LN-145-S1

SAN CARLOS, Calif., March 04, 2024 (GLOBE NEWSWIRE) -- Iovance Biotherapeutics, Inc. (NASDAQ: IOVA), a commercial biotechnology company focused on innovating, developing, and delivering novel polyclonal tumor infiltrating lymphocyte (TIL) therapies for patients with cancer, today announced that the U.S. Food and Drug Administration (FDA) lifted a partial clinical hold placed on the registrational IOV-LUN-202 trial investigating LN-145 TIL cell therapy in non-small cell lung cancer (NSCLC). In collaboration with the FDA and an independent data monitoring committee, Iovance developed additional safety measures and monitoring. Upon reviewing this proposal, the FDA has cleared Iovance to resume patient enrollment in IOV-LUN-202. The IOV-LUN-202 trial is investigating LN-145 in patients with advanced (unresectable or metastatic) NSCLC without EGFR, ROS or ALK genomic mutations who were previously treated with chemotherapy and anti-PD-1 therapy and at least one line of an approved targeted therapy if indicated by other actionable tumor mutations. Iovance expects to complete enrollment of approximately 120 patients in the IOV-LUN-202 registrational cohorts in 2025. Preliminary data from the IOV-LUN-202 trial support the potential benefit of one-time TIL therapy, including the opportunity for more durable responses than available second line chemotherapies. Initial preliminary data were reported in July of 2023. An updated analysis in November of 2023 showed additional ongoing responses and duration of response greater than six months for 71% of the confirmed responders in the trial. For more information about the IOV-LUN-202 trial please visit www.lungcelltherapy.com. About Iovance Biotherapeutics, Inc.Iovance Biotherapeutics, Inc. aims to be the global leader in innovating, developing, and delivering tumor infiltrating lymphocyte (TIL) therapies for patients with cancer. We are pioneering a transformational approach to cure cancer by harnessing the human immune system’s ability to recognize and destroy diverse cancer cells in each patient. The Iovance TIL platform has demonstrated promising clinical data across multiple solid tumors. Iovance’s Amtagvi™ is the first FDA-approved T cell therapy for a solid tumor indication. We are committed to continuous innovation in cell therapy, including gene-edited cell therapy, that may extend and improve life for patients with cancer. For more information, please visit www.iovance.com. Amtagvi™ and its accompanying design marks, Proleukin®, Iovance®, and IovanceCares™ are trademarks and registered trademarks of Iovance Biotherapeutics, Inc. or its subsidiaries. All other trademarks and registered trademarks are the property of their respective owners. Forward-Looking StatementsCertain matters discussed in this press release are “forward-looking statements” of Iovance Biotherapeutics, Inc. (hereinafter referred to as the “Company,” “we,” “us,” or “our”) within the meaning of the Private Securities Litigation Reform Act of 1995 (the “PSLRA”). Without limiting the foregoing, we may, in some cases, use terms such as “predicts,” “believes,” “potential,” “continue,” “estimates,” “anticipates,” “expects,” “plans,” “intends,” “forecast,” “guidance,” “outlook,” “may,” “could,” “might,” “will,” “should,” or other words that convey uncertainty of future events or outcomes and are intended to identify forward-looking statements. Forward-looking statements are based on assumptions and assessments made in light of management’s experience and perception of historical trends, current conditions, expected future developments, and other factors believed to be appropriate. Forward-looking statements in this press release are made as of the date of this press release, and we undertake no duty to update or revise any such statements, whether as a result of new information, future events or otherwise. Forward-looking statements are not guarantees of future performance and are subject to risks, uncertainties, and other factors, many of which are outside of our control, that may cause actual results, levels of activity, performance, achievements, and developments to be materially different from those expressed in or implied by these forward-looking statements. Important factors that could cause actual results, developments, and business decisions to differ materially from forward-looking statements are described in the sections titled "Risk Factors" in our filings with the U.S. Securities and Exchange Commission, including our most recent Annual Report on Form 10-K and Quarterly Reports on Form 10-Q, and include, but are not limited to, the following substantial known and unknown risks and uncertainties inherent in our business: the risks related to our ability to successfully commercialize our products, including Amtagvi and Proleukin, for which we obtain U.S. Food and Drug Administration (“FDA”), European Medicines Agency (“EMA”), or other regulatory authority approval; the risk that the EMA or other regulatory authorities may not approve or may delay approval for our biologics license application (“BLA”) submission for lifileucel in metastatic melanoma; the acceptance by the market of our products, including Amtagvi and Proleukin, and their potential pricing and/or reimbursement by