On August 5, 2022 Kazia Therapeutics Limited (NASDAQ: KZIA; ASX: KZA), an oncology-focused drug development company, reported the presentation of promising new data from an ongoing phase I clinical trial of paxalisib in combination with radiotherapy for the treatment of brain metastases, sponsored by Memorial Sloan Kettering Cancer Center in New York, NY (Press release, Kazia Therapeutics, AUG 5, 2022, View Source [SID1234617697]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

Interim data from the first stage of the study reports that all 9 evaluable patients experienced complete or partial response, representing an overall response rate (ORR) of 100%. For comparison, a typical ORR associated with whole brain radiotherapy alone can commonly range from 20-45% in published studies, of which some representative examples are indicated below.

The data has been accepted for an oral presentation at the upcoming 2022 Annual Conference on CNS Clinical Trials and Brain Metastases, jointly organised by the Society for Neuro-Oncology (SNO) and the American Society for Clinical Oncology (ASCO) (Free ASCO Whitepaper), and held in Toronto, Canada from 12-13 August 2022.

Key Points

Approximately 200,000 cancer patients develop brain metastases in the United States each year. Brain metastases are typically very challenging to treat and are associated with poor prognosis. Radiotherapy remains a mainstay of clinical management.

Dr. Jonathan Yang, Director, Metastatic Disease, Department of Radiation Oncology at Memorial Sloan Kettering Cancer Center is the Principal Investigator of this clinical trial that is examining the combination of paxalisib with whole brain radiotherapy for patients with brain metastases (NCT04192981). The trial is designed in two stages: an initial exploratory stage and a confirmatory expansion stage.

9 of 12 patients in the initial stage were evaluable for efficacy. All 9 patients exhibited complete or partial response, according to RANO-BM criteria, representing an ORR of 100%.

The patients comprised a range of primary tumours, with breast cancer the most common, representing one third of patients.

The safety profile of paxalisib in combination was broadly consistent with monotherapy experience in other clinical trials, and a maximum tolerated dose (MTD) of 45mg daily in combination with radiotherapy was confirmed.

Recruitment to the expansion stage has already commenced, with the objective of recruiting an additional 12 patients.
Kazia CEO, Dr. James Garner, commented, "We are encouraged by this data and by the potential benefit it may indicate to this substantial and high-need group of patients. Radiotherapy is a ubiquitous component of the treatment paradigm for brain metastases, but resistance is common. Dr. Yang’s study has shown a very promising signal that paxalisib may help to potentiate the effect of radiotherapy. We also learned recently that the ongoing Alliance study in brain metastases had graduated to an expansion stage in the breast cancer cohort, so this now represents the second positive signal for paxalisib in brain metastases, which we increasingly believe represents a very promising opportunity for the product candidate."

Brain Metastases

It is estimated that as many as 20% of all patients with cancer will develop brain metastases (secondary tumours in the central nervous system). The most common primary tumours that spread to the brain include lung, breast, colorectal, melanoma, and renal cell carcinoma. Median overall survival for patients diagnosed with brain metastases ranges from 2.3 to 7.7 months.[1] It is estimated that approximately 200,000 patients are diagnosed with brain metastases each year in the United States alone.[2]

Radiotherapy is the mainstay of treatment for brain metastases, and generally consists in either stereotactic radiosurgery (SRS) or whole brain radiotherapy (WBRT) or some combination thereof. The efficacy of WBRT differs according to the type of tumour and the number and volume of brain metastases, but several recent publications cite overall response rates of 20-45%.

Clinical Study Rationale and Design

Research by Dr. Yang and others has shown that activation of the PI3K pathway is common in brain metastases, even in some cases where it is not present in the primary tumour. Moreover, PI3K pathway activation appears to be induced by radiotherapy, and to confer upon the tumour resistance to radiotherapy. These observations provide a strong rationale for testing the combination of a brain-penetrant PI3K inhibitor with radiotherapy.

