatively less heavily-pretreated (only 31.7% had received ≥ 3 prior regimens), this response rate is impressive and superior to previous updates. Seattle Genetics will report phase I results for SGN-CD19A in NHL. Of 20 evaluable patients the abstract discloses 8 (40%) responders, 6 of whom achieved a CR. Updated results may include stronger efficacy with further dose escalation.

Roche will present phase I results for its anti-NaPi2b (DNIB0600A) and anti-mesothelin (DMOT4039A) ADCs. Both agents utilize Seattle Genetics’ technology and appear active in ovarian cancer. The abstract for DNIB0600A reports a strong response rate of 41% at the highest dose in 17 patients with NaPi2b+ tumors. Evidence of anti-tumor activity was seen in 7/21 NaPi2b+ lung cancer patients. Roche recently started a phase II in platinum resistant ovarian cancer that compares DNIB0600A versus Doxil. As Doxil has a typical response rate of ~10% and PFS OF ~3 months, updated results at ASCO will help to evaluate likelihood of success.  The abstract for DMOT4039A reports an encouraging 30% response rate in platinum-resistant ovarian cancer as well as additional signs of anti-tumor activity. There was also 1 PR in 19 pancreatic cancer patients. Bayer has a mesothelin ADC (BAY 94-9343 ,utilizes Immunogen’s technology) which demonstrated activity in mesothelioma but no responses were noted for in small cohort  of ovarian cancer patients. BAY 94-9343 is being tested in an expansion cohort of ovarian cancer patients.

Immunogen will present updated phase I results for 2 proprietary programs. Although the focus will be on ways to overcome toxicity, data may include efficacy updates. For IMGN853 (anti-FRa), Immunogen will present a modified dosing regimen designed to minimize ocular toxicity thereby allowing maximal exposure. According to the abstract, higher doses led to clinical benefit in 10/24 but actual response rate is not disclosed. IMGN529 (anti-CD37) will have phase I results in NHL. Although signs of activity were seen, the dosing protocol had to be amended to include steroids in order to prevent neurtopenia associated with cytokine release.

Additional ADCs which utilize Seattle Genetics’ technology will have data this year: ABT-414 (anti-EGFRvIII) in glioblastoma, DSTP3086S( anti-STEAP-1) in prostate cancer and MLN0264 (anti-GCC) in colon cancer.

Oral agents for CLL – Pharmacyclics under pressure  

The biggest event in CLL this year is phase III data for Pharmacyclics’ (PCYC) Imbruvica (partnered with J&J). The trial, which compares Imbruvica to Arzerra in relapsed/refractory patients was already stopped after a positive interim analysis. While the ASCO abstract is not published, the EHA abstract for this trial is available and reveals that Imbruvica generated dramatically better response rate (43% vs 4%), PFS (not reached vs. 8 months), and overall survival (HR=0.43). Despite this phenomenal data set, the market is growing increasingly skeptical about Imbruvica’s commercial potential following a weak launch. It remains to be seen whether ASCO will be the turning point for Imbruvica’s sales trajectory.

Roche will present updated results for ABT-199, which is viewed as Imbruvica’s strongest competitor, as monotherapy and in combination with Rituxan. The monotherapy abstract reports an impressive response rate of 79% (22% CR), which appears superior to Imbruvica. The drug’s safety profile was improved thanks to the new dosing regimen that appears to have resolved TLS (tumor lysis syndrome) concerns.

Next-gen sequencing (NGS) gaining momentum – Foundation Medicine is the clear leader

Multiple groups will report experience with NGS as a tool to identify actionable mutations in order to guide treatment decisions.  Many reports include Foundation Medicine’s (FMI) technology and exemplify its disruptive potential.  Importantly, NGS appears more sensitive and accurate than other technologies, and can identify effective treatments that are otherwise not commonly used for a given tumor type. The abstracts include cases in which FMI’s system identified ALK mutations in tumors originally characterized as ALK-negative. These patients were then treated with ALK inhibitors and most responded. Another group reported the identification of a novel BRAF mutation in pancreatic cancer that may confer sensitivity to BRAF/MEK inhibitors. A third abstract describes the identification actionable mutations in tumors that were considered negative for all commonly used diagnostic tests.

