On May 29, 2020 Dana-Farber Cancer Institute reported are presenting dozens of research studies at the 2020 Annual Meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) (Press release, Dana-Farber Cancer Institute, MAY 29, 2020, View Source [SID1234558682]). The studies will be presented online during the virtual scientific program taking place May 29-May 31. ASCO (Free ASCO Whitepaper) is the world’s largest clinical cancer research meeting, attracting more than 30,000 oncology professionals from around the world.

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The findings show new treatments and diagnostic advances in breast and lung cancers, lymphoma, kidney, and many others, as well as looking at using video education to guide care, and racial and ethnic disparities in cancer care. Some of the research highlights include:

Interim analysis of ZUMA-5: A phase 2 study of axicabtagene ciloleucel in patients with relapsed/refractory indolent non-hodgkin lymphoma

Author: Caron Jacobson, MD

Abstract: 8008

The vast majority of patients with follicular lymphoma or marginal zone lymphoma – two slow-growing forms of non-Hodgkin leukemia – responded to and benefited from a novel CAR T-cell therapy in a recent clinical trial, Dana-Farber Cancer Institute investigators report. The 140 participants (124 with follicular lymphoma, 16 with marginal zone lymphoma) in the ZUMA-5 trial had received a median of three treatments for their disease prior to treatment with axicabtagene ciloleucel, a CAR T-cell therapy that targets CD19 receptors on cancerous cells. Ninety-three percent of the patients showed a response to the therapy, including 80% who had a complete response – an absence of detectable cancer following treatment. In patients with an initial complete response, 80% maintained that response after a median follow-up of 15.3 months. The most common adverse effects of the therapy were neutropenia, anemia, and decreased neutrophil count, which generally were manageable. The rate of high-grade neurotoxicity was 15%. Among patients with follicular lymphoma, 23% had no cytokine release syndrome, and the median time to onset was four days, which may allow for outpatient dosing in the future.

Tucatinib vs placebo added to trastuzumab and capecitabine for patients with previously treated HER2+ metastatic breast cancer with brain metastases (HER2CLIMB)

Author: Nancy Lin, MD

Abstract: 1005

In patients with HER2+ metastatic breast cancer that has spread to the brain, combining the HER2-inhibiting agent tucatinib with trastuzumab and capecitabine can significantly delay the advance of the disease in the brain and extend patients’ lives, a clinical trial led by Dana-Farber Cancer Institute investigators has demonstrated. The HER2CLIMB study compared the three-drug regimen to trastuzumab and capecitabine alone in 291 patients whose breast cancer had metastasized to the brain. Participants in the tucatinib group experienced a median of nine months before the brain metastases grew worse, compared to 4.2 months for the non-tucatinib group, and survived a median of 18.1 months compared to 12 months for the non-tucatinib group. Based on results of HER2CLIMB, the FDA granted approval of the three-drug regimen on April 17, 2020, for the treatment of adult patients with advanced inoperable or metastatic HER2+ breast cancer, including patients with brain metastases, who have received one or more prior anti-HER2-based regimens in the metastatic setting.

A multicenter phase 2 study of venetoclax plus dose-adjusted R-EPOCH (VR-EPOCH) for Richter’s syndrome

Author: Matthew S. Davids, MD, MMSc

Abstract: 8004

Adding a relatively new targeted drug, venetoclax, to a standard chemoimmunotherapy regimen has shown promising activity in Richter’s syndrome, a transformation of a more indolent disease, chronic lymphocytic leukemia, into an aggressive form of non-Hodgkin lymphoma (NHL) with a particularly poor prognosis, say researchers from Dana-Farber. There is no standard of care for treatment, but a commonly used regimen is R-EPOCH, a combination of four chemotherapeutic agents plus rituximab, a monoclonal antibody immunotherapy drug. Although R-EPOCH is highly effective for some forms of NHL, in Richter’s syndrome the rate of complete response is only about 20%, and the average survival is only three to six months.

