Nektar Therapeutics (NKTR) 2018 Q3 法說會逐字稿

Good day, ladies and gentlemen, and welcome to the Nektar Therapeutics Q3 2018 Financial Results Conference Call. (Operator Instructions) As a reminder, this conference call may be recorded.

I would now like to introduce your host for today's office, Ms. Jennifer Ruddock, Head of Investor Relations. Ma'am, you may begin.

Thank you. Good afternoon, everyone, and thank you for joining us today. With us are Howard Robin, our President and CEO; Gil Labrucherie, our Chief Financial Officer; Stephen Doberstein, our Head of R&D; Dr. Jonathan Zalevsky, our Chief Scientific Officer; and Dr. Mary Tagliaferri, our Chief Medical Officer. On today's call, we expect to make forward-looking statements regarding our business, including the timing of future clinical trials and clinical trial results; clinical development plans, including the plans to start future clinical trials; the therapeutic potential of certain drugs and drug candidates as well as those of our partners; our financial guidance for 2018 and certain other statements regarding the future of our business. Because forward-looking statements relate to the future, they are subject to inherent uncertainties and risks that are difficult to predict, and many of which are outside of our control. Important risks and uncertainties are set forth in the Form 10-Q that we filed on August 9th, 2018, which is available at www.sec.gov. We undertake no obligation to update any of these forward-looking statements whether as a result of new information, future developments or otherwise. A webcast of this call will be available on the IR page at Nektar's website at nektar.com.

With that, I will now turn the call over to our President and CEO, Howard Robin.

Thank you, Jennifer, and thank you everyone for joining us today for our third quarter 2018 conference call. On today's call, we will review our accomplishment in 2018 to date and also our planned milestones over the coming months, including the initiation of the broad registration program for NKTR-214, which includes multiple trials during this year in melanoma, renal cell carcinoma and bladder cancers as well as the new expansion arm in PIVOT enrolling second-line non-small cell lung cancer patients. We will also reiterate our financial guidance for the remainder of 2018.

As you know, we're planning to presenting data at this weekend's SITC meeting in Washington, D.C. for Stage IV melanoma patients being treated with NKTR-214 plus Opdivo from the PIVOT study. The presentation will include a number of important metrics, including depths of responses over time as well as the complete response rate and disease control rate for the population. We will host a call on Saturday morning at 9 a.m following the oral presentation of updated efficacy safety and bio market data of the evening before.

On the call, we will re-present the data from the previous evening's oral session. Dr. Harriet Kluger of the Yale Cancer Center and Dr. Adi Diab of MD Anderson Cancer Center will join us to review Dr. Diab's presentation and discuss our Phase III trial in melanoma patients, which is underway. In addition, we will also be presenting early data from the first patients in the REVEAL trial evaluating NKTR-262 plus NKTR-214. As we stated last quarter, as data from each of the PIVOT cohorts and other tumor types mature over the next 6 to 18 months, Nektar and Bristol are planning to present each of the data sets at various medical meetings, including tumor-specific conferences. We are currently planning the next presentation of PIVOT data from our bladder cancer cohort at the upcoming ASCO GU meeting in February of 2019. We continue to be very excited about the data being generated in the PIVOT trial and the future potential of NKTR-214 as a backbone therapy in immuno-oncology.

I'll start today by reviewing the multiple successes we have achieved over our pipeline of Nektar invented medicines across 3 therapeutic areas, immuno-oncology, immunology and pain. So first, let me cover NKTR-181. We all recognize the severe opioid epidemic that is facing our country right now. One significant building block to addressing this crisis is providing new pain medications that don't carry the same profile as the existing opioid medications on the market. We continue to work closely with the FDA during the review of NKTR-181 as we have done throughout its development. And as a reminder, our PDUFA date is May 29, and we currently understand the FDA plans to hold an advisory committee meeting to review our NDA. However, we have not been given a date for this meeting yet. As I stated last quarter, we are in the process of establishing a separate commercial subsidiary with one or more capital partners to launch this important molecule. We believe this will allow us to ensure the commercial launch of NKTR-181 is optimized, and we continue to be very excited about the future for NKTR-181.

Now let's talk about immuno-oncology. We remained focused on our strategy to develop a full pipeline of new potential medicines that address the key components of the immune cycle in order to restore immune surveillance and properly harness the body's immune system to fight cancer. With this year's collaboration for NKTR-214 with the Bristol-Myers Squibb, we are now in an exceptionally strong financial position, which allows us to execute on our vision for Nektar's portfolio in immuno-oncology. The Bristol-Myers collaboration gives us a unique and broad platform for us to rapidly develop our lead I-O candidate, NKTR-214.

As a reminder, the collaboration includes a broad joint-development plan with 20 registrational trials across multiple tumor types.

