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Moreover, our other earlier-stage clinical programs including our MTA cooperative PRMT5 inhibitor and our KRAS enabling SOS1 inhibitor showed tremendous progress. Furthermore, we have a potentially transformational opportunity on the horizon with Sitravatinib in lung cancer in combination with PD-1. We believe this pipeline has vast potential to create significant value for our shareholders. Alongside the development of these programs, we have built a scalable and synergistic commercial organization, particularly in lung cancer. At present, our US commercial team is exclusively focused on launching KRAZATI. Furthermore, Mirati remains disciplined in how we deploy and invest our capital. We continue to focus on the combination of clinical data analysis and the corresponding commercial opportunity to drive our investment decisions.

Looking back, 2022 was a year of remarkable execution and major achievements for Mirati. Key clinical highlights include accelerated approval for KRAZATI in the US in second line and beyond KRAS G12C mutated non-small cell lung cancer. Best in class intracranial response rates with adagrasib in patients with active and untreated CNS metastases, differentiated clinical data demonstrating adagrasib plus PD-1 combination is safe and tolerable with promising early signs of efficacy. Broader potential in third-line and beyond colorectal cancer indication for the combination of adagrasib and cetuximab. An investigational new drug application for MRTX1133, our first-in-class oral KRASG12D selective inhibitor, advancement of MRTX1719, our MTA cooperative PRMT5 precision medicine for people with an MTAP-deleted tumor.

And MRTX0902, our potential first-in-class SOS1 KRAS signaling modify our program into clinical trials. Looking ahead, 2023 is a year where several important upcoming catalysts and ambitious goals, which we will detail on today's call. We'll start with an overview of the KRAZATI launch, which is off to a strong start. I'll now turn the call over to Ben, who will provide you with an update on our early commercial experience. Ben?

Ben Hickey: Thank you, David and good afternoon, everyone. I'm pleased to report that we're off to a strong start to the launch of KRAZATI. As a reminder, KRAZATI was approved in mid-December right before the holiday season. Therefore, I will limit my comments to that brief fourth quarter timeframe. I look forward to giving a more detailed update on our first quarter earnings call. Our initial launch experience has been very positive and we're confident that we can successfully deliver on our commercial goals. As a reminder, our US commercialization team has specific and extensive experience in lung cancer, supporting multiple launches. This includes a fully-integrated team of market access sales, digital marketing and medical affairs.

The team has already had extensive high quality interactions with key target accounts and are focused on ensuring an industry-leading experience for physicians and patients. For example, initial patients treated in December are receiving treatment with an approximately five days of a prescription being written versus industry analogs of closer to 10 days. And our unique patient and physician-centric approach to distribution and our patient access programs have been well received. We continue to leverage our experience in the community setting where over 40% of our pivotal study was enrolled and where nearly 80% of KRAS G12C patients are treated. From an access and coverage perspective, we are pleased with our initial progress. KRAZATI was included in NCCN guidelines within one week of approval, which is exceptionally fast and helps from a coverage and reimbursement perspective, particularly with Medicare patients.

Overall, we've made strong initial progress in establishing broad reimbursement coverage with no significant access restrictions to date. Our interactions with physicians have been positive on our key messages centered around a 44% response rate and 14.1 months of median overall survival as demonstrated in a pooled analysis of Phase 1 and Phase 2 non-small cell lung cancer patients and low treatment-related discontinuation rates are resonating well. Additionally, data showing KRAZATI's activity in patients with central nervous system metastasis has been favorably received by physicians who recognize the importance for the approximately 40% of patients known to have CNS metastases. The second line KRAS G12C non-small cell lung cancer market is significantly under-developed.

As a result, our team continues to focus on markets expansion priorities such as increasing both testing and identification of KRAS G12C eligible patients, particularly in the community setting. We estimate with a KRAS G12C testing rate at the time of diagnosis is approximately two-thirds while testing rates for EGFR and ALK mutations are closer to 85%. So, there is a significant opportunity to grow the market and meaningful opportunities to better identify patients with a KRAS G12C mutation at the local account level where we've established partnerships with community oncology providers. In summary, we believe that the important differentiating clinical characteristics of KRAZATI combined with an experienced and focused commercialization organization position KRAZATI to ultimately become the market leading KRAS G12C inhibitor.