This phase I study is a single-arm prospective trial comprising patients with brain metastases or leptomeningeal metastases from any primary tumour. The primary objective is safety and tolerability. All patients have PI3K pathway mutations at baseline. The first stage of the study is intended to establish the MTD of paxalisib in combination with WBRT and to characterise safety and tolerability. The second stage is intended to elicit confirmatory signals of efficacy, with the intent to recruit a further 12 patients.

Next Steps

Enrolment to the second stage of the study is already underway and we currently estimate preliminary data from the second part of the phase I clinical trial in CY2023.

Kazia expects to discuss emerging data from this study, along with other research in brain metastases, with its scientific advisors and regulatory consultants in due course, with potential FDA consultation at a future date.

Summary of Abstract

Session 2: Multimodality Approaches to Primary and Secondary Brain Tumors – Invited
Speakers and Oral Abstracts
Friday, 12 August 2022
11am – 1pm

Abstract MMAP-05 – Phase I study of concurrent paxalisib and radiation therapy in patients with solid tumor brain metastases or leptomeningeal metastases harboring PI3K pathway mutations: results from the dose-escalation cohort (NCT04192981)
Lead Author: T Jonathan Yang, MD, PhD
Institution: Memorial Sloan Kettering Cancer Center, New York, NY

On August 5, 2022 IMV Inc. ("IMV" or the "Company") (Nasdaq: IMV; TSX: IMV) a clinical-stage company developing a portfolio of immune-educating therapies based on its novel DPX platform to treat solid and hematologic cancers, reported that it plans to maintain its existing at-the-market facility initially announced on October 16, 2020 under its recently renewed base shelf prospectus, which is effective for a period of 25 months from July 25, 2022 (Press release, IMV, AUG 5, 2022, View Source [SID1234617696]). IMV has entered into an equity distribution agreement (the "EDA") dated August 4, 2022 with Piper Sandler & Co. ("Piper Sandler") pursuant to which the Company may from time to time sell through "at-the-market" offerings (the "ATM Offering"), with Piper Sandler acting as sales agent, on the Nasdaq Capital Market (the "Nasdaq") such number of common shares that have an aggregate offering price of up to US$50 million under the ATM Prospectus Supplement (as defined below).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

The ATM Offering will be made by way of a prospectus supplement (the "ATM Prospectus Supplement") to the Company’s Canadian final base shelf prospectus dated July 22, 2022, and the Company’s United States final base shelf prospectus which is contained in the Company’s U.S. registration statement on Form F-10 dated July 25, 2022, as amended (File No. 333-266082) (the "Registration Statement"). The Registration Statement was effective on filing with the United States Securities and Exchange Commission (the "SEC") on July 25, 2022. The ATM Prospectus Supplement has been filed with the Nova Scotia Securities Commission, as principal regulator in Canada, and in the United States with the SEC. The common shares that may be issued by the Company through the ATM Offering have been conditionally approved for listing on the Toronto Stock Exchange ("TSX") and the required notices related to the ATM Offering have been filed with the Nasdaq as well. In obtaining TSX listing approval, the Company has relied on the "Eligible Interlisted Issuer" exemption from TSX rules under section 602.1 of the TSX Company Manual.

Piper Sandler, at IMV’s discretion and instruction, will use its commercially reasonable efforts to sell the common shares at market prices from time to time. No offers or sales of common shares will be made in Canada or through the facilities of the TSX or any other trading market in Canada.

The Company plans to use the net proceeds from the ATM Offering for general corporate purposes, including but not limited to working capital expenditures, capital expenditures, research and development expenditures, and clinical trial expenditures.

Copies of the ATM Prospectus Supplement and the accompanying final base shelf prospectus relating to the offered common shares may be obtained for free from the offices of Piper Sandler & Co., Attention: Prospectus Department, 800 Nicollet Mall, J12S03, Minneapolis, MN 55402, via telephone at (800) 747-3924 or via email at [email protected].