From the start of this collaboration, we've talked about the scope and scale of this development program, and I'm pleased to share with you today that the first 8 of these 20 trials in our joint development plan have been initiated or are being initiated shortly. As you know, our Phase III melanoma trial is already underway, and we dosed our first patients in September. For RCC and bladder cancers, BMS and Nektar are initiating a total of 3 registrational trials in each tumor setting, 3 in the first-line RCC setting and 3 in the first-line bladder cancer setting. As the start of our lung cancer registrational work, BMS and Nektar have added a newly-defined cohort of approximately 100 second-line non-small cell cancer patients to the ongoing PIVOT trial. This is designed to provide us with a potential pathway to registration in this new patient population.

You will see these additional trials begin to be posted externally on clinicaltrials.gov over the coming months and I'll let Mary share more about these 8 study designs and patient populations in a moment. In addition, BMS and Nektar are currently working on the designs for the next wave of trials in the joint development plan, so these can be initiated in the first half of next year.

The BMS collaboration is exceptionally important to the development of NKTR-214 with Opdivo in multiple tumor types. Recognizing that NKTR-214 is a broad-based mechanism as we told you in the past, we have always planned to collaborate with additional strategic partners to allow us to combine NKTR-214 with other anti-PD-1 and anti-PD-L1 agents in tumor types that are not within the BMS joint development plan. We have substantial interest from companies that recognize the importance of the unique mechanism of NKTR-214 in immuno-oncology, and that is one of the most promising I-O agents in development based on the large body of preclinical and clinical data we've generated for this agent.

To this end, yesterday, we announced an exciting new clinical collaboration with Pfizer to develop new -- NKTR-214 with several agents in their portfolio in 2 new tumor types. The collaboration will pursue development of NKTR-214 in metastatic castration-resistant prostate cancer and squamous cell carcinoma of the head and neck. Under the new agreement, Pfizer will develop various doublet and triplet combinations with NKTR-214 and Pfizer and Merck Serono's anti-PD-L1 agent avelumab; Pfizer's PARP inhibitor, talazoparib; and Pfizer and Astellas' anti-androgen agent, enzalutamide. We've worked -- we've enjoyed working very closely with the talented team at Pfizer Oncology to design this important clinical program for these patient populations with a high unmet need. Pfizer will be running the clinical work and will serve as the sponsor of this trial. And later, Mary will summarize the design of the multiple-arm clinical study in prostate and head and neck cancer. We're also planning to initiate 2 additional trials with NKTR-214, which you will see on clinicaltrials.gov within the next several months. The first will be a Phase I trial with Takeda to evaluate NKTR-214 Takeda's dual SYK-FLT inhibitor known as TAK-659, in patients with Non-Hodgkin Lymphoma. That is scheduled to start in the first part of next year. The second will be a Phase I trial with Syndax to evaluate NKTR-214 with Syndax's HDAC inhibitor in patients with IO refractory melanoma , which is also planned to start in the first part of next year. In addition, over the last several months, we've entered into new clinical collaborations with 2 new partners, Vaccibody and BioXcel, both of which will include clinical trials with unique mechanisms in combination with NKTR-214. For Vaccibody, we will combine NKTR-214 with their personalized neoantigen cancer vaccine. BioXcel and Nektar are collaborating on the combination of NKTR-214 with their small molecule immunomodulator, a combination DPP 8/9 and FAP inhibitor, and a checkpoint inhibitor in patients with pancreatic cancer. We plan to initiate these trials in the first half of 2019.

As you know, our pipeline of I-O candidates beyond NKTR-214 includes NKTR-262, a TLR 7/8 agonist; and NKTR-255, an IL-15 candidate, which can stimulate both NK cells and memory T cells. In April, we dosed the first patient in the REVEAL trial, which is evaluating a combination of NKTR-262 with NKTR-214. The combination of NKTR-262 and NKTR-214 has enormous potential. Our preclinical data for the combination of these 2 agents demonstrates clearly how the individual agents, NKTR-262 and NKTR-214, work together to engage the innate and adaptive arms of the immune system, control the maturation and function of the underlying myeloid and lymphoid cell populations. And most importantly, modify systemic immunology to drive an abscopal anti-tumor response in tumor models. The dose escalation phase of the trial of NKTR-262 and NKTR-214 is continuing to determine initial safety, efficacy, PK and biomarker characterization. We will also have the later option in the trial to evaluate a triplet of NKTR-262 and NKTR-214 plus Opdivo. As I stated earlier, we plan to share some of the early clinical data from this trial this weekend at SITC. Once we've identified the recommended phase II dose, the trial is projected to enroll up to 400 patients with 8 different tumor types in first and second line as well as refractory settings.

