8-K

UNITED STATES

SECURITIES AND EXCHANGE COMMISSION

Washington, D.C. 20549

___________________________

FORM 8-K

___________________________

CURRENT REPORT

Pursuant to Section 13 or 15(d)

of the Securities Exchange Act of 1934

Date of Report (Date of earliest event reported):  January 9, 2023

___________________________

G1 THERAPEUTICS, INC.

(Exact name of registrant as specified in its charter)

___________________________

Delaware	001-38096	26-3648180
(State or other jurisdiction of incorporation)	(Commission File Number)	(IRS Employer Identification No.)

700 Park Offices Drive Suite 200 Research Triangle Park, NC	27709
(Address of principal executive offices)	(zip code)

Registrant’s telephone number, including area code: (919) 213-9835

___________________________

Check the appropriate box below if the Form 8-K filing is intended to simultaneously satisfy the filing obligation of the registrant under any of the following provisions:

o Written communications pursuant to Rule 425 under the Securities Act (17 CFR 230.425)

o Soliciting material pursuant to Rule 14a-12 under the Exchange Act (17 CFR 240.14a-12)

o Pre-commencement communications pursuant to Rule 14d-2(b) under the Exchange Act (17 CFR 240.14d-2(b))

o Pre-commencement communications pursuant to Rule 13e-4(c) under the Exchange Act (17 CFR 240.13e-4(c))

Securities registered pursuant to Section 12(b) of the Act:

Title of each class	Trading Symbol	Name of each exchange on which registered
Common stock, $0.0001 par value	GTHX	The Nasdaq Stock Market

Indicate by check mark whether the registrant is an emerging growth company as defined in Rule 405 of the Securities Act of 1933 (17 CFR §230.405) or Rule 12b-2 of the Securities Exchange Act of 1934 (17 CFR §240.12b-2).

Emerging Growth Company o

If an emerging growth company, indicate by check mark if the registrant has elected not to use the extended transition period for complying with any new or revised financial accounting standards provided pursuant to Section 13(a) of the Exchange Act. o

Item 7.01    Regulation FD Disclosure.

Attached to this Current Report on Form 8-K as Exhibit 99.1 is a presentation (the “Presentation”), which is incorporated herein by reference. The Company will use the Presentation in various meetings with securities analysts, investors, and others beginning January 9, 2023.

Pursuant to General Instruction B.2 of Current Report on Form 8-K, the information contained in, or incorporated into, Item 7.01, including the Presentation attached hereto as Exhibit 99.1, is being furnished and shall not be deemed “filed” for the purposes of Section 18 of the Securities Exchange Act of 1934, as amended (the “Exchange Act”), or otherwise subject to the liabilities of that section, nor shall it be deemed incorporated by reference into any registration statement or other filing under the Securities Act of 1933, as amended, or the Exchange Act, except as shall be expressly set forth by specific reference to such filing.

Item 9.01    Financial Statements and Exhibits.

(d)Exhibits

Exhibit No.	Description
99.1	Presentation dated January 2023
104	Cover Page Interactive Data File (embedded within the Inline XBRL document)

SIGNATURES

Pursuant to the requirements of the Securities Exchange Act of 1934, the Registrant has duly caused this report to be signed on its behalf by the undersigned thereunto duly authorized.

	G1 THERAPEUTICS, INC.
	By:	/s/ James Stillman Hanson
		James Stillman Hanson
		General Counsel
Date: January 9, 2023

EX-99.1

1 41st Annual J.P. Morgan Healthcare Conference Wednesday January 11, 1:30 PM PT Advancing our Mission to Improve the Lives of those Affected by Cancer

2 This presentation contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Words such as "may," "will," "expect," "plan," "anticipate," "estimate," "intend" and similar expressions (as well as other words or expressions referencing future events, conditions or circumstances) are intended to identify forward-looking statements. Forward- looking statements in this presentation include, but are not limited to, those relating to expectations for the commercial success of COSELA® (trilaciclib), our ability to accelerate adoption of COSELA in the treatment of small cell lung cancer, the therapeutic potential of trilaciclib in the treatment of colorectal cancer, triple negative breast cancer, and other cancers, our ability to generate data to maximize trilaciclib’s applicability to future treatment paradigms, and our reliance on partners to globally develop and commercial licensed products. In addition, COSELA may fail to achieve the degree of market acceptance for commercial success, and the impact of pandemics such as COVID-19 (coronavirus), are based on our expectations and assumptions as of the date of this presentation. Each of these forward-looking statements involves risks and uncertainties. Factors that may cause our actual results to differ from those expressed or implied in the forward-looking statements in this presentation are discussed in our filings with the U.S. Securities and Exchange Commission, including the "Risk Factors" sections contained therein and include, but are not limited to, our ability to successfully commercialize COSELA; our ability to complete clinical trials for, obtain approvals for and commercialize additional indications of COSELA and any of our product candidates other than COSELA; our initial success in clinical trials may not be indicative of results obtained when these trials are completed or in later stage trials; the inherent uncertainties associated with developing new products or technologies and operating as a commercial-stage company; and market conditions. Lerociclib is not approved by the FDA. Except as required by law, we assume no obligation to update any forward-looking statements contained herein to reflect any change in expectations, even as new information becomes available. Forward-Looking Statements G1Therapeutics® and G1Therapeutics logo and COSELA® and COSELA logo are trademarks of G1 Therapeutics, Inc. ©2022 G1 Therapeutics, Inc. For Investor Use Only