Our commercialization team has a singular focus, delivering KRAZATI to the physicians and patients who could benefit from it. I look forward to providing additional information as our launch progresses. I'll now turn the call over to Alan for an update on our clinical activities. Alan?

Alan Sandler: Thanks Ben and hello everyone. I'll begin by discussing adagrasib starting with non-small cell lung cancer. In first-line non-small cell lung cancer, we expect to share key updates across our multipronged development approach this year. As a reminder, our initial and most advanced adagrasib combination approach in first-line non-small cell lung cancer is the concurrent dosing of adagrasib with pembrolizumab. Our experience with this combination provides us with confidence in the path forward based on three key points. First, there is a strong scientific rationale for improved durable outcomes with the combination relative to the existing first-line standard of care. Second, adagrasib in combination with pembrolizumab has demonstrated a safe and tolerable profile.

And third, while the efficacy outcomes are still maturing, they are compelling and we look forward to evaluating the clinical outcomes with additional follow-up and more patient data on later this year. Overall, the advancement of our first-line non-small cell lung cancer strategy will continue to be informed by data from ongoing clinical studies. We expect to provide an update in the second half of this year, which will include a first look at durability measures such as duration of response and potential six-month landmark PFS analysis. Within the KRYSTAL-7 study, we are also evaluating adagrasib as a monotherapy in patients with TPS score of less than 1%. In addition to the KRYSTAL-7 combination update in the second half of 2023, we will also provide an update on the first-line monotherapy data and next steps at that time.

Part of our multipronged first-line development approach, we are also evaluating adagrasib in combination with KEYNOTE-189 regimen of carboplatin, pemetrexed and pembrolizumab, which is enabled by the tolerability profile we seeing with adagrasib plus pembrolizumab. The Phase 1b-2 study evaluating this combination has been initiated as part of the KRYSTAL-17 study with an initial focus on the safety and tolerability of the combination. Finally, beyond the US, we are continuing to advance discussions with the European Medicines Agency on their review of adagrasibs marketing authorization application and anticipate potential approval in the third quarter. I'll now move to colorectal cancer where we have several important upcoming milestones. Adagrasib in combination with cetuximab has shown a compelling and differentiated profile and is our primary approach in colorectal cancer moving forward.

Photo by National Cancer Institute on Unsplash

In the most recent results, which are representative at ESMO in September of last year, the combination demonstrated a response rate of 46% and a median progression-free survival of 6.9 months. Notably, these results suggest the potential for a substantial improvement compared to the current standard of care of regorafenib or chemotherapy, which have very poor outcomes with low-single digit response rates and progression-free survival of only approximately two months. Based on recent input from the FDA, we will be moving forward with an accelerated approval pathway for the combination of adagrasib plus rituximab in third-line or later colorectal cancer. We expect to submit the supplemental NDA in the fourth quarter. Our KRYSTAL-10 Phase III registrational study in second-line colorectal cancer patients evaluating the same combination of adagrasib plus cetuximab versus chemotherapy continues to enroll well.

We expect to achieve full enrollment of KRYSTAL-10 by year-end and we anticipate reporting the final analysis of progression-free survival with interim overall survival in 2024 with plans for regulatory submission based on these results. In addition, other important development opportunities for adagrasib include pancreatic adenocarcinoma, cholangiocarcinoma, non-colorectal gastrointestinal malignancies and other solid tumors harboring the KRAS G12C mutation. We plan to present updated data in these tumor types at a medical meeting in the second quarter. I'll now briefly touch on Sitravatinib, which is being studied in a registrational Phase 3 study called SAPPHIRE. SAPPHIRE is on track for a topline final analysis for overall survival in the second quarter of this year.