This press release shall not constitute an offer to sell or a solicitation of an offer to buy, nor shall there be any sale of these common shares in any jurisdiction in which an offer, solicitation or sale would be unlawful prior to registration or qualifications under the securities laws of any such jurisdiction.

On August 5, 2022 Guardant Health, Inc. (Nasdaq: GH), a leading precision oncology company, reported that studies utilizing its portfolio of blood tests and real-world data will be presented at the IASLC 2022 World Conference on Lung Cancer (WCLC 2022), hosted by the International Association for the Study of Lung Cancer, August 6-9 in Vienna, Austria (Press release, Guardant Health, AUG 5, 2022, View Source [SID1234617695]). Among the 10 abstracts are oral presentations and posters highlighting the use of Guardant360 to help physicians inform treatment decisions, GuardantOMNI to advance cancer therapy trials, and GuardantINFORM for targeted drug development to improve outcomes for patients with lung cancer.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"We look forward to sharing new data at WCLC that demonstrate the utility of our liquid biopsy tests and datasets to create more accurate tumor profiles and impact outcomes for lung cancer patients around the world," said Helmy Eltoukhy, Guardant Health co-CEO. "The data from retrospective and real-world analyses will show how blood-based tests provide critical insights into tumor evolution and treatment resistance throughout each lung cancer patient’s treatment journey and contribute more broadly to further developing the field of thoracic oncology."

Full List of Presentations:

Guardant360

Clinical and molecular profile of patients with non-small cell lung cancer (NSCLC) with incidental pathogenic germline variants detected in cfDNA (oral)
Patterns of KEAP1 genomic co-alterations in advanced lung cancer as identified by plasma-based genotyping (e-poster)
Germline HRR mutations in metastatic NSCLC and impact on progression-free survival: A single-center retrospective study (e-poster)
Targetable alterations in non-small cell lung cancer according to age and sex (e-poster)
Liquid biopsies first to make treatment decisions in patients with metastatic non-small cell lung cancer (NSCLC) (e-poster)
Landscape of EGFR extracellular domain mutations in advanced non-small cell lung carcinoma (e-poster)
The patient impact of liquid biopsy – health-related quality of life in patients undergoing liquid biopsy for advanced non-small cell lung cancer (e-poster)
GuardantINFORM

Impact of germline BRCA1/2 alterations on EGFR mutant advanced non-small cell lung cancer outcomes (e-poster)
Real-world landscape of EGFR C797X mutation as a resistance mechanism to osimertinib in non-small cell lung cancer (oral)
GuardantOMNI

Durvalumab + olaparib vs. durvalumab alone as maintenance therapy in metastatic NSCLC: Outcomes from the phase 2 ORION study (poster)

On August 5, 2022 Forma Therapeutics Holdings, Inc. (Nasdaq: FMTX), a clinical-stage biopharmaceutical company focused on sickle cell disease, prostate cancer and other rare hematologic diseases and cancers, reported financial results for the second quarter ended June 30, 2022 (Press release, Forma Therapeutics, AUG 5, 2022, View Source [SID1234617694]). The company also highlighted recent progress and upcoming milestones for its pipeline programs.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"In the second quarter, we announced encouraging new analyses from the etavopivat program in sickle cell disease at our inaugural R&D Day. We also recently appointed two new members of our executive team to help drive our next phase of global development and commercialization and entered into a license agreement for olutasidenib," said Frank Lee, President and Chief Executive Officer of Forma. "We are well-positioned to continue to advance our pipeline and are actively managing expenses as we progress in our mission to deliver transformative medicines to patients with rare hematologic diseases and cancers."