3 Evolution of G1: Building Upon Unique Product - Trilaciclib Original Premise Unique Product Initial Indication Robust OS in TNBC Dual Benefits To protect HSPCs from damage caused by chemo through transient G1 arrest Rationally designed and optimized a unique IV transient CDK4/6 inhibitor Demonstrated robust myeloprotection across three randomized SCLC studies Improved survival in randomized trial consistent with immune-modulation Aggressively investigating dual benefit impact across multiple tumor types Transient arrest in G1 Phase HSPCs Potential to improve overall survival through:OS hazard ratios in Ph2: 0.31 – 0.40 Maximizing the dual benefits of trilaciclib with the potential to improve overall survival Enhanced anti-tumor immunity2 Increased cytotoxic exposure 1 For Investor Use Only

4 2023: Establishing the Foundation for Near-Term Growth • 1L CRC: February 2023 pivotal / 4Q 2023 PFS data; large opportunity with potential launch in early 2024 • 1L TNBC: 2H 2023 pivotal readout; high confidence based on Ph. 2 data with potential launch in late 2024 • 2L / 3L TNBC (ADC): Initial efficacy data expected in 2Q 2023; preliminary data suggests reduced AEs • Neoadjuvant TNBC (MOA): Pathologic CR data expected in 2Q 2023; initial data supported immune MOA • 1L mUC: Longer term anti-tumor efficacy endpoints, including PFS and DOR, expected in mid-2023 • COSELA trial usage at key accounts has been encouraging but limited depth remains a challenge • Refocusing commercial resources on largest opportunities to drive increased depth • Planning to secure a partner for global expansion (beyond U.S. and China) in 2023 • Evaluating additional late-stage studies for 2H 2023 initiation; pursuing research next generation products • Strengthened financial position heading into data-rich period with $52.4M net proceeds from 4Q 2022 offering Two meaningful near-term commercial opportunities Ph2 readouts to inform additional pivotal studies Considerable growth potential remaining in ES-SCLC market Positioning company for global expansion and long-term growth For Investor Use Only Note: CRC: Colorectal cancer; TNBC: Triple negative breast cancer; MOA: Mechanism of Action; mUC: Metastatic urothelial carcinoma; PFS: Progression free survival; CR: Complete response: DOR: Duration of response.

5 Myeloprotection: Protecting Bone Marrow from Cytotoxic Damage Trilaciclib helps protect HSPCs and myeloid and lymphoid cell lineages from damage caused by cytotoxic therapy - providing multiple potential benefits Hematopoietic tree adapted from ‘Hematopoietic Tree, Plasma Cell’, National Cancer Institute Visuals Online: https://visualsonline.cancer.gov/details.cfm?imageid=7177 1. Weiss J, et al. Ann Oncol. 2019 Oct; 30(10): 1613–1621. 2. He S, et al. Sci Transl Med. 2017;9:eaal3986. 3. Bisi JE, et al. Mol Cancer Ther. 2016;15:783-93. Bone Marrow Hematopoietic stem cells Lymphoid progenitor cell Myeloid progenitor cell Neutrophil B lymphocyte Natural killer cell Erythrocytes Platelets Myeloblast Lymphoblast Eosinophil Basophil T lymphocyte Granulocytes  Improves patients’ QoL  Decreases rescue interventions, hospitalizations, associated costs  Protects immune system function from damage by cytotoxic therapy  Enables patients to tolerate greater exposure to cytotoxic therapy Potential Benefits of Myeloprotection For Investor Use Only