Jakafi in pancreatic cancer and PV

Incyte will present phase II and phase III data for its Jakafi (Jak1/2 inhibitor) in pancreatic cancer and PV (polycythemia vera), respectively.

The pancreatic cancer trial did not show an overall survival benefit for the entire patient population, but a subset analysis in patients with high CRP levels (n=60) demonstrated a survival benefit. At ASCO, investor focus will be on the reliability and robustness of CRP levels as a selection criterion for the upcoming phase III.

In the PV trial, Jakafi achieved the primary endpoint in a highly significant manner, leading to a response in 21% of patients vs. 1% in the control arm. Although this response rate is lower than expected, responses were highly durable and most patients derived some sort of clinical benefit with Jakafi. These results will likely lead to approval in PV, which should translate to accelerated growth in Jakafi sales (already factored in by investors).

Additional notable abstracts

MEK162 – Novartis will present multiple data sets for, MEK162, a MEK inhibitor licensed from Array (ARRY) Biopharma. The most intriguing abstract is for a combination with LEE001 (CDK4/6 inhibitor) in NRAS mutated melanoma. MEK162, is currently in phase III in NRAS melanoma based on a 20% response rate.  Preliminary results for the combination include a response rate of 43% but most responses were not confirmed so more follow up is needed. Another study evaluated MEK162 with BYL719 (PI3K-alpha inhibitor) and demonstrated preliminary signs of activity in KRAS-mutated ovarian cancer (3 of 4 patients had a response).  Attempts to combine MEK inhibitors with PI3K inhibitors encountered limited success to date due to a narrow therapeutic window. Using an isoform-selective PI3K inhibitor may finally allow simultaneous inhibition of the 2 pathways.

CSF1R inhibitors – Roche and Plexxikon (Daiichi Sankyo) will present impressive efficacy for their respective CSF1R inhibitors in a rare joint tumor (PVNS) characterized by constant activation of CSF1R. Interestingly, although Roche targets CSF1R via an antibody and Plexxikon utilizes a small molecule kinase inhibitor, the clinical effect appears comparable between the two agents. Roche’s antibody (RG7155) led to responses in 7/10 (70%) patients, who were not amenable to surgery. Responses were associated with symptomatic improvement and appear durable (up to 17 months). Plexxikon’s PLX3397 led to responses in 7/11 (64%) of patients, which were also associated with symptomatic improvement.

MEK/BRAF combination in melanoma – GSK will present phase III results from COMBI-d, which evaluated Tafinlar/Mekinist vs. Talifnar in 1st line BRAF+ melanoma. Although the PFS benefit was marginal (2 weeks), preliminary survival analysis provides reason for optimism with a HR of 0.63 (p=0.023). If the survival benefit is maintained in the final analysis, MEK/BRAF combination will likely be the standard of care for 1st line BRAF+ melanoma. Later in the year, Roche will report phase III results for its MEK/BRAF combination in the same setting.

Combination regimens for BRAF+ colorectal cancer – At ASCO investigators will present data for combination regimens in BRAF+ colorectal (CRC) cancer. In contrast to experience in melanoma, BRAF+ CRC is not sensitive to BRAF inhibitors (5% response rate). Three abstracts report intriguing preliminary activity in combination with other agents. One abstract reports that 4/5 patients achieved durable responses when treated with Zelboraf combined with Erbitux (anti-EGFR) and chemotherapy.  Another study evaluates GSK’s MEK/BRAF combo (Tafinlar/Mekinist) with Erbitux  and the abstract reports responses in 4/6 evaluable patients. A third study evaluates LGX818 (Novartis’ BRAF inhibitor) and Erbitux with or without BYL719 (PI3K-alpha inhibitor). Of 18 patients, there were 3 PRs and 2 very durable cases of stable disease (1 year). At ASCO, investigators will present updated results with the triple arm.