For NKTR-255, our IL-15 candidate, we've been conducting preclinical studies evaluating NKTR-255 in oncology models driven by NK cell expansion and activation. NKTR-255 is a powerful agonist that allows us to modify NK biology for the treatment of hematological malignancies in combination with targeted antibody mechanisms. We plan to file an IND for NKTR-255 in the first half of next year.

In another application, we've been evaluating NKTR-255 in combination with multiple experimental CAR-T cell therapies in collaboration with the Fred Hutchinson Cancer Center. High levels of native IL-15 has been associated with remissions and longer duration of response in patients with lymphoid malignancies who have undergone CAR-T regimens. So we're excited about the potential of NKTR-255 to greatly enhance CAR-T incomes as well as its potential to be combined with other mechanisms in I-O. Now moving on to our immunology program. Let me give you an update on the advancement of NKTR-358 with our partner Eli Lilly. As we've stated in the past, the initial data from the ongoing first-in-human Phase IA trial of NKTR-358 in healthy volunteers has shown dose-dependent increases in T regulatory cell levels with no increase in conventional T-cells or NK cells. This is comparable to what we saw in our nonhuman primate models, and we're extremely pleased that this mechanism has now been confirmed in humans. We expect to present complete data from the Phase IA trial at a medical meeting in the first half of 2019. We also recently started the Phase Ib multiple ascending dose trial in patients with lupus. The trial is advancing very quickly and we're very excited about the potential for NKTR-358 as a resolution therapeutic to bring a new paradigm to the treatment of autoimmune diseases and chronic, inflammatory conditions.

With that, I'll hand the call over to Mary to review additional details on the clinical work plan with Pfizer in head and neck prostate cancers and the Phase III trials in melanoma, RCC and bladder cancer with BMS.

Thanks, Howard. Let me first start with reviewing the clinical plans with Pfizer in prostate and head and neck cancer. We are very excited to be working with Pfizer oncology to explore the potential of combining multiple mechanisms in 2 new solid tumor settings. Prostate cancer is the second leading cause of death for American men. Metastatic castration-resistant prostate cancer is an incurable disease with a very poor prognosis and a 5-year survival rate under 30%. Squamous cell carcinoma of the head and neck tends to be diagnosed very late and also has a poor prognosis. Under the new clinical collaboration, Pfizer oncology will conduct and sponsor a trial with multiple arms evaluating NKTR-214, Pfizer and Merck Serono's anti-PD-L1 agent avelumab; Pfizer's PARP inhibitor, talazoparib; and Pfizer and Astellas' androgen receptor inhibitor, enzalutamide. The planned Phase Ib/II clinical trial will include multiple patient arms. One will be a Phase II cohort to evaluate NKTR-214 plus avelumab in patients with recurrent or metastatic squamous cell carcinoma of the head and neck who have not received any prior systemic treatment for metastatic disease. Enrollment will include patients with both PD-L1 negative and PD-L1 positive baseline tumors. The second and third cohorts of the study will feature one Phase Ib dose escalation followed by a Phase II component to evaluate NKTR-214 plus avelumab, combined with either talazoparib or with enzalutamide in patients with metastatic CRPC who have progressed on one or more prior regimens. Pfizer and Nektar are finalizing the protocol and we plan to start the clinical trial in 2019. Cohorts will include 20 to 40 patients, and we will measure clinical success based on the specific combinations and reference outcomes in the various settings being investigated in the study. Now I'll spend some time reviewing the plans for melanoma, renal cell and urothelial carcinoma, which Howard mentioned are the first 3 tumor types in which BMS and Nektar will launch our registrational trials. I'll also talk about the PIVOT expansion in second-line non-small cell lung cancer, which is currently underway. Our strategy with BMS is to secure as many potential approvals in early and first-line settings across multiple solid tumor types to establish NKTR-214 plus Opdivo as the standard of care. To that end, we are initiating 3 separate studies in renal cell carcinoma, 3 separate studies in bladder cancer, and we continue to advance our registrational clinical development strategy in melanoma and non-small cell lung cancer. First in melanoma, we are very fortunate to be collaborating with BMS, the only company to have developed an immuno oncology doublet therapy for melanoma patients. We are enrolling 760 patients with advanced or metastatic melanoma into our Phase III trial or NKTR-214 plus Opdivo. Patients will be stratified by PD-L1 status, stage of disease and BRAF. The primary endpoints are progression-free survival and overall survival with the projected 22-month timeline for the final PFS analysis. Both the FDA and CHMP have agreed to an open-label study design and to our comparator arm. This pivotal study in melanoma is designed to secure NKTR-214 plus Opdivo as the first-line I-O standard of care, and we are very excited patient dosing is underway. For more details, the Phase III trial design is available on clinicaltrials.gov. In renal cell carcinoma, Bristol and Nektar are planning to launch multiple registrational trials in advanced patients, which will include separate trials to evaluate the doublet and triplet regimens of NKTR-214 plus Opdivo and NKTR-214 plus Opdivo and Yervoy in this indication.