6 Favorably Alters Tumor Microenvironment Cancer immunity cycle graphic adapted from Chen & Mellman. Oncology Meets Immunology: The Cancer-Immunity Cycle. Immunity. 2013;39(1):1-10. doi:10.1016/j.immune.2013.07.012. 1. Goel S, DeCristo MJ, et al. CDK4/6 inhibition triggers anti-tumour immunity. Nature. 2017. 2. Deng J, Wang ES, Jenkins RW, et al. CDK4/6 inhibition augments antitumor immunity by enhancing T-cell activation. Cancer Discov. 2018;8(2):216-233. doi:10.1158/2159-8290.CD-17-0915. 3. Uzhachenko R, et al. Metabolic modulation by CDK4/6 inhibitor promotes chemokine-mediated recruitment of T cells into mammary tumors. Cell Rep. 2021;35(1):108944/j.celrep.2021.108944. 4. Lai AY, et al. CDK4/6 inhibition enhances antitumor efficacy of chemotherapy and immune checkpoint inhibitor combinations in preclinical models and enhances T-cell activation in patients with SCLC receiving chemotherapy. Journal for ImmunoTherapy of Cancer. 2020; 8:e000847. doi:10.1136/ jitc-2020-000847. 5. Lelliott EJ, et al. CDK4/6 Inhibition Promotes Antitumor Immunity through the Induction of T-cell Memory. Cancer Discov. 2021 Oct;11(10):2582-2601. DOI: 10.1158/2159-8290.CD-20-1554; and Heckler M, Ali LR, et al. Inhibition of CDK4/6 promotes CD8 T-cell memory formation. Cancer Discov. 2021 Oct;11(10):2564-2582. doi: 10.1158/2159-8290.CD-20-1540 Potential to Enhance Anti-Tumor Immunity 1 Release of Cancer Cell Antigens 3 Priming and Activation 4 Trafficking of T Cells to Tumors 2 Cancer Antigen Presentation 5Infiltration of T Cells into Tumors 6Recognition of Cancer Cells by T Cells 7Killing of Cancer Cells IL-2 & IFN-γ Secretion2 MHC-1 Upregulation1 Enhances T Cell Activation Immunosuppressive Cell Populations2,4 (Tregs and MDSCs) CCL5/CXCL9/CXCL10 Chemokines2,3 Memory T Cells5 Improves Long-Term Immune Surveillance Mechanistic Roles of Trilaciclib Cancer Immune Cycle 1 2 3 Trilaciclib enhances multiple immunological processes – providing synergistic benefit in combination with chemotherapy, ADCs and checkpoint inhibitors For Investor Use Only

7 Trilaciclib Opportunity Marketed Product Providing Pipeline-in-a-Molecule ES-SCLC + Milestones and Royalties 1L CRC 1L Bladder (PD-L1 Combo) Registrational Phase 3 Trials Phase 2 Trials 1L TNBC 2L/3L TNBC (ADC Combo) Neoadj TNBC (MOA Study) TBD 1L NSCLC (PD-1/L1 Combo) Initial results2 expected in February 2023 Initial results3 expected in 2H 2023 Other Expansion Areas (e.g., new tumor types, combinations, settings) 1. COSELA is marketed in the U.S. by G1 and conditionally approved in Greater China to be marketed by our partner, Simcere conditionally approved in Greater China to be marketed by our partner, Simcere. Trilaciclib is an investigational drug in all other indications and its safety and efficacy has only been established in ES-SCLC 2. 1L CRC data readout in 1Q 2023 expected to include results for myeloprotection and early indicators for anti-tumor efficacy: Initial PFS expected 4Q 2023 3. 1L TNBC data readout in 4Q 2023 expected to include interim results for Overall Survival (OS); event-driven interim OS analysis to be conducted by its DMC in 4Q 2023 Planning stages for potential 2023 initiations Marketed1 ES-SCLC (lurbinectedin) PFS and duration of response data expected midyear 2023 Pathologic complete response (pCR) results expected in 2Q23 Investigator- sponsored study (ISS) Initial data readouts began in 4Q2022 Initial data readouts beginning in 2023 Initial efficacy results expected in 2Q23 Initial results released in 4Q22 Initial results released in 1Q23 Initial results at 2022 SABCS For Investor Use Only

8 Phase 3 Data in 2023: CRC and TNBC

9 1L CRC: Significant Near-Term Opportunity  Chemotherapy remains primary backbone for mCRC - Majority of patients have microsatellite stable (MSS) tumors - ~47k annual first-line drug-treated MSS CRC patients in the U.S  FOLFOXIRI only used in ~10% to ~20% of U.S. patients - Most efficacious regimen but currently limited due to toxicities - Typically reserved for younger healthier patients with larger tumors  Significant potential to expand FOLFOXIRI usage - Meaningfully reducing adverse events would address critical hurdle - Further increasing efficacy would be transformative advancement 315K Patients with Active Disease 152K Patients with Active Metastatic Disease 47K First-Line Drug- Treated Patients (MSS) U.S. CRC Patient Population (2021)1 1. Estimates from Kantar Health CancerMPact Patient Metrics, and internal research and analysis Trilaciclib has potential to optimize the tolerability and efficacy of FOLFOXIRI and meaningfully improve care for patients living with metastatic CRC For Investor Use Only

10 FOLFOXIRI: Most Efficacious; Tolerability Issues Limit Use 1. Meta -analysis: Cremolini C, et al. Individual Patient Data Meta-Analysis of FOLFOXIRI Plus Bevacizumab Versus Doublets Plus Bevacizumab as Initial Therapy of Unresectable Metastatic Colorectal Cancer. J Clin Oncol 2020;38:3314 -3324 2. Note: Grade 4 neutropenia ~19% for FOLFOXIRI + bevacizumab and ~7% for doublet + bevacizumab based on TRIBE2 results (Cremolini, et al. Upfront FOLFOXIRI plus bevacizumab and reintroduction after progression versus mFOLFOX6 plus bevacizumab followed by FOLFIRI plus bevacizumab in the treatment of patients with metastatic colorectal cancer (TRIBE2): a multicentre, open-label, phase 3, randomised, controlled trial. Lancet Oncol 2020; 21: 497–507. FOLFOXIRI + bevacizumab1 (N = 846) Doublet + bevacizumab1 (N = 851) P Value1 Efficacy Data: ORR 64.5% 53.6% <.001 Median PFS 12.2 9.9 <.001 Median OS 28.9 24.5 <.001 Most Common Adverse Events: (Grade 3 - 4 AEs occurring > 5%) Neutropenia2 45.8% 21.5% <.001 Diarrhea 17.8% 8.4% <.001 Arterial Hypertension 7.8% 7.8% .938 Febrile Neutropenia 6.3% 3.7% .019 Nausea 5.5% 3.0% .016 Venous Thromboembolism 5.5% 5.7% .892 Mucositis 5.1% 2.9% .024 For Investor Use Only