Key Business Updates

On July 27, 2022 Forma entered into an exclusive worldwide license agreement with Rigel Pharmaceuticals, Inc. to develop, manufacture, and commercialize olutasidenib. Olutasidenib is a mutant isocitrate dehydrogenase-1 (mIDH1) inhibitor for the treatment of relapsed or refractory acute myeloid leukemia. Under the terms of the agreement, Forma will receive an upfront payment of $2.0 million, and is eligible to receive an additional $17.5 million upon the achievement of certain near-term regulatory, approval, and first commercial sale milestones. In addition, Forma is eligible to receive a total of up to an additional $215.5 million in connection with the achievement of certain development and commercial milestones. Forma is also eligible to receive tiered royalties in the low-teens to mid-thirties. The U.S. Food and Drug Administration (FDA) has accepted Forma’s new drug application (NDA) for olutasidenib. The Prescription Drug User Fee Act (PDUFA) target action date is February 15, 2023.
Agustín Melián, M.D., named Executive Vice President, Head of Research and Development. Dr. Melián is a physician-scientist with over 20 years of experience developing patient-centric, rare, and orphan disease therapeutics across multiple therapeutic areas, modalities, and phases of development.
Linea Aspesi named Senior Vice President, Chief Human Resources Officer. Ms. Aspesi brings over 25 years of human resources leadership experience in life sciences and health care services and has a track record of aligning talent plans to company vision and strategy while fostering an equitable and inclusive environment.
Forma presented new data on the etavopivat clinical development program at multiple hematology conferences. Presentations included analyses from the Phase I open-label extension study of etavopivat in sickle cell disease indicating that etavopivat decreased the frequency and severity of pain-related adverse events, and the design of the Phase II Gladiolus study of etavopivat in patients with sickle cell disease (SCD) receiving chronic transfusions or transfusion-dependent or non-transfusion-dependent thalassemia. These data were presented at the European Hematology Association (EHA) (Free EHA Whitepaper) 2022 Hybrid Congress, the Foundation for Sickle Cell Disease Research (FSCDR) Sickle Cell Disease Research and Educational Symposium and Sickle Cell Disease Scientific Meeting, and the Global Congress on Sickle Cell Disease (GCSCD).
Forma hosted its first Research and Development (R&D) Day. The company provided an overview of its clinical development programs and research pipeline strategy.
Upcoming Milestones

Patient enrollment ongoing in global pivotal Phase II/III trial of etavopivat for the treatment of SCD, the Hibiscus Study. The first interim analysis (IA1) in the Hibiscus Study is expected to be reached by the end of 2022. IA1 is designed to select the dose for the Phase III portion of the trial.
Additional etavopivat development programs. Forma has initiated a Phase II trial in patients with either TD-SCD, TD-thalassemia, or non-TD-thalassemia, with initial results expected in late 2022. By year-end 2022, Forma plans to begin clinical trials in pediatric SCD and lower-risk myelodysplastic syndrome (MDS).
Update on FT-7051 clinical trial in mCRPC. Forma is planning to evaluate an alternative dosing schedule in a less heavily pretreated population and is currently processing the protocol amendment. Forma plans to provide updated results in the first half of 2023.
Possibility of COVID-19 impact remains. The COVID-19 pandemic remains a factor in the successful completion of these milestones and ongoing clinical trials. Many clinical trials across the biopharma industry, including Forma’s trials, have been impacted by the COVID-19 pandemic. Clinical trial sites implementing new policies in response to COVID-19 have impacted enrollment of clinical trials and/or the ability to access sites participating in clinical trials.
Financial Results