The first Phase III trial in first-line metastatic RCC patients will evaluate NKTR-214 plus Opdivo versus a TKI of physician's choice -- either sunitinib or cabozantinib in approximately 600 patients with intermediate or poor risk RCC. This trial design is available on clinicaltrials.gov as well. Patients will be randomized 1 to 1, and will be stratified in the trial based upon multiple factors, including PD-L1 status, IMDC prognostic score and choice of TKI. The study will look at overall survival and has an estimated time to the first interim analysis of survival of 27 months, currently forecasted to read out by the first quarter of 2021. The second Phase III trial in RCC will evaluate NKTR-214 with Opdivo and Yervoy as compared Opdivo and Yervoy in patients with previously untreated metastatic RCC. The study will enroll approximately 800 patients with intermediate or poor risk IMDC scores and will also stratify by PD-L1 status.

The third registrational trial in RCC will be a TKI inclusive regimen with NKTR-214 plus Opdivo and a TKI compared to nivo plus a TKI in patients with metastatic untreated RCC with clear cell component and all IMDC risk levels. The study will include a safety lead-in to determine the TKI combination dose for the second part of the study, which will then evaluate ORR, PFS and overall survival. As you know, we've demonstrated that treatment with NKTR-214 plus Opdivo can convert over 50% of patients whose tumors have a baseline negative PD-L1 expression to positive PD-L1 expressors. We also observed this conversion with NKTR-214 monotherapy in our first Phase I trial with NKTR-214. This is why we believe that NKTR-214 plus Opdivo can deliver on the promise of becoming the preferred standard of care as a doublet I-O regimen in many different tumor types. As the first example, we are working to incorporate this advantage of NKTR-214 observed in PD-L1 negative baseline patients into our registrational strategy in bladder cancer.

In bladder, we're also planning a registrational program to gain approvals in first-line metastatic bladder cancer and other settings. Cis-ineligible bladder cancer patients are a population with a very high unmet need, particularly those with PD-L1 negative disease at baseline for whom single agent checkpoint inhibitors are no longer the preferred standard of care. With this in mind, our first trial in bladder cancer will be in cisplatin-ineligible patients and will focus on patients with baseline PD-L1 negative disease. We are currently finalizing the design of this study with input from the FDA. The trial will enroll over 150 patients and we are planning to include a chemotherapy comparative reference arm into the study. You will see this trial design posted on clinicaltrials.gov within the next month. The second Phase III trial on bladder cancer is planned to start in January 2019, and will be conducted in patients with newly diagnosed muscle invasive bladder cancer. The third trial in metastatic bladder cancer will be in the first-line metastatic patient population who are both cis-eligible and cis-ineligible. As Howard stated earlier, we are expanding the second-line relapse non-small cell lung cancer cohort in PIVOT to enroll approximately 100 patients who received a checkpoint inhibitor with chemotherapy in first-line. The original design of PIVOT envisions that an expansion arm in an appropriate patient population could potentially serve as a faster registrational pathway in this population which has limited options once their disease has progressed following a checkpoint inhibitor with chemotherapy in first-line.

As Howard stated, BMS and Nektar are highly focused on continuing to advance our broad joint development plan. And to that end, we are now designing the next wave of clinical trials beyond the 8 that I just reviewed. As Howard also communicated, we are advancing NKTR-214 with Takeda's dual SYK/FLT inhibitor, known as TAK-659, into a Phase I/II clinical trial in non-Hodgkin lymphoma before the end of this year. TAK-659 is a clinical stage compound developed by Takeda that has already shown clinical activity in non-Hodgkin lymphoma. In preclinical mass tumor models, TAK-659 was shown to reduce the levels of myeloid-derived suppressor cells and increase the levels of pro-inflammatory N1 macrophages in the tumor microenvironment. Since NKTR-214 and TAK-659 target different cell populations, the 2 compounds provide a unique nonoverlapping and highly complementary mechanism to TAK-659. As the first trial with NKTR-214 in a liquid tumor setting, the study provides a strategic opportunity for us. The trial will enroll patients who are relapsed or refractory to at least 2 prior lines of therapy, but no more than 3 prior treatments. And we expect this trial to start in the first part of 2019. With Syndax, we are designing the first combination trial of NKTR-214 with entinostat in patients with IO relapse refractory melanoma, and we expect to finalize the design before the end of this year with first patients dosed in early 2019. With that clinical update, I'd like to hand the call over to Gil.

Thank you, Mary, and good afternoon, everyone. I will start with a brief review of highlights from Nektar's third quarter of 2018 financial results and then I will review our 2018 financial guidance.