MET inhibitors – Despite failures of Roche’s Metmab and Arqule’s (ARQL) tivatinib, the industry is still very interested in Met inhibitors based on the large amount of active programs. Although some abstracts report limited activity even in biomarker-defined tumors, there are preliminary encouraging signs in some of the trials that could help defining relevant niche populations. Amgen’s AMG 337 achieved 5 responses among 7 gastric cancer patients with MET amplification. Pfizer’s Xalkori, which is also a MET inhibitor, generated a response rate of 33% among 12 lung cancer patients with MET-amplified tumors with a median duration of response of 8 months.

33 thoughts on “Drugs to watch at ASCO 2014

  1. Hey Ohad
    thanks, as always, great job in giving us the detail and the broad picture.
    Who is your star for the conference?
    Dan

  2. Thanks Dan. This year I still don’t have a clear winner.
    I think that if lucitanib demonstrates good efficacy and CO-1686’s data are strong, CLVS could be a huge winner. We’ll see…

    Ohad

  3. Hi Ohad,

    Do you think Astra might be a star this year at the conference? During their battle against Pfizer they had some high forecasts on some of their IO pipeline. Someone said this could be their conference. But do you think they are overstating things?

    Best,

    Omar

  4. Omar – So far, Astra’s PD-L1 data does not look differentiated (at best). The CTLA4 combination dogma is questionable so their real star this year so far is AZD9291.

    Ohad

  5. Ohad, Hutchison MediPharma’s sulfatinib doesn’t hit as many targets as lucitanib (only hits FGFR1 as opposed to FGFR1/2 and doesn’t hit PDGFR like lucitanib). Do you see this as a drawback in potential efficacy for sulfatinib or are there specific tumors that can be targeted where it won’t be necessary to also hit FGFR2 and PDGFR? Presumably we can say that the fewer targets are at least likely to lend to better safety for sulfatinib but may not mean much if efficacy isn’t comparable as well.

    Hutchison MediPharma also has a MET inhibitor partnered with AZN. Have you looked at that yet? They recently announced AZN will start Phase 2 in papillary renal cell carcinoma due to strong Phase 1 data (3/6 PRCC pts had PR).

  6. mcbio – It’s hard to tell but it appears that selectivity towards FGFR1 and VEGFR2 is what drives the effect in FGFR1+ cells. Therefore, a more selective compound may enable better targeting of FGFR1-amplified tumors, but this needs to be proven experimentally.
    Yes I saw Hutchison’s MET inhibitor, their activity in PRCC reminds me of what was observed with XL880 (GSK/EXEL).
    http://www.ncbi.nlm.nih.gov/pubmed/23213094

  7. Hey Ohad
    thanks.
    So we hold on, wait for the CLVS results, and then decide whether to add a new position? The stock took a 10% cut yesterday. I didn’t see any news… maybe some investors just hedging their bets ahead of the release of data?
    Dan

  8. That’s what I plan on doing. I would like to see more mature data sets for both CO-1686 and lucitanib before adding more CLVS.

  9. Very comprehensive write up Ohad. Thanks. Im surprised to see CLVS headed down into ASCO especially on heels of BTD and insider buys. Reminds me of YMI before ASH, and then a week later they were acquired. Im thinking INCY might get a decent pop even on mediocre results. I plan to add in the $40-$42 range.

  10. Hi Ohad,
    Thank you. I’m curious about CLVS going down. Is there a reason to get worried In your opinion?
    Thanks, Chris.

  11. Thank you Ohad – very helpful – hope you find some time to sneak out and enjoy this great city – Saturday and Sunday should be gorgeous.