Venetoclax, the first of a class of drugs known as BCL2 inhibitors, had a 43% overall response rate as a single agent in small cohort of patients with Richter’s syndrome in a phase 1 study. In the current study, venetoclax was combined with R-EPOCH (VR-EPOCH) with the rationale that the venetoclax may work as a "chemosensitizing" agent to help the chemotherapy be more effective. This single-arm, phase 2 investigator-initiated multicenter study enrolled 26 patients at Dana-Farber, MD Anderson, and Ohio State. In the 20 patients who began combination therapy, 16 (80%) responded, including 13 (65%) who had complete response as best response. Eight patients had allogeneic stem cell transplants, with the first such patient now still in complete remission over two and half years after completing transplant. Patients who were not transplant candidates could continue on venetoclax maintenance, and the longest such patient has now been in complete remission for over two years after completing the chemotherapy portion of the study. The side effects were typical of those seen with R-EPOCH alone, including infections and low blood counts.

Matthew S. Davids, MD, MMSc, is the principal investigator and first author of the study and said about two-thirds of the patients who started the VR-EPOCH combination achieved complete remission, far higher than the 20% achieved historically with R-EPOCH alone and this chemosensitization strategy will be further explored in additional studies in this patient population.

Idecabtagene vicleucel, a BCMA-targeted CAR T-cell therapy, in patients with relapsed and refractory multiple myeloma; initial KarMMa results

Author:Nikhil Munshi, MD

Abstract: 8503

A potential CAR T-cell therapy that targets a key plasma cell antigen on cancer cells produced deep and lasting responses in patients with relapsed and treatment-resistant multiple myeloma who had undergone several previous treatments, according to preliminary data from an international clinical trial led by Dana-Farber Cancer Institute researchers. The 128 patients in the KarMMa study were treated with idecabtagene vicleucel, a genetically engineered CAR T-cell therapy made from patients’ own T cells that targets the B-cell maturation antigen (BCMA) on myeloma cells. After a median follow-up of 13.3 months, 73.3% of participants had a partial or complete response to the therapy, and the median interval before the disease worsened was 8.6 months, both of which were higher at increased doses. The most common adverse effects were cytopenia (a low red blood cell count) and cytokine release syndrome, a common side effect of CAR T-cell therapies.

A randomized controlled trial of video education or in-person genetic counseling for men with prostate cancer

Author:Huma Q. Rana, MD

Abstract: 1507

This study compared a novel video education method with in-person genetic counseling in advance of genetic testing for men with potentially lethal prostate cancer and found no significant differences in acceptability of genetic testing. Although the study has not been completed, this randomized trial suggests that video education can be used to improve access to cancer genetics education and testing to patients who, for various reasons including the coronavirus pandemic, lack access to in-person genetic counseling.

Led by Huma Q. Rana, MD, and Mary-Ellen Taplin, MD, the trial, called ProGen, recruited men with potentially lethal prostate cancer. This includes metastatic disease, a high Gleason score, rising PSA (prostate specific antigen) after local therapy, diagnosis at age 55 or younger, and other factors. Rana found 13% of subjects had pathogenic or likely pathogenic variants in cancer susceptibility genes; 32% of subjects with a positive result had pathogenic variants were in BRCA1 and BRCA2. Identifying those variants through genetic testing may lead to targeted therapy and can guide cancer surveillance. Genetic testing is recommended to these patients, but access to genetic counseling and testing is limited by strained resources. The ProGen study examined a novel video pretest model aimed at providing access to genetic testing for men who have been traditionally underserved/unrepresented in cancer genetics clinics.

Over a two-year period, 662 men were randomized 3:1 to video education or genetic counseling in person. At the time of the intervention, most men agreed or strongly agreed that their assigned arm – video or in-person – was useful. The researchers concluded that both the novel video education modality and traditional genetic counseling "yielded high genetic testing uptake without significant differences in outcome measures of acceptability and satisfaction."

US trends and racial/ethnic disparities in opioid access among patients with poor prognosis cancer near end of life

Author:Andrea Enzinger, MD

Abstract: 7005

Efforts to mitigate the opioid addiction crisis may have unintended consequences for cancer patients near the end of life, particularly for black patients and other racial/ethnic minorities. According to a recent Dana-Farber study, cancer patients’ access to opioids at the end-of-life has decreased substantially since 2007, with even greater declines among African Americans.