We ended the third quarter with $2 billion of cash and investments. Total revenue was $27.8 million for the quarter and $1.15 billion for the 9 months ended September 30, 2018, compared to $152.9 million for the third quarter of 2017. And $212.2 million for the 9 months ended September 30, 2017. This significant increase in 2018 revenue is a result of the Bristol-Myers Squibb collaboration that we closed last quarter. R&D expense came in at $102.9 million in Q3 and $290.7 million for the first 9 months of 2018 as compared to $65.7 million for the third quarter of 2017, and $187 million for the first 9 months of 2017. We expect our R&D expense to increase as we continue to execute on the registrational joint development plan with BMS over the coming months. In addition, we will be initiating multiple trials combining NKTR-214 with other synergistic mechanisms in various cancer settings, including trials with Takeda, Syndax, BioXcel, Vaccibody, and our trial with Pfizer in multiple tumor types. It is important to keep in mind that our annual R&D funding obligation with Bristol is subject to $125 million annual funding cap. This cap will not limit our aggregate annual GAAP R&D expense recognition, but will limit our annual cash funding obligation to $125 million prior to the commercialization of NKTR-214. We recognized a net loss of $96.1 million for the quarter, and net income of $779.5 million for the 9 months ended September 30, 2018. As compared to net income of $60.9 million for the third quarter of 2017, and a net loss of $62.9 million for the 9 months ended September 30, 2017. Now let's turn to our 2018 financial guidance. Our financial guidance is unchanged. Our full-year revenue guidance remains at $1.165 billion to $1.175 billion, which includes $1.06 billion of revenue recognized in Q2 from the BMS upfront collaboration payment and a portion of the equity investment and an additional $105 million to $115 million of product sales, royalties and other revenues. Our GAAP expense guidance also remains unchanged. We continue to expect 2018 R&D expense to range between $400 million and $425 million, which includes approximately $60 million of noncash stock compensation and depreciation expense.

G&A expense for 2018 is still projected to be between $72 million and $75 million, which includes $28 million of noncash stock compensation and depreciation expense. We continue to estimate that we will end 2018 with a cash position between $1.9 billion and $1.925 billion.

And with that, I will open the call for questions. Operator?

(Operator Instructions) And our first question comes from Chris Shibutani from Cowen.

We appreciate the updates on the programs, in particular with regards to lung, it's interesting to hear about the strategy that you are taking with the expansion of the cohort. And I believe in the past, you have talked about potentially seeking an accelerated path. And obviously in Phase II, this would be based on a single-arm study. Can you confirm what's your thoughts are in terms of when we might be able to see data on perhaps the earlier group of patients that might have been already enrolled in the lung study? And then get a better sense for how you're thinking about the potential for doing a randomized study in the event that an accelerated wouldn't be the path for an approval. I think we have some other industry competitors who have some updated data and have declared plans to take regulatory pivotal path, that involves a randomized trial in for lung.

Chris, it's Mary. Thanks for your question. So to address the first part of your question, in PIVOT-02 we did -- we have a cohort that is second and third line non-small-cell lung cancer patients. As you know, when we saw you at ASCO this year, we did present 3 cases from that cohort and Dr. Gettinger walked through that these patients had been previously treated both with chemotherapy and at least one prior checkpoint inhibitor. Based on the early data that we saw in that cohort, we did go and have a discussion with the FDA about starting a new cohort in non-Small cell lung cancer patients that are relapsed to a checkpoint inhibitor in chemotherapy, the same regimen administered in KEYNOTE-189. Through that discussion with the FDA, this new cohort now includes 100 patients that just it's the second line -- not second and third line as our original cohort was. And we just began enrolling to this cohort: first patient is already in and we anticipate enrolling this cohort over the next 12 months. We then would follow these patients for roughly 6 months, and at that time have data to potentially present to the FDA. To address your second question about randomized trial, as both Howard and I mentioned, we are in the process of developing the next wave of clinical trials, and we do have plans for going in randomized trials both in the early setting of non-small cell lung cancer as well as later setting. And this includes a very broad program that we've shared with you before that touches on chemo-sparing regimens in the first-line settings, chemo combinations in the first-line settings and then also looking at randomized trials for patients who have recapped on prior checkpoint inhibitors with chemotherapy. In addition, also under consideration for us, is looking at stage III patients and who are unresectable as well as those patients who are resectable, who are Stage IIb, IIIa and looking at the combination of NKTR-214 plus nivolumab in the adjuvant setting.

So then specifically with the patients, I guess, with the 6 that you presented at SITC last year and the additional anecdotal patients, isn't it fair to assume that we have had more experience with patients? I'm not sure what that number is, perhaps you could tell me. And would we be able to see that data during 2019, perhaps at ASCO -- realistic opportunity for an update with some sort of denominator that might be maybe more than a dozen patients? I realize that you're moving forward with the expansion cohort, but looking back upon the past 12, 18 months and then looking at that experience with the lung patients and then looking forward to 2019, can we expect data during 2019 from the lung setting?