  12. Manish – Re CLVS , I guess investors start to factor in serious competition from AZN following such a strong abstract and a distinct safety profile. Data at ASCO must be strong to push the stock higher. Re: INCY, all eyes are on IDO…

    Chris – See my reply to Manish above

    Kirk – Thanks! Indeed a great city. Saturday and Sunday are fully booked but tomorrow I will try to walk around.

  13. Hi Ohad, how was ASCO so far? What is your opinion on CLVS. I really liked what the CEO said that the ORR might go up as they expect some of the patients to achieve PR and > 12 months PFS. Ive been waiting for some clarity before adding more to my existing positions. Would love to hear your opinion. Thanks.

  14. So far not a lot of surprises. Have to admit I don’t have concrete insight on the CLVS vs. AZN debate. Both drugs are AMAZING (median PFS of >9-12 months) and will likely reach the market but the safety profiles are very different with each side claiming victory. Talking with people at CLVS’ analyst event got me even more confused with some claiming Astra are “hiding something” and CLVS talking about a new metabolite which inhibits IGF1R AS the cause for hyperglycemia. (portrayed that as a potential beneficial thing). Turns out that both companies are seeing ILD like symptoms but they look manageable and not problematic like what is observed with Tarceva.

    Ohad

    Ohad

  15. Agree both drugs are significantly better than existing EGFR TKIs from both safety and efficacy fronts at this point. I think many people try to make this a case of winner taking all, which is very unlikely IMO. One thing few noticed is 2/3 of patients in AZD9291 trial are Asians who tend to have better efficacy based on response to previous EGFR TKIs – watch if ORR/DOR are lower in Caucasians. Given both drugs with safety profile much better than previous EGFR TKIs, somewhat distinct from each other but very manageable for oncology drugs, my guess is eventually the one with better efficacy will take slightly higher market share. This will be not known until registration ph2 trials are completed from both drugs.

  16. Ohad, my AMBI was to have two presentations at ASCO. I’m sure they were not on anyone’s priority list, but I was wondering if you heard anything.

  17. JQ – Agree it’s not a winner takes all game but in light of the impressive efficacy both drugs demonstrate, even subtle differentiators can make a difference.

    Richard – AMBI are presenting 2 posters today. I don’t expect they will garner a lot of attention, though as the data have been already out there. The next important data set is for the maintenance setting, which may make people more excited about the p3 design.

    Ohad

  18. So Ohad
    what about CLVS? you think results are strong enough to add shares?
    also, with all that talk about 1686, what about the other two candidates. Is Rucaparib a positive surpirse? Here too, seems AZN is again, going head to head with CLVS with similar drug/indication.
    Thanks
    Dan

  19. Richard – They still haven’t presented. Good question on what I would like to see on the maintenance study. Ideally, many long term remissions and conversion to MRD negative status.

    Dan – CLVS will probably see some pressure this week after ASCO. The drug is great but after considering the totality of data it appears that Astra has a better safety profile with similar efficacy for now. This may change at the next data readout of course when CLVS has more mature data set which might be better than the current one (there are very few progressors and many pts improve over time).
    Don’t think rucaparib is important for the current valuation.
    Bottom line, I would add more only if there’s a dramatic fall (25%) in share price today.

    Ohad

  20. Hi Ohad – I hope you´ll take some time to comment on the two CD38 antibodies after the oral presentations today. And also if you have some comments to the poster presentations from friday ?

    Do you know when to use dexamethasone, prednisone or methylprednisone in MM – can see Genmab changed from dexamethasone in their fase I/II study with daratumumab to methylprednisone in the pivotal fase II study – why ?

  21. Hi Ohad,

    Not at ASCO but heard SGN-CD19a ADC has shown some ocular tox. Previously had been widely reported with Maytansinoid Conjugates (IMGN901 esp) but now SGN too. Have also heard rumours of similar issues with THIOMAB platform (genentech’s site specific platform).