11 Ongoing Ph3 First-Line CRC Pivotal Trial: PRESERVE 1 P R I M A R Y E N D P O I N T: Myeloprotection: SN during Induction & DSN Cycles 1-4 SECONDARY ENDPOINTS: PRO, PFS, OS ENROLLMENT COMPLETED: 326 participants Myeloprotection results in February 2023; Initial PFS expected 4Q 2023 Evaluating trilaciclib prior to FOLFOXIRI/bevacizumab in 1L CRC (pMMR/MSS) patients Cycle X Day 2 Cycle X Day 1 Cycle X Day 2 Cycle X Day 1 Cycle X Day 14 R an do m iz at io n 1: 1 placebo + CI FU Treatment Phase placebo + FOLFOXIRI + bevacizumab trilaciclib + FOLFOXIRI + bevacizumab trilaciclib + CI FU Induction Phase 14-day cycles Maintenance Phase 14-day cycles placebo + bev + CI FU placebo + CI FU trilaciclib + bev + CI FU trilaciclib + CI FU Maximum of 12 cycles Until Progression Positive myeloprotection results enables sNDA submission; initial PFS data likely available prior to any future launch For Investor Use Only

12 Three Key Areas for 1L CRC February Data Readout Impact on Severe Neutropenia Additional Tolerability Benefits Potential for Improving Survival • Primary Endpoints – Achieving myeloprotection endpoints enables sNDA submission • Grade 3 or 4 Diarrhea – Reducing severe diarrhea would improve FOLFOXIRI tolerability • Patient Reported Outcomes – Potential for patients to feel meaningfully better while on treatment • Treatment Exposure – Increasing exposure/duration could signal potential for improved PFS / OS February data readout will clarify the overall opportunity in 1L CRC 1 2 3 For Investor Use Only

13 Potential to Become Standard of Care in 1L CRC First-Line CRC Treated Patients (MSS) U.S. Patients by Standard 1L Treatment Option Patients Receiving FOLFOXIRI + bevacizumab (~10% - 20% of patients) Patients Receiving Doublet + anti-EGFR (~10% - 20% of patients) Patients Receiving Doublet + bevacizumab (~60%+ of patients) Trilaciclib could optimize the most efficacious treatment regimen with potential to improve tolerability and increase survival With Improved Tolerability With Improved Tolerability and Survival Note: Figure above is for illustrative purposes. Target patient population for Trilaciclib + FOLFOXIRI / bevacizumab with improved tolerability alone Target patient population for Trilaciclib + FOLFOXIRI / bevacizumab with improved tolerability and survival For Investor Use Only

14 1L TNBC: Important Area of High Unmet Need Potential to meaningfully increase overall survival across 1L TNBC subpopulations 55K Patients with Active Disease 20K Patients with Active Metastatic Disease 9K First Line Drug- Treated Patients U.S. TNBC Patient Population (2021)1  TNBC tumors are aggressive and difficult to treat - Categorized by lack of HR expression and HER2 gene amplification - Trilaciclib demonstrated robust survival benefit with chemo in Ph2  Chemo +/- targeted therapy remains first-line TNBC SoC - ~9k annual first-line drug treated TNBC patients in the U.S. - Targeted therapies only demonstrated benefit in subpopulations  Trilaciclib demonstrated broad benefit in Randomized Phase 2 - Benefit observed across PD-(L)1+ and PD-(L)1- subpopulations - Patients receive 4 vials of trilaciclib for each 3-week cycle 1. Estimates from Kantar Health CancerMPact Patient Metrics, and internal analysis and primary research For Investor Use Only

15 Observed Robust OS Improvement in mTNBC Foundational Data for PRESERVE 2: Completed Randomized Phase 2 Trial 1. O'Shaughnessy et al., 2020 San Antonio Breast Cancer Symposium (SABCS), Poster #PD1-06. Note: primary endpoints relating to reduction in severe neutropenia not achieved in this study. 2. Patients randomized to receive gem/carbo chemotherapy only (Group 1) or gem/carbo plus one of two dosing schedules of COSELA: COSELA administered on the day of chemotherapy (Group 2) or COSELA administered the day prior to and the day of chemotherapy (Group 3). Fast Track Designation granted as a result of these data (July 2021) Treatment Group2 Median OS, months Hazard Ratio (95% CI) P Value Group 1: (gem/carbo) 12.6 - - Group 2: (gem/carbo + trilaciclib) Not Reached 0.31 (0.15-0.63) 0.0016 Group 3: (gem/carbo + trilaciclib) 17.8 0.40 (0.22-0.74) 0.0004 Overall Survival in Intent-to-Treat Population1 Group 1 (gem/carbo)2 Group 3 (trilaciclib + gem/carbo)2 Group 2 (trilaciclib + gem/carbo)2 For Investor Use Only