I'm going to make that answer very short and simple. Yes. In 2019, you can expect to see lung data from PIVOT-02.

Our next question comes from Robert Hazlett from BTIG.

My question is also with regards to data. It's good to hear the Takeda and other collaborations are beginning to dose. One quick one, I guess, is with regard to entinostat and the Syndax collaboration. There is some intriguing data already with high dose IL-2. Obviously it's not NKTR-214, but that's in renal cell carcinoma. Could you talk about how you thought about the potential combination in the setting with entinostat? And why you went toward melanoma?

Bert, thank you for the question. This is Jonathan Zalevsky. So we definitely were very aware of the data with high-dose IL-2 and entinostat in renal cell carcinoma. That was actually one of the reasons that started our initial collaboration with Syndax altogether. And then from those earliest discussions, we went into a very substantial preclinical program where we studied the 2 mechanisms in a range of different mouse and genetic tumor models to address how the underlying mechanisms of each drug work together. And where the synergy might come from when the 2 are dosed together into the same immune system. And one of the things that we discovered was a very high proportion of what we call high cytokine effector cells, that we detected into the tumor microenvironment when both drugs were dosed together. So this means specifically immune cells that were very high in like interferon gamma, TNF, and other kinds of effector cytokines. And so that was the impetus to then look into, in particular, the relapse refractory setting. Because those kind of cells are expressly the kind of cells that can overcome certain kind of resistance mechanisms. So then targeting the relapse refractory melanoma setting became a very attractive utilization of the 2 molecules. And this is why we prioritized that tumor type into the clinical trial.

And then one other follow-up. Are you using any biomarkers in these studies? And then just a general question. When might we see our first data for any of these, let's call them, collaborations beyond Bristol-Myers, whether it's Takeda or Syndax or any of the other ones?

There will definitely be an extensive biomarker program because these are now new mechanisms. And so just like we've have done with 214 plus a checkpoint, we always want to translate all of the things that we learned in the preclinical species into the human clinical settings. We did that in the PIVOT program. We're also doing that in the REVEAL where we're combining NKTR-262 and NKTR-214. And likewise, in both the Takeda collaboration as well as in the Syndax collaboration, there are a lot of mechanism-specific biomarkers that we're employing to address that the 2 mechanisms are there, and that they are working both independently and that they are working together in a complementary and synergistic way. And then to the second, data presentations for these trials -- because -- since the trials will be running next year, they are just getting underway. So what we will be doing is working closely with both Takeda on the Takeda program, and Syndax on that program on the dates for presentation of data from those trials as they mature.

And our next question comes from Tyler Van Buren with Piper Jaffray.

Had a couple of clarifying questions on the abstract that was released yesterday morning just going into the presentation on the weekend. Firstly, I guess there were 41 patients enrolled and we saw that number at ASCO as well and 38 were evaluable for response at the time of the cut-off. Were those 3 patients -- have they not just received a scan yet or why were they not note evaluable? And should we expect data from 38 or 41 patients Friday evening?

Thank you very much for asking the question, Tyler. Yes, those 3 patients did not have a scan and were not evaluable and we will certainly provide the update for the reason why those 3 patients were not included in the 41 during Dr. Diab's presentation. In addition, we will be updating the confirmed objective response rate, and we will be providing objective response rate per independent radiology. We did something very unique in the PIVOT program, is we embedded independent radiology review into our study. And so that will be new information presented by Dr. Diab as well as the complete response rate and disease control rate as Howard mentioned. We also will continue to share with you the tolerability profile of NKTR-214 plus nivolumab. And we look forward to seeing all of you at SITC.

That's helpful. Of the 19, I guess, the 19 that responded as of the abstract cut-off and 19 didn't respond or didn't respond yet. Could you tell us of those 19 nonresponders, how many had 1 scan? I guess, I am trying to assess how many of those could potentially respond in a second scan as we go into the update Friday evening.

Yes, thanks, Tyler. Let me just share with you that the median follow-up is just over 7 months for the patients enrolled to this cohort, and we're very happy to present all the data to you in the next 2 days when Dr. Diab presents at SITC in his oral presentation. And we're certainly happy to answer questions following his presentation. So look forward to seeing you there.

Okay, wonderful. I guess, we'll get the update from PIVOT cohort, the bladder PIVOT cohort, at ASCO GU. I guess I was just a little surprised to see the bladder data being presented before the renal cell if I have that accurately. Is I guess, given the lack of efficacy of PD-1s in this population,did that cohort just enroll much quicker? Based upon the last cut-off we saw, or should we expect -- be expecting renal cell sometime in the first half as well or not far behind?