    Any thoughts as doesn’t seem platform specific. Have heard opinions on cause ranging from “leaky” linkers to non-specific binding to dividing corneal cells.

  22. Hello Ohad,
    ASCO news regarding binimetinib (MEK162) and selumetinib of ARRY. Encouraging.
    What do you think?
    Thanks.
    Toby

  23. Hi Ohad,

    not at ASCO…

    Syndax has submitted an S1 file to the SEC in March. They plan their IPO. I think it is impressive that with Entinostat they have a PIII asset in the pipeline which has received the breakthrough status by the FDA.
    The FDA very seldom awards the breakthrough status to small enterprises such as Syndax. That is why I wonder whether Entinostat is an especially promising program? I have read that the PII data were impressive concering the criteria ‘progression free survival’ and ‘overall survival’.
    What is your opinion on Syndax and on Entinostat in particular?

    Also Kite Pharma has submitted an S1 file to the SEC. Will you be allowed to report about this obviously fascinating and promising enterprise?

    Many thanks for all your work und your readiness to share your knowledge with us.

    Kind regards,
    Hubert

  24. Hi Ohad,

    There was a less heralded paper about Cabozantinib and Erlotinib at ASCO where it was mentioned that there are “Ongoing correlative studies are to determine correlation of response with MET amplification and T790M mutation.”

    Any opinion on if and where Cabo fits in the NSCLC regimen with the new T790M resistance drugs from AZN and CLVS?

  25. Ohad
    your prediction of 25% drop of CLVS turned out to be accurate: -25.3% down from Friday close. Is ‘game over’ for CLVS? At least Citi analyst Yaron Werber thinks so.

  26. Ohad, thanks for introducing me $AGIO. We are still holding $EXEL.

    $CLVS seems like safety issues still an overhang. Good buy now? What about $MGNX, $BLUE, $XLRN?

  27. Sukkeralf – I attended both the oral and poster sessions for CD38 antibodies. Overall, the 2 antibodies look comparable to me as mono or in combination with Revlimid. I was somewhat disappointed with dara’s efficacy at the 8 mg/kg dose although the 16 mg/kg cohort had good efficacy. (This can be explained by the 2-3 fold higher Cmax observed at P1).
    Don’t know what the significance of switching to methylprednisone is. It’s mainly a measure to minimize infusion reactions.

    james – From what I understand SGN-19A’s ocular toxicity is not target related but has to do with general accumulation of he payload (MMAF). This is also seen with IMGN’s CD19 ADC (SAR3419) and with Abraxane to a certain extent.

    roy – I am following OMER but my focus is on their earlier stage pipeline, especially the anti-MASP2 antibody and the orphan GPCR platform.

    Toby – Overall it was a good meeting for MEK inhibitors in combination regimens. The survival signal of Tafinlar+Mekinist in melanoma is very encouraging, needs to be corroborated later this year. MEK162+LEE001 data in NRAS melanoma look promising but more work is needed to manage side effects (1 death in the study). Also encouraging data for Tafinlar+Mekinist+ Vectibix had a response rate of 40% in BRAF mutated colon cancer (small sample size).

    Hubert – It’s been a while since I last looked at Syndax, their NSCLC data using E-cadherin as a biomarker was encouraging but retrospective.
    Re: Kite, agree it’s a very exciting company but I prefer not to discuss it for obvious reasons.

    Dan and Robert – I plan on adding more CLVS subject to price fluctuations but I don’t see a reason to add right now as the next readout is probably several months away.

    Wildbiftek – That’s a good question. MET has been implicated in resistance to Tarceva but I am not sure whether it plays a role in the context of T790M resistance.

    andre – I don’t think it’s a “game over” but so far AZD9291 has a better safety profile so one has to assume CLVS will not be the market leader. Still, it’s a 300-600M drug.

    Bridgette – Re CLVS, will wait for a better entry price. MGNX and XLRN are a little bit pricy imo. BLUE I like.

    Ohad

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