16 Overall Survival Most Significant Effect in mTNBC Study Randomized Phase 2: Combination with Chemotherapy 1. O'Shaughnessy et al., 2020 San Antonio Breast Cancer Symposium (SABCS), Poster #PD1-06. Note: primary endpoints relating to reduction in severe neutropenia not achieved in this study. 2. Patients randomized to receive gem/carbo chemotherapy only (Group 1) or gem/carbo plus one of two dosing schedules of trilaciclib : trilaciclib administered on the day of chemotherapy (Group 2) or trilaciclib administered the day prior to and the day of chemotherapy (Group 3). 0.001 0.108 0.235P-Values Greatest Effect Least Effect 29% 43% 0% 25% 50% 75% 100% Best Overall Response R es po ns e R at e M on th s Not Reached Group 1 Group 2 + Group 3 (trilaciclib arms) Trilaciclib demonstrated the most robust effect on OS, consistent with its observed immunomodulatory effects For Investor Use Only

17 OS Improvement Observed, Regardless of PD-L1 Status Overall Survival for PD-L1 Positive Tumors1 Treatment Group2 Patients Median OS (95% CI), Months Hazard Ratio (95% CI) P Value Group 1: (gem/carbo) 17 10.5 (6.3 – 18.8) - - Group 2 and 3: (gem/carbo + trilaciclib) 32 32.7 (17.7 – NR) 0.34 (0.2 – 0.7) 0.004 Overall Survival for PD-L1 Negative Tumors1 Treatment Group2 Patients Median OS (95% CI), Months Hazard Ratio (95% CI) P Value Group 1: (gem/carbo) 10 13.9 (12.6 – NR) - - Group 2 and 3: (gem/carbo + trilaciclib) 26 17.8 (13.1 – NR) 0.48 (0.2 – 1.2) 0.093 Overall Survival improvement was observed regardless of tumor PD-L1 status (greater effect in PD-L1 positive tumors) 1. O'Shaughnessy et al., 2020 San Antonio Breast Cancer Symposium (SABCS), Poster #PD1-06. Note: primary endpoints relating to reduction in severe neutropenia not achieved in this study. 2. Patients randomized to receive gem/carbo chemotherapy only (Group 1) or gem/carbo plus one of two dosing schedules of COSELA: COSELA administered on the day of chemotherapy (Group 2) or COSELA administered the day prior to and the day of chemotherapy (Group 3). For Investor Use Only

18 Ongoing First-Line TNBC Ph3 Pivotal Trial: PRESERVE 2 Pivotal study evaluating trilaciclib in mTNBC building upon robust OS benefit observed in prior randomized Phase 2 study Placebo + gem/carbo on Days 1 and 8 every 21 days until progression trilaciclib + gem/carbo on Days 1 and 8 every 21 days until progression 1L TNBC (checkpoint naive) Initial positive evidence of efficacy across subsets and line of treatment in Phase 2 trial1 Evaluating 1L patients (PD-L1 positive and negative patients) R an do m iz at io n 1: 1 P R I M A R Y E N D P O I N T: Overall Survival SECONDARY ENDPOINTS: PFS, ORR, PRO, myeloprotection measures ENROLLMENT COMPLETE: 187 participants Interim OS analysis at 70% of events expected in 2H 2023 1. O'Shaughnessy et al., 2020 San Antonio Breast Cancer Symposium (SABCS), Poster #PD1-06 For Investor Use Only

19 Ongoing Phase 2 Studies and Future Development

20 1. Demonstrate ability to increase survival across additional tumors3 2. Evaluate if synergistic benefits with a CPI observed preclinically is translatable to humans 1. Evaluate myeloprotection benefits with an ADC (sacituzumab govitecan in this study)1 2. Determine whether increased cytotoxic exposure and potential synergy increases PFS / OS Three Ongoing Phase 2 Proof of Concept Studies 2L / 3L TNBC (Phase 2) 1L Bladder Cancer (Phase 2) Proof of Concept Study Key Goals of Study Related to Trilaciclib 1. Clinically confirm mechanistic effects that appear to be driving increased immunomodulation2 2. Evaluate if there is an anti-tumor efficacy signal in early stage TNBC patients Neoadjuvant TNBC (Phase 2) 1. Preliminary myeloprotection data for first 18 patients announced in press release November 11, 2022 2. Preliminary change in CD8+ T-cell / Treg ratio announced in press release on December 7, 2022 3. Initial data including ORR endpoints announced in press release January 4, 2023 For Investor Use Only