Yes, I think you can definitely expect the renal cell carcinoma data to be not far behind the bladder. And as we've shared with you before, in some different -- in some tumor types, we see responses occur very rapidly as we've seen in both melanoma and bladder. And as we've shared with you previously in renal cell carcinoma, we've seen patients respond all the way out 10 months after being on treatment. And so we wanted to allow the data to be mature for the renal cell carcinoma cohort. And yes, we will be presenting bladder at ASCO GU and renal cell soon thereafter.

Our next question comes from Jessica Fye from JP Morgan.

Mary, I've got a couple more for you. You talked about the updated complete response rate in the melanoma cohort we're going to see at SITC. And I'm curious if heading into that, you could just benchmark for us what other I-O combinations have shown in first-line melanoma as it relates to the CR rate? I saw some in the 20% range, but it looked like they were kind of more mature. And it seems that the maturity of the data set you compare to matters here. So what would you view as compelling on the CR rate? And then I got a couple on lung.

Yes, thank you for asking that question. So I -- I just mentioned that our median follow-up is going to be just over 7 months. And I think the apples-to-apples comparison is to look at the CheckMate-067 study that had a median follow-up around the same time. And if you pull then the James Larkin New England Journal of Medicine 2015 manuscript, you will see that the median follow-up at this time was just over 12 months. And when you look at the complete response rate for ipi plus nivo in that paper, it was 11.5%, which is much lower than what you saw in the 4-year follow up that was just published in Lancet Oncology. And then if you look at single agent nivolumab, it was 8.9%. So I think that, that's the fair benchmark to the data that we're going to present at SITC.

Okay, thanks for laying that out. I also just want to make sure I understand, in the press release, you mentioned lung as one of the tumor types with another trial starting in the next several months. Was that a reference to the 100 patient second-line non-small cell cohort you added to PIVOT? Or was that referring to something else like a Phase III starting up in several months?

I like these easy yes questions. The answer is yes. But that refers to the 100 patient non-small cell lung cancer second-line cohort that we have in PIVOT.

Okay. And then maybe just following up on Chris' question about what we're going to see from a lung data standpoint '19? Will we get updates from that kind of post-189 regimen population as you go along? And is there a Fleming analysis built into that, that you might disclose when you hit that threshold? Or is this a cohort you need to sort of not report on, so you can do it all at once and bring it to the FDA? And I'm also curious if in 2019 we'll see the data from those 35 second-line, third-line -- I'm going to imagine mostly post- single agent PD-1 patients you had entered as of ASCO. And what you think investors can and cannot read across from data in that population to think about what you might show in the patients who progressed on PD-1 plus chemo in the first-line, assuming that data probably comes a little later?

Yes, we definitely plan to present additional lung data in 2019. And we said this repeatedly, as these cohorts mature, we will present the data. And in addition to the relapse refractory population, we'll also be looking to present the data in the first line, both the PD-L1 low, medium and high. So we have plans for both of those 2 different cohorts. I think the one differences is, again, that I just highlighted, is the cohort that we've been enrolling to in PIVOT-02 has been a mixed second- and third-line population. And we've moved to a pure second-line population for the accelerated approval potential pathway with the small cell lung cancer -- non-small cell lung cancer cohort.

Okay. And just the last one . What do you think you would need to show in that 100 patient, pure second-line cohort to secure an accelerated approval?

Yes, at ASCO, Dr. Scott Gettinger went on the record to say roughly a 20% response rate in that population would be highly compelling for accelerated approval. And that makes a lot of sense when you think of docetaxel in second-line has about a 9% response rate. We have engaged the FDA regarding our strategy and we're having an ongoing dialogue with the agency as we move forward and gather more data in this cohort.

Our next question comes from Difei Yang from Mizuho Securities.

So just a couple here. Sounding like you are in the planning phase of starting a number of registrational trials. Can we assume -- you have seen data from the PIVOT -- ongoing PIVOT study, which allows you to make this -- joint decision with BMS?

Yes, we have. We have -- we've been analyzing data from the PIVOT-02 trial and we have been reviewing these data with BMS and jointly been making the decision as to where we see the signals are and advancing into registrational trials based on that.

Was there a pre-determined threshold for efficacy to get to the decision?

So the decision to move forward in a registrational trial is multifactorial. We have been looking at patient populations where there's a high unmet medical need. We have been looking at populations where those patients with PD-L1 negative disease are underserved by checkpoint inhibitors. We've looked at broad patient populations such as melanoma where we have seen an early cohort compelling data, both from our biomarkers, our response rates and our safety data to warrant moving forward into registrational trials. And last, of course, we look at the competitive landscape and see where we have opportunities to improve upon standard of care.

Then a financial question. So with regards to the collaboration with Pfizer and Takeda, et cetera. What is the financial commitment from R&D spending perspective on Nektar?