Cash Position: Cash, cash equivalents and marketable securities were $395.9 million as of June 30, 2022, as compared to $490.3 million as of December 31, 2021. Current cash runway is projected through the third quarter of 2024.
R&D Expenses: R&D expenses were $39.1 million for the quarter ended June 30, 2022, as compared to $31.6 million for the quarter ended June 30, 2021. The increase was primarily attributable to the increase in research and development staff to support the advancement of etavopivat and other programs, including the conduct of our Phase II/III Hibiscus trial in SCD patients and Phase II trial of etavopivat in thalassemia.
General and Administrative (G&A) Expenses: G&A expenses were $13.9 million for the quarter ended June 30, 2022, as compared to $12.5 million for the quarter ended June 30, 2021. The increase was primarily attributable to professional services, costs due to executive and staff hiring, and other related general and administrative costs.
Net Loss: Net loss was $52.6 million for the quarter ended June 30, 2022, as compared to net loss of $43.6 million for the quarter ended June 30, 2021.
Forma will conduct a conference call and webcast August 5, 2022 at 8:00 a.m. Eastern Daylight Time (EDT) to discuss second quarter 2022 results and business updates. Investors may participate in the call by using the registration link here. Once registered, participants will receive a dial-in number as well as a PIN to enter the event.

A live webcast of the conference call will be available in the "News & Investors" section of Forma’s website at www.formatherapeutics.com.

On August 5, 2022 The European Organisation for Research and Treatment of Cancer (EORTC) reported that it has finished patient recruitment for the EORTC-1612-MG trial in patients with unresected or metastatic melanoma (Press release, EORTC, AUG 5, 2022, View Source [SID1234617692]). The randomised trial will study the effect of combined targeted therapy (encorafenib and binimetinib) followed by combined immunotherapy (ipilimumab and nivolumab) as compared to immediate combined immunotherapy, in patients with unresectable or metastatic melanoma with a BRAF V600 mutation.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

Systemic therapy options for metastatic melanoma currently depend on whether the patient’s tumour expresses the so-called BRAF mutation. Activating mutations in the BRAF gene (a protein kinase) occur in 40-60% of patients, the most common mutations being V600E, followed by V600K. In recent years, the approval of immunomodulatory agents and targeted agents for treatment of advanced or metastatic melanoma has dramatically changed the landscape and is leading to a potential broad range of applications for combination therapies.

To date, there is no consensus on the optimal first line treatment for patients with BRAF mutant metastatic melanoma.

Evidence suggests that targeted agents can provide not only additive effects to immunotherapy but can also sensitise the tumour cells to immune attacks (by increasing antigen expression) and improve the effector function of immune cells. Pre-clinical data support the rationale for intermittent regimens with BRAF inhibitors, showing that the development of resistance could be delayed with intermittent therapy. The hypothesis is that a sequential approach could merge the high response rate of target therapy with the peculiarity of immunotherapy to achieve long-term durable responses, prior to secondary resistance to the targeted therapy occurring.

Recruitment to the EORTC-1612-MG trial started in November 2018. Completion of recruitment marks a crucial milestone for the trial.

‘I would like to sincerely thank all the persons who made this study possible in spite of the difficulties we went through in this troubled period. We will finally soon be in a position to answer the important questions that we wanted to address with this study’, says Professor Caroline Robert from the Gustave Roussy Cancer Institute, Villejuif, France and Coordinator of this trial for the EORTC Melanoma Group.

About the study
This is a multicentre, 2-arm open-label, randomised comparative phase II study. Its primary objective is to prospectively assess whether a sequential treatment approach with an induction period of 12 weeks with chemotherapy drugs encorafenib + binimetinib, followed by an immunotherapy combination with immunomodulatory agents nivolumab + ipilimumab, improves Progression Free Survival (PFS) compared to a nivolumab + ipilimumab immunotherapy combination alone as first line treatment, in patients with BRAF V600 mutation–positive unresectable or metastatic melanoma.

A total of 270 patients with unresectable or metastatic (stage IV) (as per AJCC Cancer Staging Manual, 7th edition) melanoma were randomised to receive either one of the two treatments:

Treatment arm A: nivolumab 3 mg/kg once every 3 weeks + ipilimumab 1 mg/kg once every 3 weeks or 4 infusions followed by nivolumab 480 mg intravenously once every 4 weeks until completion of 2 years total treatment or disease progression. Then treatment will be left at the investigator choice and continued until the second progression.