While we remain blinded to the ongoing study, we believe it was sufficiently powered to demonstrate both statistically significant and clinically meaningful outcomes. With that, I'll turn the call over to Jamie for an update on our earlier stage development pipeline.

James Christensen: Thank you, Alan. Today, I will cover progress on our early clinical pipeline assets, MRTX1133, MRTX1719 and MRTX0902. I'll begin with MRTX1133, our highly potent selective and potentially first-in-class oral KRASG12D inhibitor, which targets both the active and inactive states of the KRASG12D mutant protein. The KRASG12D mutation is predominantly associated with poor outcomes on standard therapy in several types of cancer. We estimate that just within pancreatic, colorectal, endometrial and non-small cell lung cancers, there is a prevalence of approximately 180,000 patients with KRASG12D mutations in the US and Europe. We believe that MRTX1133 has the potential to be an impactful treatment option for these underserved patients.

We filed an IND for MRTX1133 and received clearance from the FDA in January. Activation of clinical trial sites is underway and enrollment of first patients in the Phase 1/2 study will begin this quarter. The study is designed to evaluate the safety, tolerability PK-PD and anti-tumor activity of MRTX1133 in patients with advanced solid tumors that harbor on KRASG12D mutation. The study will utilize the formulation designed to enhance oral absorption and increase systemic drug exposure. Positive attributes of MRTX1133 includes subnanomolar potency in tumor cells, high plasma free fraction, long targeted residence time and a long plasma half-life of greater than 50 hours. These attributes are all consistent with a low target plasma concentration threshold for maximal target coverage for the full duration of the dosing cycle.

This has increased our confidence in the successful development path for MRTX1133. MRTX1133 has the potential to provide a transformative treatment option for the large and underserved KRASG12D patient population. Now moving on to MRTX1719, our potentially best-in-class MTA cooperative PRMT5 inhibitor. MRTX1719 is enrolling in a Phase 1/2 clinical study for patients harboring MTAP gene deletion. An MTAP gene deletion occurs in approximately 10% of all human cancers. This translates to greater than 200,000 patients in the US and European Union annually. While MRTX1719 has the potential to address a wide range of tumor types, initial priorities for our development program will include pancreatic cancer, lung cancer, mesothelioma and malignant peripheral nerve sheath tumors.

MRTX1719 has demonstrated promising preclinical data in these tumors and the potential to make a significant difference in treatment outcomes in these particularly difficult to treat tumor types. This may enable a rapid development path. Now as a reminder, MRTX1719 selectively binds to the PRMT5 MTA complex. This complex is uniquely present only in tumor cells harboring an MTAP gene deletion. This results in extensive selectivity for our education of MTAP-deleted tumor cells compared with normal cells. The wide therapeutic index and ability to safely achieve near complete target inhibition with MRTX1719 provides a clearly differentiated therapeutic mentality compared with first generation non-selective PRMT5 inhibitors, which were limited by mechanism-based bone marrow and systemic toxicities.

Finally, the greater than 70 fold selectivity of MRTX1719 is potentially the highest selectivity ratio for MTAP-deleted tumor cells relative to other reported PRMT5 MTA complex inhibitors. Our early clinical experience in the Phase 1 study has been encouraging. PK and systemic exposure are consistent with expectations to achieve therapeutically meaningful drug concentrations based on our preclinical projections without the associated 50 challenges that limited the utility of prior generation PRMT5 inhibitors. Also as a reminder, we were granted Fast Track designation for MRTX1719, which reflects the strength of our preclinical data and the potential for this agent to have a positive impact on these patients who have limited treatment options.

We plan to share the initial clinical data in the second half of 2023. The focus of this update will be add safety and tolerability with the potential to also report early signs of clinical activity. Finally, we initiated a Phase 1 study for MRTX0902, our first-in-class SOS1 inhibitor. Preclinical data have demonstrated that MRTX0902 has the potential to enhance the activity of adagrasib and as an example of our strategy to maximize the value of our KRAS portfolio, by pursuing a broad range of KRAS targeting strategies and indications. We expect to initiate dose escalation cohorts combining MRTX0902 and adagrasib and are presently ongoing Phase 1/2 clinical study in the second half of this year. In addition, compelling preclinical research support the utility of MRTX0902 in augmentation of EGFR inhibitors and EGFR mutated lung cancers.