Yes, this is Howard. Thanks for the question. Look we haven't -- Pfizer would prefer that we don't disclose the financial conditions of that collaboration. I will tell you that clearly we try to make these collaborations similar to other ones that we've done. And both of us will be contributing to the cost of those clinical trials, and we're very pleased with what we are doing together with Pfizer.

Our next question comes from Asthika Goonewardene from Bloomberg Intelligence.

I wanted to query you about the relapse refractory patient population that you had enrolled in the PIVOT-02 study, mainly in the melanoma and the RCC subgroups. You had about 38 -- 36 melanoma patients and what, 15 RCC relapse refractory patients enrolled at ASCO. I'd like to know when you plan on releasing some data in these patient groups?

Yes. We said this in on our last call as well. Over the course of next 6 to 12 to 18 months, we plan to have an ongoing stream of data from PIVOT-02. And strategically, we feel like it's important to show up in large conferences as well as tumor-specific conferences when we are strategically moving forward into a Phase III trial, and can run investigator meetings. So we have a very broad publication strategy to release data on an ongoing basis over the next 6 to 12 months. In addition, as you know, we are also moving forward in relapse refractory patient population with our toll-like receptor agonist, and we are combining that with NKTR-214. So I'd also like to turn this over to the Jonathan Zalevsky to comment on our approach on the relapse refractory patient population.

Yes, thank you, Mary, and very much to the point that I was making earlier about overcoming resistance mechanism, we know that is a key feature of any kind of successful immuno-oncology regimen. And one of the things that we learned when we were developing NKTR-262 in our preclinical setting was that it could really overcome a lot of immune limitations in the context of an antitumor I-O kind of regimen. And to that end, the REVEAL clinical study that began earlier this year, is really focusing on evaluating NKTR-262 plus NKTR-214 doublet in relapse refractory patient populations. And so there, we are rolling relapse refractory patients across a range of different tumor types. And so we are very pleased that we will be presenting some of the early results of that trial. Also coming up later this weekend. What we are able to see is how the mechanism of intertumoral administration of NKTR-262 can really impact the innate immune system, draw innate immune cells into the tumor and then, in combination with NKTR-214, can drive systemic immune responses. So we'll be presenting both the clinical update and in addition to that, also additional preclinical data as well as we continue our investigations of those 2 agents.

Okay, and could you remind me how you define relapse and refractory to PD-1?

Yes, so these are patients who, for example, in melanoma have been our prior checkpoint inhibitor and progressed according to our protocol. We show that the patient has progressed on 2 prior scans before enrolling and treating the patients on NKTR-262 plus NKTR-214. And the same eligibility criteria applies in our PIVOT-02 program.

(Operator Instructions) And our next question comes from Andy Hsieh from William Blair.

Again my question will be for Mary and it has to do with the 3 pivotal RCC trials that has either started or under the planning phase. So first one has to do with the first of 3 RCC trials. I'm just wondering the reason behind including ORR -- which is not an approvable endpoint in RCC -- as one of the co-primary endpoints. Because if you include that, obviously that would split the power. Just wondering what the rationale of including that was? And related to that, in terms of the comparator arm, cabo and Sutent, obviously, those 2 are standard of care. But I think, you know, from a market share perspective, pazopanib is actually used more in the front line setting. So wondering why that agent wasn't really included in the trial?

Andy, this is Mary. Thanks for your question. So when you split your alpha, we've only allocated a very small proportion of our alpha to objective response rate. And when you do that, it allows you to include in your label the results from the comparison of the ORR, so just to clarify that. And then you could bring a bunch of GU oncologists in the room, and you will have varying input from these GU oncologists as to their TKI of choice. We did bring together a steering committee of folks led by Dr. Tannir from MD Anderson, and this was the recommendation of the oncology community. And going in a global trial, Sutent is commonly used in countries outside the United States, which is why that's one of the 2 TKIs included in the study.

Got it. That totally makes sense. Related to that, I think the third trial that you talked about, which is the one that's inclusive of a TKI. Did you discuss how that will be chosen? Is that dealer's choice? Obviously, there's a lot of IO-TKI combinations out there, so it's a little bit harder right now to foresee what will be used more as that market matures over time.

Yes. So in this study, we actually in the Phase I part are looking at more than 1 TKI. And we'll make a decision following the Phase I part of that trial as to which one to take forward into the registrational pivotal part of the study.

And that will conclude our question-and-answer session for today's conference. I would now like turn the call back over to Howard Robin for any closing remarks.

Well, thank you everyone for joining us this afternoon. And as always, I want to thank the Nektar employees for the incredible progress that they've made in developing medicines to treat devastating diseases. And we look forward to seeing all of you at SITC. Thank you very much.

Ladies and gentlemen, thank you for participating in today's conference. This does conclude the program, and you may all disconnect. Everyone, have a wonderful day.