Andrea Enzinger, MD, is first author of this study which included 243,124 Medicare patients with poor prognosis cancers who died between 2007 and 2016. The analysis revealed that the proportion of cancer patients filling an opioid prescription in the 30 days before death or hospice enrollment fell from 41.7% to 35.7% over the study period, with greater decreases among black patients (39.3% to 29.8%) than white patients (42.2% to 36.5%). Use of long-acting opioids, which are important for managing severe cancer pain, also fell from 17% in 2007 to 12% in 2016. Blacks patients were also significantly less likely than white patients to be prescribed long-acting opioids and were prescribed significantly lower doses of opioids. Rates of emergency department visits for pain near the end of life increased from 13.2% to 18.8% over the study period. Again, black patients were significantly more likely than whites to receive care for their pain in an emergency department.

The researchers concluded that cancer patients’ access to opioids near the end-of-life decreased substantially from 2007 to 2016, while pain-related visits to emergency departments increased. Along with this trend, the scientists report that there are significant racial and ethnic disparities in opioid access, with black patients receiving fewer opioids at lower doses, and having more emergency-department-based care for pain near the end of life.

On May 29, 2020 CytomX Therapeutics, Inc. (Nasdaq: CTMX), a clinical-stage oncology-focused biopharmaceutical company pioneering a novel class of investigational antibody therapeutics based on its Probody therapeutic technology platform, reported the availability of oral and poster presentations at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper)’s (ASCO) (Free ASCO Whitepaper) ASCO (Free ASCO Whitepaper)20 Virtual Scientific Program taking place from May 29 – May 31, 2020 (Press release, CytomX Therapeutics, MAY 29, 2020, View Source [SID1234558680]).

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"A comprehensive body of evidence was presented today at ASCO (Free ASCO Whitepaper) 2020 that continues to validate our approach to conditional antibody activation and therapeutic target engagement with the Probody platform," said Amy Peterson, M.D., chief development officer of CytomX Therapeutics. "The seven presentations collectively highlight the potential of the Probody platform to enable successful engagement of previously undruggable targets, like CD71 and CD166, and create next generation immune-checkpoint inhibitors such as the anti-PD-L1 Probody therapeutic, CX-072, and BMS-986249, a Probody version of ipilimumab. The findings underpin the advancement of all four drug candidates into Phase 2 and our commitment to bringing meaningful advances to patients living with cancer."

CX-2029: Validating CD71 As A First-in-Class Oncology Target

In the oral abstract 3502, Dr. Melissa Johnson of the Sarah Cannon Research Institute at Tennessee Oncology, presented preliminary clinical data from the first-in-human, dose-escalation, monotherapy Phase 1 study of CX-2029, a Probody drug conjugate (PDC) targeting CD71 (transferrin receptor). CX-2029 is conjugated to the cytotoxic payload MMAE and is being developed by CytomX in partnership with AbbVie. As of an April 20, 2020 data cutoff, 45 patients with advanced solid tumors were enrolled into 8 escalating dose cohorts between 0.1 mg/kg – 5 mg/kg CX-2029 administered intravenously every three weeks.

Evidence of target lesion reduction was seen, principally in patients with tumors of squamous histology. (Figure 1)
° 3 confirmed partial responses were observed in 17 response-evaluable patients treated at doses ≥2 mg/kg of CX-2029, 2 in patients with squamous non-small cell lung cancer (SqNSCLC) and 1 in a patient with head and neck squamous cell cancer (HNSCC).
° 2 of the partial responses (both at the 3 mg/kg dose) were confirmed after the April 20th cutoff date.
CX-2029 Waterfall Plot (Doses 2–5 mg/kg)