Other KRAS pathway inhibitors and RAS mutated cancers, including the possibility of KRAS mutant allele-specific inhibitors such as MRTX1133. Overall, we pleased with the significant progress we've made across our portfolio and look forward to providing additional updates in the near future. With that, I'll turn the call over to Laurie.

Laurie Stelzer: Thank you, Jamie. I will begin by walking through our income statement and touching on a few other key financial metrics. Please see our press release from earlier this afternoon for additional details about our fourth quarter and full year 2022 financial results. Revenue for the fourth quarter of 2022 was $0.9 million, which was driven by $0.7 million of KRAZATI sales and $0.2 million of licensing and collaboration revenues. This compares to revenue of $0.3 million for the fourth quarter of 2021, which consisted solely of license and collaboration revenues. As a reminder KRAZATI was approved in mid-December, shortly before the holiday season. Of the $0.7 million of KRAZATI sales in the fourth quarter, a majority was associated with inventory in the channel.

Research and development expenses for the fourth quarter of 2022 were $141.2 million compared to $153.8 million for the same period in 2021. The decrease is primarily driven by a reduction in manufacturing costs for the adagrasib program following our 2021 NDA filing, partially offset by an increase in headcount related costs including share-based compensation and salaries associated with the growth of our headcount to support our growing portfolio. Selling, general and administrative expenses for the fourth quarter of 2022 were $70.8 million compared to $43.5 million for the same period in 2021. The increase is primarily due to an increase in head count related costs including share-based compensation and salaries and commercial readiness costs as we prepared for the commercial launch of KRAZATI.

Net loss for the fourth quarter of 2022 was $202.5 million or $3.51 per share basic and diluted, compared to what net loss of $199.6 million or $3.72 million per share basic and diluted for the same period in 2021. We ended the fourth quarter with approximately $1.1 billion in cash, cash equivalents and short-term investments, which gives us a cash runway into 2025. Cash burn from operations was $570.6 million for the full year of 2022. We recognize that a disciplined data-driven approach to capital deployment is critical as we advance our pipeline, invest in innovation and effectively launch products to drive sustainable long-term growth. We have focused our investments on our highest priority opportunities, those that have the greatest potential to benefit patients, create value and drive shareholder returns.

We will continue to manage expenses closely and we expect our 2023 cash burn from operations to annualize within a similar range as 2022. Our 2023 cash burn expectations include the partial offset to spend we'll achieve from sales from the launch of KRAZATI. Finally, we are actively exploring ex-US partnerships as a source of capital and risk sharing, and as a means of enhancing and accelerating our portfolio. And with that, I'll hand it back over to David.

David Meek: Thank you, Laurie. Before opening the call for questions, let me conclude by saying how pleased I am with the considerable progress our team has made in 2022 as we delivered on our objectives across the key facets of the business. I'm proud of the work this team has accomplished thus far to execute on our mission, but we know our work is far from complete. We believe Mirati is very well positioned for future success and value creation. KRAZATI combined with our clinical pipeline addresses patient populations amounting to a multi-billion dollar potential market opportunities and our commercial organization had also a great start. We also have multiple near-term catalysts and we expect the case for KRAZATI to only strengthen over time as our adagrasib data matures.

We also has the Sitravatinib Phase 3 overall survival readout, initial clinical data for MRTX1719 and MRTX1133 entering the clinic with initial data expected in the first half of next year. In addition, we expect strong progress across the rest of our innovative pipeline of programs that can serve hundreds of thousands of patients with unmet needs. If just one or two of our earlier stage programs demonstrate meaningful clinical activity, we expect it will have a substantial impact on the valuation of the company. As such, we are excited about our future and expect 2023 will be another standout year of execution and progress on our goals. On behalf of all of us at Mirati, we thank you for your continued support and interest in the company. And with that, Cynthia, we are ready to open the call for questions.

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