Treatment arm B: encorafenib 450 mg once a day + binimetinib 45 mg twice a day orally for 12 weeks followed, after a week of pause, by nivolumab 3 mg/kg once every 3 weeks + ipilimumab 1 mg/kg once every 3 weeks for 4 infusions, followed by nivolumab 480 mg intravenously once every 4 weeks until completion of 2 years total treatment or disease progression. Then patients will be rechallenged with encorafenib 450 mg once a day + binimetinib 45 mg twice a day orally continuously until the second progression.

This is an academic trial supported by the EORTC Melanoma Group, and a restricted educational grant from Pierre Fabre and Bristol Myers Squibb, who supply encorafenib & binimetinib and nivolumab & ipilimumab, respectively, for the duration of the trial.

First results from the trial are expected around mid-2023.

About Melanoma
Melanoma is the deadliest form of skin cancer. Historically, melanoma was a rare cancer, but in the last 50 years its incidence has risen faster than almost any other cancer [1] making it the 19th most commonly occurring cancer worldwide,[2] with over 320,000 new cases and over 55,000 deaths, in 2020.[3] After Australia and New Zealand, European countries have highest rates of melanoma incidence. According to GLOBOCAN, in Europe there are approximately 144.000 cases diagnosed per year and 27.000 deaths related.[4] By 2025, the number of cases is expected to increase to over 340,000.[5] Approximately half of the cases diagnosed have BRAF mutations, a key target in the treatment of metastatic melanoma.[6-8]

Melanoma develops when unrepaired DNA damage to skin cells triggers mutations that may lead them to multiply and form malignant tumours.[9] Starting from pigment-producing cells (melanocytes) in the skin, melanoma spreads to other parts of the body through metastasis.

Before the development of immune checkpoint inhibitors and anti-BRAF-targeted therapy, patients with metastatic melanoma had a median OS of less than 12 months. Both targeted therapy (anti-BRAF + anti-MEK) [11] and immunotherapy (anti-PD1 +/- anti-CTLA-4) have significantly prolonged the OS of patients with BRAF mutant metastatic melanoma.[11]

Matthews NH, Li WQ, Qureshi AA, et al. Epidemiology of Melanoma. In: Ward WH, Farma JM, editors. Cutaneous Melanoma: Etiology and Therapy [Internet]. Brisbane (AU): Codon Publications; 2017 Dec 21. Chapter 1. Available from: View Source doi: 10.15586/codon.cutaneousmelanoma.2017.ch1
WCRF International, Cancer trends – Skin cancer statistics; View Source
Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA CANCER J CLIN 2021;71:209–249. View Source
Melanoma Patient Network Europe, Melanoma – the facts. View Source
Melanoma UK. 2020 Melanoma Skin Cancer Report. View Source
American Cancer Society. What Causes Melanoma Skin Cancer. View Source
International Agency for Research on Cancer. Melanoma of skin. View Source
Klein O, et al. Eur J Cancer 2013;49:1073–1079.
2016;63(4):510-7. doi: 10.4149/neo_2016_40
Zeynep Eroglu, Antoni Ribas. Combination therapy with BRAF and MEK inhibitors for melanoma: latest evidence and place in therapy. Ther Adv Med Oncol. 2016; 8(1): 48–56. View Source
Anand Rotte. Combination of CTLA-4 and PD-1 blockers for treatment of cancer. Journal of Experimental & Clinical Cancer Research 2019; 38:255. View Source
About the EORTC Melanoma Group
The Melanoma Group aims to improve the clinical care of patients suffering with cutaneous, mucosal, or ocular melanoma, and to increase knowledge about melanoma acquisition and progression. Group sub-committees focus on topics including epidemiology, early-stage melanoma, surgery, pathology, and systemic therapy (adjuvant and for advanced disease).