21 Phase 2 ADC Combination Study: 2L/3L Metastatic TNBC Cycle X Day 8 Cycle X Day 1 Cycle X Day 21 Treatment Phase trilaciclib + sacituzumab govitecan-hziy trilaciclib + sacituzumab govitecan-hziy Patients Treated Until Progression P R I M A R Y E N D P O I N T: PFS SECONDARY ENDPOINTS: ORR, CBR, OS, myeloprotection measures TARGET ENROLLMENT: Up to 40 participants PATIENTS TREATED UNTIL PROGRESSION PFS data expected 2Q 2023 Evaluate synergistic combo potential of trilaciclib and sacituzumab govitecan-hziy, each of which have individually demonstrated clinically meaningful OS improvements in TNBC Strong belief in clinical rationale underlying this combination; data generated will be instructive in evaluating future ADC combination possibilities Every 3 months Survival Single Arm: 2L/3L TNBC For Investor Use Only

22 Summary of TEAEs in patients receiving sacituzumab govitecan-hziy*1 Adverse Event Any Grade Grade 3-4 Fatigue 52% 4% Nausea 62% <4% Constipation 37% <1% Diarrhea 65% 11% Headache 18% 1% Neutropenia 64% 52% Decreased Appetite 28% 2% Leukopenia 17% 10% Abdominal Pain Upper 21% 3% Alopecia 47% 0% Summary of other relevant treatment-related adverse events in patients receiving sacituzumab govitecan-hziy2 Adverse Event Any Grade Grade 3-4 Anemia 34% 8% Febrile neutropenia 6% 6% Thrombocytopenia 5% 2% Initial Results from Phase 2 ADC Combination Study Summary of TEAEs (≥ 15% of patients) in patients receiving trilaciclib in combination with sacituzumab govitecan-hziy Adverse Event Any Grade Grade 3-4 Fatigue 44% 0% Nausea 39% 0% Constipation 28% 0% Diarrhea 28% 0% Headache 28% 0% Neutropenia 22% 17% Decreased Appetite 22% 0% Leukopenia 17% 17% Abdominal Pain Upper 17% 0% Alopecia 17% 0% Summary of other relevant TEAEs in patients receiving trilaciclib in combination with sacituzumab govitecan-hziy Adverse Event Any Grade Grade 3-4 Anemia 6% 0% Febrile Neutropenia 0% 0% Thrombocytopenia 0% 0% Adverse events in patients receiving trilaciclib in combination with sacituzumab govitecan-hziy (n=18) Adverse events in patients receiving sacituzumab govitecan-hziy (n=258) *Only includes subset of TEAEs reported in patients receiving trilaciclib and sacituzumab govitecan-hziyCutoff: 14 October 2022 Preliminary data highlight potential to reduce adverse events, including on target effects on neutropenia and diarrhea Note: TEAE = Treatment emergent adverse event 1. Adapted from Bardia A, et al. Sacituzumab Govitecan in Metastatic Triple-Negative Breast Cancer. N Engl J Med 2021;384:1529-41. DOI: 10.1056/NEJMoa2028485. Table S1 2. Adapted from Bardia A, et al. Sacituzumab Govitecan in Metastatic Triple-Negative Breast Cancer. N Engl J Med 2021;384:1529-41. DOI: 10.1056/NEJMoa2028485. Table 3 For Investor Use Only

23 Phase 2 Neoadjuvant TNBC: Mechanism of Action (MOA) Study Single Dose Monotherapy Up to 21 Days trilaciclib P R I M A R Y E N D P O I N T: Immune-based MOA SECONDARY ENDPOINTS: pCR, immune response and profiling measures ENROLLMENT COMPLETED: 24 patients pCR data expected 2Q 2023 Confirm immune-based properties of trilaciclib and its potential role in increasing the anti-tumor efficacy of chemotherapy with and without a checkpoint inhibitor Data will inform design of future additional studies across multiple tumor types and treatment combinations 3-5 Weeks After Treatment Phase Single Arm: Early-stage TNBC Screening Lead-In Baseline Tumor Tissue Collected First 4 Cycles Next 12 Cycles trilaciclib + AC chemo ± pembro Treatment Phase Biopsy ~7 Days Later trilaciclib + taxane chemo ± carbo ± pembro Surgery Final Sample Collected (Assuming Residual Disease) For Investor Use Only

24 Initial data suggests favorable alterations in tumor microenvironment following single administration of trilaciclib Change in CD8+ T-cell / Treg Ratio in Tumor Tissue Over 7 Days Post Trilaciclib Monotherapy (N=23); Per Patient (A) and Overall (B) Initial Results from Phase 2 MOA Study in Neoadjuvant TNBC CD8+ T-Cell/ Treg Ratio Baseline, Pre-Trilaciclib Dose (n = 23) Day 7 (+/- 1), Post-Trilaciclib Dose (n = 23) Change, Post – Pre Dose (n = 23) Median (Q1, Q3) 2.0 (1.4, 2.6) 2.2 (1.4, 4.0) 0.3 (-0.5, 2.7) P-valueb - - 0.101 Mean (SD) 2.6 (2.436) 3.8 (3.979) 1.3 (4.784) a Patient had TNBC with neuroendocrine features b Calculated using the Wilcoxon signed-rank test CD8: Cluster of differentiation 8; Q: Quarter; Treg: regulatory T cell. a For Investor Use Only