CX-2029 Waterfall Plot (Doses 2–5 mg/kg)
Figure 1 is available at View Source

Safety Profile Supports Recommended Phase 2 Dose of 3 mg/kg, Every Three Weeks

CX-2029 was generally well tolerated at doses up to 3 mg/kg.
At doses of 0.25 – 5 mg/kg, CX-2029 circulated predominantly as the intact species (>90%).
The most common treatment related adverse events (TRAE) were infusion related reactions, anemia, and neutropenia/leukopenia.
° Infusion related reactions were mostly Grade 1/2, occurred at the first dose, were not dose dependent and resolved upon initiation of supportive care.
° Hematologic TRAEs Grade ≥ 3 were dose dependent.
• Anemia and neutropenia are commonly observed with the MMAE payload.
• Anemia was managed with transfusions and supportive care.
No CX-2029 treatment related deaths were reported and late onset Grade 3/4 TRAEs were predominately anemia and neutropenia.
The etiology of anemia is under investigation and is likely multifactorial, including MMAE-related and CD71 expression on red blood cell precursors.
CytomX is preparing to advance the dose of 3 mg/kg of CX-2029 administered every 3 weeks into 4 dose-expansion cohorts: HNSCC, SqNSCLC, esophageal carcinoma and diffuse large B cell lymphoma.
"Targeting CD71 with this novel approach has the potential to address areas of unmet medical need in difficult to treat tumor types, improving patient benefit," said Melissa L. Johnson, M.D., CX-2029 principal study investigator and associate director of lung cancer research at Sarah Cannon Research Institute at Tennessee Oncology. "This first-in-human data of CX-2029 establishes the transferrin receptor as a high potential anticancer target addressable with CytomX’s Probody technology."

CX-2009: Encouraging Clinical Activity Supports Advancement in HER2 Negative Breast Cancer

In Poster 18, Dr. Valentina Boni of START Madrid-CIOCC, presented updated data on CX-2009, a PDC targeting CD166 and conjugated to the cytotoxic payload DM4. As of an April 20, 2020 data cutoff, 96 patients were enrolled into the dose escalation Phase 1 study and received CX-2009 at escalating doses of 0.25 – 10 mg/kg every 3 weeks (86 patients) or 4 – 6 mg/kg every 2 weeks (10 patients).

Durable Clinical Activity Observed in HER2 Negative (HER2-) Breast Cancer

Evidence of target lesion reduction was observed at doses or dose equivalents of ≥4 mg/kg every 3 weeks across 68 evaluable patients including those with HER2- breast cancer, ovarian cancer, NSCLC and HNSCC.
° HER2- breast cancer patients were heavily pretreated with a median of 7 prior lines of therapy.
26 patients with HER2– breast cancer who received ≥4 mg/kg of CX-2009 were response-evaluable:
° 2 confirmed partial responses were observed, both in patients with hormone receptor positive (HR+) breast cancer.
° 3 unconfirmed responses were observed in patients with triple negative breast cancer (TNBC).
° Clinical benefit rates of 39% and 35% were observed at 16 and 24 weeks (CBR16 and CBR24, respectively).
• All 4 TNBC patients who achieved CBR16 also achieved CBR24.
CX-2009 Waterfall Plot and Spider Plot: HER2- Breast Cancer (≥4 mg/kg Every 3 Weeks)

CX-2009 Waterfall Plot and Spider Plot
Figure 2 is available at View Source

Safety Profile Supports Recommended Phase 2 Dose of 7mg/kg, Every 3 Weeks

CX-2009 was generally well tolerated at doses up to 7 mg/kg administered every three weeks.
No dose limiting toxicities (DLTs) were reported at doses up to 7 mg/kg.
DM4-related toxicities, including ocular, neuropathic, and hepatic were higher in frequency at dose equivalents greater than 7 mg/kg dosed at every three weeks compared to 7 mg/kg or lower.
° Occurrence and severity of ocular adverse events were dose dependent: One Grade 3+ event was observed in a patient treated at 5 mg/kg, none at 7 mg/kg.
° 20% of patients dosed at ≥8 mg/kg experienced Grade 3+ ocular adverse events.
Preliminary pharmacokinetic (PK) data showed that CX-2009 circulates predominantly intact at all doses and PK is not strongly influenced by target-mediated drug disposition or anti-drug antibodies (ADAs). (Poster 329)
In December 2019, CytomX announced the initiation of a Phase 2 expansion study of CX-2009 monotherapy at 7 mg/kg administered every three weeks in up to 40 patients with hormone receptor (ER, PR) positive, HER2 negative breast cancer. In March 2020, CytomX announced the decision to temporarily pause new patient enrollment and new site activation in this study due to the impact of the COVID-19 pandemic. CytomX continues to closely monitor emerging Health Authority guidance and IRB/Ethics Committee recommendations and intends to resume the CX-2009 clinical program as soon as practicable.