payors, if approved (in the case of our product candidates), in the U.S. and other international markets and whether such acceptance is sufficient to support continued commercialization or development of our products, including Amtagvi and Proleukin, or product candidates, respectively; our ability or inability to manufacture our therapies using third party manufacturers or at our own facility may adversely affect our commercial launch; the results of clinical trials with collaborators using different manufacturing processes may not be reflected in our sponsored trials; the risk regarding the successful integration of the recent Proleukin acquisition; the risk that the successful development or commercialization of our products, including Amtagvi and Proleukin, may not generate sufficient revenue from product sales, and we may not become profitable in the near term, or at all; the risk that future competitive or other market factors may adversely affect the commercial potential for Amtagvi or Proleukin; the risks related to the timing of and our ability to successfully develop, submit, obtain, or maintain FDA, EMA, or other regulatory authority approval of, or other action with respect to, our product candidates; whether clinical trial results from our pivotal studies and cohorts, and meetings with the FDA, EMA, or other regulatory authorities may support registrational studies and subsequent approvals by the FDA, EMA, or other regulatory authorities, including the risk that the planned single arm Phase 2 IOV-LUN-202 trial may not support registration; preliminary and interim clinical results, which may include efficacy and safety results, from ongoing clinical trials or cohorts may not be reflected in the final analyses of our ongoing clinical trials or subgroups within these trials or in other prior trials or cohorts; the risk that enrollment may need to be adjusted for our trials and cohorts within those trials based on FDA and other regulatory agency input; the risk that the changing landscape of care for cervical cancer patients may impact our clinical trials in this indication; the risk that we may be required to conduct additional clinical trials or modify ongoing or future clinical trials based on feedback from the FDA, EMA, or other regulatory authorities; the risk that our interpretation of the results of our clinical trials or communications with the FDA, EMA, or other regulatory authorities may differ from the interpretation of such results or communications by such regulatory authorities (including from our prior meetings with the FDA regarding our non-small cell lung cancer clinical trials); the risk that clinical data from ongoing clinical trials of Amtagvi will not continue or be repeated in ongoing or planned clinical trials or may not support regulatory approval or renewal of authorization; the risk that unanticipated expenses may decrease our estimated cash balances and forecasts and increase our estimated capital requirements; the effects of the COVID-19 pandemic; and other factors, including general economic conditions and regulatory developments, not within our control. CONTACTS Iovance Biotherapeutics, Inc:Sara Pellegrino, IRCSenior Vice President, Investor Relations & Corporate Communications650-260-7120 ext. 264Sara.Pellegrino@iovance.com Jen SaundersSenior Director, Investor Relations & Corporate Communications267-485-3119Jen.Saunders@iovance.com

Engineering a patient’s immune cells into cancer treatments works for treating blood cancers, but has fallen short in solid tumors—until now. An Iovance Biotherapeutics treatment employing a different type of cell has won accelerated FDA approval for advanced melanoma, marking the first product approval of any cell therapy for a solid tumor. The regulatory decision announced Friday covers melanoma in adults whose cancer cannot be surgically removed or has spread following treatment with an immunotherapy or a targeted cancer therapy. The cell therapy of San Carlos, California-based Iovance, known in development as lifileucel, will be marketed under the brand name Amtagvi. Amtagvi, a one-time treatment, is made from a type of cell called a tumor-infiltrating lymphocyte, or TIL. The body produces TILs to fight cancer, and they are found in the tumor. The Iovance cell therapy is made by surgically removing a small piece of a patient’s tumor and isolating TILs from that sample. Those TILs are multiplied in a lab, then shipped back to the hospital for infusion into the patient. The TIL manufacturing process is similar to that of CAR T-therapies, which are made by harvesting and multiplying a patient’s T cells. One key difference is what happens in the lab. CAR T-treatments are engineered to go after a target on the surface of a cancer cell. TILs don’t need this engineering step because they already have the ability to recognize a patient’s cancer cells. Amtagvi’s Clinical Trial Results The FDA based its approval on the results of an open-label, single-arm Phase 2 clinical trial. Participants had advanced melanoma that was previously treated with at least one systemic therapy, including a type of immunotherapy called a checkpoint inhibitor, and if positive for a BRAF mutation, a BRAF inhibitor. The main goal was to measure the objective