25 Phase 2 Bladder (mUC) Study: PRESERVE 3 Cycle X Day 1 Cycle X Day 8 Cycle X Day 1 Cycle X Day 21 R an do m iz at io n 1: 1 platinum- based chemotherapy Treatment Phase platinum- based chemotherapy trilaciclib + platinum-based chemotherapy trilaciclib + platinum-based chemotherapy Induction Phase 21-day cycles Maintenance Phase 14-day cycles avelumab trilaciclib + avelumab Maximum of 6 cycles P R I M A R Y E N D P O I N T: PFS SECONDARY ENDPOINTS: ORR, DCR, DOR, OS, myeloprotection measures ENROLLMENT COMPLETED: 92 participants PATIENTS TREATED UNTIL PROGRESSION PFS and duration of response expected mid-2023 Building on strong rationale for trilaciclib in a known immunogenic tumor; focused on ability to increase PFS in checkpoint combination Phase 2 study will provide meaningful data to help define future combination studies Until Progression Every 3 months Survival For Investor Use Only

26  Confirmed objective response rate (ORR) per RECIST v1.1 was comparable between arms – ORR was 40.0% (n=18/45) and 46.7% (n=21/45) in the trilaciclib and control arms, respectively – Longer-term follow-up required to characterize additional anti-tumor endpoints:  Median duration of confirmed objective response (DOR)  PFS (primary endpoint of the study)  Safety and tolerability profile is generally consistent with expectations for patients treated with gemcitabine plus cisplatin/carboplatin and avelumab maintenance in 1L mUC – DMC has recommended the study continue as planned Initial Results from Phase 2 Bladder Study For Investor Use Only

27 Potentially Ideal Treatment Settings for Future Studies ADCs (in areas ADC monotherapy may become SoC) CPI Maintenance (metastatic or adjuvant uses) CPI + Chemo/ADC (in immunogenic tumors) Future CPI Combos (e.g., PD-(L)1i + anti-LAG3; PD-(L)1i + anti-CD73) Other Highly Myelotoxic Regimens (e.g., other GI tumors) ADC Combinations (in areas ADC combinations may become SoC) Myeloprotection: Enabling increased cytotoxic exposure while protecting immune system Immunomodulation: Improving overall immune response 1 2 Focused on ideal treatment settings where trilaciclib has unique ability to further improve survival in combination with important leading and emerging treatments For Investor Use Only

28 COSELA® (trilaciclib) in ES-SCLC

29 COSELA in ES-SCLC: Opportunity to Impact Many Lives  Demonstrated reductions in multiple myelosuppressive consequences and hematologic adverse events - Across multiple randomized SCLC studies and Real-World Evidence studies  ES-SCLC patients predominantly treated with highly myelosuppressive chemo regimens - Opportunity for innovation given aggressiveness of disease (1L median OS ~1 year4) - Standard treatment includes ~4 cycles of chemo  Strong reimbursement, majority in Medicare 20K Eligible 1L / 2L Patients Receiving Indicated Chemotherapy U.S. ES-SCLC Patient Population (2022) 1. Based on incidence of 29k for all SCLC with 80% of patients being diagnosed at Extensive Stage; Cerner Enviza, CancerMPact, Patient Metric Dashboards 2021. 2. Based on 22k 1L SCLC total patients (20K de novo ES-SCLC and 2K late relapse LS-SCLC) treated at an assumed 80% treatment rate (from internal analysis and primary market research). 3. Based on 12.3k 2L SCLC total patients (10.8k progressed 1L SCLC and 1.5k early relapse LS-SCLC) treated at an assumed 72% treatment rate (from internal analysis and primary market research). 4. Demonstrated in COSELA G1T28-02 and G1T28-05 study control arms. COSELA can significantly improve the chemotherapeutic experience and improve the lives of patients with ES-SCLC 20K Eligible 1L / 2L Patients Receiving Indicated Chemotherapy 27K 1L / 2L Patients Treated Annually1-3 43K Patients with ES- SCLC For Investor Use Only

30 0 1000 2000 3000 4000 5000 6000 7000 8000 1Q 2Q 3Q 4Q Vi al V ol um e 2022 Quarterly COSELA Vial Volume +58% growth -1% growth Eight Percent (8%) Vial Volume Growth in 4Q22 5-10% current penetration; considerable growth potential remaining in ES-SCLC market +8% growth +20% growth For Investor Use Only Note: Growth figures above represent sequential quarterly growth

31  69 of Top 100 US customer organizations have trialed COSELA launch to date (8 new in 4Q22) – >30% of US market potential in these 69 Top 100 organizations Progress with 4Q22 Account Depth and Breadth Top 100 Organizations 31 Not Yet Trialed 69 Ordered >80% with orders in Q4  Depth continues to be the challenge – 14% depth in Top 100 organizations – 17% depth across all organizations with utilization Continued breadth of trial, especially in Community, with opportunity to grow depth For Investor Use Only