"Patients with advanced breast cancer continue to need treatment options, this is especially true for patients with hormone receptor positive and HER2 negative breast cancer that is refractory to hormonal based therapies," said Alison L. Hannah, M.D., chief medical officer of CytomX Therapeutics. "We believe that targeting CD166, previously considered undruggable as an oncology target, using our Probody drug conjugate platform, may provide a unique treatment opportunity for this patient population. The data in patients with triple negative breast cancer are equally interesting and support the advancement of CX-2009 monotherapy into Phase 2 where we will also evaluate CX-2009 in combination with CX-072, our Probody therapeutic directed against PD-L1."

CX-072: Anti-PD-L1 Probody Checkpoint Inhibitor

In the oral presentation of Abstract 3005 by Dr. Fiona Thistlethwaite of The Christie NHS Foundation Trust at the University of Manchester, updated data were presented from the Phase 1/2 trial of PROCLAIM-CX-072 monotherapy and CX-072 in combination with ipilimumab with a focus on patients who received long-term treatment, defined as ≥ 6 months of treatment. The CX-072 10 mg/kg monotherapy expansion arm enrolled 114 patients in seven tumor types.

As of an April 20, 2020 data cutoff, CX-072 monotherapy continued to demonstrate durable anti-tumor activity in patients with IO sensitive tumors such as TNBC, anal squamous cell carcinoma (aSCC), cutaneous squamous cell carcinoma (cSCC) and tumors with high mutational burden (hTMB).
As of the same data cutoff, CX-072 in combination with ipilimumab had been administered to 27 patients with advanced solid tumors. Durable anti-cancer activity was observed including one complete response in a patient with aSCC who remains on study more than two years after first dose.
Of the 141 patients across the monotherapy and combination arms: 34 patients received long term treatment in the monotherapy arm (median 11.3 months), and 6 patients received long term treatment in the combination arm (median 21.3 months).
Grade 3/4 TRAEs were 10% and 5.9% for who received monotherapy < 6 months and ≥ 6 months, respectively, and 33% in each group in the combination arm.
Long term patients experienced fewer irAEs and had no grade 3+ irAEs suggesting that tolerability early on can impact duration of treatment.
Preliminary clinical PK data (Poster 332) and translational analyses of pre- and on-treatment biopsies (Poster 172) were supportive of the Probody mechanism of action.
CX-072 Monotherapy Waterfall Plots and Spider Plots (10 mg/kg)

CX-072
Figure 3 is available at View Source

Continued Dr. Hannah "Our ASCO (Free ASCO Whitepaper)20 clinical, translational, and pharmacokinetic presentations on CX-072 reinforce previously presented data and show clear evidence of anti-cancer activity and favorable tolerability for this unique checkpoint inhibitor. These integrated data support a differentiated profile for CX-072 that we believe can be of potential utility as a unique combination partner for other anti-cancer agents, including CX-2009."

BMS-986249: Anti-CTLA-4 Probody Demonstrates Encouraging Safety Profile in Phase 1 Trial

Bristol Myers Squibb presented dose escalation data from their Phase 1/2 trial of BMS-986249, a Probody version of the anti-CTLA-4 antibody ipilimumab in Abstract 3508. This trial assessed the safety, pharmacokinetics and pharmacodynamics of escalating doses of BMS-986249 as monotherapy or in combination with the anti PD-1 antibody nivolumab in patients with advanced cancers. The doses of BMS-986249 ranged from 240 mg to 2400 mg (approximately 3 – 30 mg/kg). BMS-986249 was generally well tolerated as monotherapy and in combination with nivolumab. Bristol Myers Squibb has initiated a randomized clinical trial to explore various doses of BMS-986249 in combination with nivolumab in patients with advanced melanoma.

ASCO20 Virtual Scientific Program – Posters and Presentations

Copies of the ASCO (Free ASCO Whitepaper)20 presentations and posters are available under the Scientific Publications section of the CytomX website at www.CytomX.com.

Conference Call and Webcast

CytomX senior management will host a conference call and live webcast with slides today, Friday, May 29, 2020, from 5:00 p.m. – 6:00 p.m. ET/ 2:00 p.m. – 3:00 p.m. PT to discuss these presentations. This event can be accessed in three ways:

From the CytomX website: View Source Please access the website 15 minutes prior to the start of the call to download and install any necessary audio software.