response rate and the duration of response. Of the 73 patients who received Amtagvi within the recommended dosing range, the overall response rate was 31.5%. The median duration of response was not reached. Results were published in in 2022 in the Journal for ImmunoTherapy of Cancer. The most common adverse reactions reported from the clinical trial included chills, fever, fatigue, faster than normal heart rate, and diarrhea. Amtagvi’s label carries a black box warning that the treatment can lead to death. In the clinical trial, treatment-related mortality was 7.6%. Adverse reactions associated with these deaths included severe infections, internal bleeding, kidney failure, respiratory failure, and abnormal heart rhythm. Patients may experience prolonged and severe cytopenia, which is a low levels of certain blood cells. The risk of heart and kidney injury are also flagged in the boxed warning. CAR T-therapies also carry black box warnings, with the main complications risks being an excessive immune response called cytokine release syndrome and neurotoxicity. Fred Vogt, interim Iovance CEO and the company’s president and general counsel, noted that Amtagvi was not associated with either of these complications risks. FDA approval of CAR T-therapies came with Risk Evaluation Mitigation Strategies (REMS), programs to manage the risks associated with treatment. “The [Amtagvi] black box is pretty good, we think it’s much better than what the CAR T’s have,” Vogt said during a Friday conference call. “It doesn’t have a REMs, first and foremost, like the CAR T’s do. It’s got boxed warnings essentially for known risks, from the lymphodepletion and the IL-2 therapies that we provide.” Lymphodepletion, a key step in all cell therapies, involves using chemotherapy to reduce levels of a patient’s immune cells to improve the survival chances of the cell therapy. IL-2 refers an engineered version of a protein that stimulates an immune response. In the clinical trial, treatment with Amtagvi was followed by aldesleukin, an IL-2 therapy whose uses include the treatment of metastatic melanoma. In the Amtagvi treatment regimen, aldesleukin’s role is to activate the TILs’ anti-tumor activity. Aldesleukin also has risks: Its label includes a black box warning of a potential complication called capillary leak syndrome, leading to low blood pressure and low levels of the protein albumin in the blood. This complication can lead to life-threatening organ damage. Because aldesleukin is a key part of the Amtagvi treatment regimen, Iovance last year acquired global rights to Proleukin, an IL-2 product from Clinigen. Iovance paid £166.9 million (about $207.2 million) up front for the product’s rights. The acquisition agreement puts Clinigen in line for milestone payments and royalties from sales. Premium Pricing for the First TIL Cell Therapy Iovance set a $515,000 wholesale price for Amtagvi, which is higher than the $373,000 to $475,000 price range for currently available CAR T-therapies. The company will make the TIL therapy at its Philadelphia manufacturing facility. Together with a nearby contract manufacturer, the company says it has the capacity to produce Amtagvi for “several thousand patients annually.” The current manufacturing process is 34 days, which is a comparable to the lengthy, multi-step manufacturing process for CAR T-therapies. Vogt said Iovance believes it can improve Amtagvi’s manufacturing timeframe. Jim Ziegler, executive vice president, commercial, said about 30 authorized treatment centers are now ready to collect and ship tumor tissue for Amtagvi manufacturing. He expects that number to grow to 50 centers within the next three months. Based on interactions with payers, Ziegler said Iovance expects coverage of Amtagvi will be similar to insurance coverage of approved CAR T-therapies. TIL therapy competition is coming. The Achilles Therapeutics pipeline includes a TIL therapeutic candidate currently in a Phase 1/2 clinical trial evaluating it in combination with a checkpoint inhibitor as a potential treatment for melanoma. Lyell Immunopharma has a TIL therapy in early clinical development in melanoma, colorectal cancer, non-small cell lung cancer (NSCLC), and other solid tumors. Instil Bio’s pipeline includes a TIL in Phase 1 development in NSCLC, ovarian, and kidney cancers. Instil’s former lead program had reached mid-stage clinical development in advanced melanoma, but that therapy was discontinued in late 2022 due to a pipeline reprioritization. Iovance is also testing Amtagvi in combination with the Merck checkpoint inhibitor Keytruda as a frontline treatment for melanoma. This Phase 3 study will serve as the confirmatory clinical trial required of the therapy’s accelerated approval. The Iovance pipeline also includes tests of Amtagvi—by itself and in combination with checkpoint inhibitors—in cervical cancer, NSCLC, and head and neck squamous cell carcinoma. Another Iovance TIL therapy, LN-145, has reached pivotal testing in NSCLC. This study was placed under an FDA clinical hold in late December due to a fatality potentially related to the therapy’s preconditioning regimen. Vogt said Iovance is working to resolve the clinical hold and hopes to have an update in a few weeks. Photo by Iovance Biotherapeutics