32 Challenges to Building Depth  Relatively rare tumor type – Variable incidence across territories – Not top of mind when even large clinics have only one or two eligible patients at a time – Reluctance to make systematic changes in process for small number of patients  Short duration of chemotherapy treatment – <90-day duration of chemotherapy for most patients means no continuing business quarter to quarter  Palliative care focus – Many physicians prefer to dose reduce or delay given poor survival prognosis – Academic organizations more focused on implementing change for survival outcomes Response to Challenges in ES-SCLC Market Actions Being Taken  Community Clinic Focus – Multiple volume-based contracts in place for Q1 (more anticipated) – Patient Reported Outcome focus of promotion – Specialist EMR team to support clinic adoption  Optimizing field deployment for community clinics – 29 territories with highest opportunity – Virtual hybrid sales representative augmenting enhanced digital marketing for unstaffed territories  Medically-led model for academic centers – Scientific engagement with academic lung experts Refocusing commercial resources on largest opportunities to drive increased depth For Investor Use Only

33 1L/2L ES-SCLC 1L CRC Significantly Larger Commercial Opportunity in 1L CRC Comparing Opportunity Characteristics Duration of Therapy• ~4 cycles over ~3 months (~24 vials of trilaciclib) • ~12-24 cycles over ~6-12 months (~48-96 vials of trilaciclib) Patient Mix• Smaller patient population skewed to Medicare • Higher patient frequency; even mix of Commercial and Medicare Therapeutic Goals • Typically, poorer prognosis at diagnosis • Trilaciclib primarily supportive care in this setting • Better prognosis facilitates more aggressive therapeutic approaches • Trilaciclib may enable a more efficacious regimen and increase OS Addressable Market• ~20K addressable patients • ~47K addressable patients Broader use in 1L CRC may help increase awareness and adoption of trilaciclib in ES-SCLC patients For Investor Use Only

34 Conclusion

35 Efficiently Managing Capital Potential for Meaningful Incremental Value from Out-Licensed Assets $13M milestone in 3Q22 for approval in China; up to $156M in milestones; double-digit royalties on annual net sales Greater China (COSELA approved) Up to $290M in milestones; tiered royalties on annual net sales Up to $40M in milestones; tiered royalties on annual net sales US, EU, Japan Asia PAC CDK2 Discovery Platform Lerociclib Trilaciclib Formerly Arc Therapeutics Milestones and sales-based royalties Potential for $461 million in milestone payments (as of 12/31/22) plus royalties Additional potential proceeds from existing license agreements $123M in cash, cash equivalents, and marketable securities as of Sept. 30, 2022 • Additional $25M of debt facility currently available but not yet drawn Additional $52.4M in net proceeds from 4Q22 public offering For Investor Use Only

36 2023 Key Clinical and Regulatory Catalysts Ph3 PRESERVE 1 (CRC): Initial results Feb ‘23 Ph2 MOA trial: Initial pathologic CR results Ph2 Bladder trial: Initial efficacy results Potential regulatory filing for label expansion into CRC Ph2 ADC trial: Initial efficacy results Ph3 PRESERVE 2 (mTNBC): Interim OS analysis at 70% of events Potential initiation of additional trilaciclib clinical trials 2Q ‘23 Mid ‘23 2H ‘23 Ph3 PRESERVE 1 (CRC): Initial PFS results (4Q23) For Investor Use Only

37 G1 Therapeutics Unique Investment Opportunity Poised for Near-Term Growth • Considerable growth potential remaining in ES-SCLC market • Focusing on increasing depth at top accounts Growth Potential in Marketed Indication • Additional data from three Ph2 studies in 2023 • Will inform additional late- stage studies Multiple Phase 2 Data Readouts • 1L CRC: Pivotal data February 2023; potential early 2024 lauch • 1L TNBC: Interim OS 2H 2023; given fast-track designation with potential 2024 launch Near-Term Commercial Opportunities • Planning to secure a partner for global expansion in 2023 • Pursuing research on next generation products Global Expansion For Investor Use Only

XML

Cover	Jan. 09, 2023
Cover [Abstract]
Document Type	8-K
Document Period End Date	Jan. 09, 2023
Entity Registrant Name	G1 THERAPEUTICS, INC.
Entity Incorporation, State or Country Code	DE
Entity File Number	001-38096
Entity Tax Identification Number	26-3648180
Entity Address, Address Line One	700 Park Offices Drive
Entity Address, Address Line Two	Suite 200
Entity Address, City or Town	Research Triangle Park
Entity Address, State or Province	NC
Entity Address, Postal Zip Code	27709
City Area Code	(919)
Local Phone Number	213-9835
Written Communications	false
Soliciting Material	false
Pre-commencement Tender Offer	false
Pre-commencement Issuer Tender Offer	false
Title of 12(b) Security	Common stock, $0.0001 par value
Trading Symbol	GTHX
Security Exchange Name	NASDAQ
Entity Emerging Growth Company	false
Amendment Flag	false
Entity Central Index Key	0001560241