By telephone: Participants can access the call by dialing 1-877-809-6037 (United States) or 1-615-247-0221 (International) referencing Conference ID 4267278.

By replay: A replay of the webcast will be located under the Investor Relations section of CytomX’s website approximately two hours after the conclusion of the live call and will be available for 30 days following the call.

On May 29, 2020 Constellation Pharmaceuticals, Inc. (Nasdaq: CNST), a clinical-stage biopharmaceutical company using its expertise in epigenetics to discover and develop novel therapeutics, reported that the Company will participate in an upcoming virtual investor conference (Press release, Constellation Pharmaceuticals, MAY 29, 2020, View Source [SID1234558679]). Jigar Raythatha, CEO, will present at the Jefferies Virtual Healthcare Conference at 2:30 PM EDT on June 2. A live audio webcast of Mr. Raythatha’s presentation and archives for replay will be available on the Investor Relations section of Constellation’s website at View Source The audio webcast replay will be available for 30 days following the live presentation.

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On May 29, 2020 AstraZeneca and Daiichi Sankyo Company, Limited (Daiichi Sankyo) reported that Detailed results from the positive, registrational, randomised controlled Phase II DESTINY-Gastric01 trial showed Enhertu (trastuzumab deruxtecan) demonstrated a statistically significant and clinically meaningful improvement in objective response rate (ORR) and overall survival (OS), a key secondary endpoint, versus chemotherapy (Press release, AstraZeneca, MAY 29, 2020, View Source [SID1234558678]).

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The trial evaluated patients with HER2-positive unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma that had progressed following two or more treatment regimens including trastuzumab and chemotherapy.

Gastric cancer is the third leading cause of cancer mortality with a five-year survival rate of 5% for metastatic disease.1,2 Approximately one in five gastric cancers are considered HER2 positive.3,4

The confirmed ORR, assessed by independent central review, was 42.9% with Enhertu monotherapy (6.4mg/kg) compared to 12.5% with investigator’s choice of chemotherapy (paclitaxel or irinotecan). Ten complete responses (CRs) and 41 partial responses (PRs) were seen in patients treated with Enhertu versus no CRs and seven PRs seen in patients treated with chemotherapy.

Patients treated with Enhertu had a 41% reduction in the risk of death versus patients treated with chemotherapy (based on a hazard ratio [HR] of 0.59; 95% confidence interval [CI] 0.39-0.88; p=0.0097) at a pre-specified interim analysis. The median OS was 12.5 months versus 8.4 months with chemotherapy. The estimated OS rate at one year in the Enhertu arm was 52.1% and 28.9% with the chemotherapy arm.

Kohei Shitara, MD, Chief of Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Chiba, Japan and principal investigator in the Phase II DESTINY-Gastric01 trial, said: "Once patients with HER2-positive metastatic gastric cancer progress following initial treatment with an anti-HER2 regimen, there are limited options and no approved HER2-targeted therapies. Based on the compelling results of the DESTINY-Gastric01 trial, Enhertu has the potential to become a new standard of care for these patients."

José Baselga, Executive Vice President, R&D Oncology, said: "In DESTINY-Gastric01, the response rate was more than three times higher with Enhertu versus chemotherapy. Additionally, more than half of patients treated with Enhertu were alive at one year compared to less than a third with chemotherapy. In addition to the impressive results we saw in HER2-positive metastatic breast cancer in DESTINY-Breast01, these results in gastric cancer may help further define the role of Enhertu in transforming patient outcomes across multiple HER2-targetable cancers."

Antoine Yver Executive Vice President and Global Head, Oncology Research and Development, Daiichi Sankyo, said: "Enhertu is the first HER2-directed therapy to show an improvement in overall survival for patients with previously treated HER2-positive metastatic gastric cancer. These data are encouraging and meaningful since patients with advanced gastric cancer have limited therapeutic options once they progress and face markedly high mortality rates. We are working with regulatory authorities to bring Enhertu to patients with metastatic gastric cancer as quickly as possible."

Enhertu showed a confirmed disease control rate (DCR) of 85.7% versus 62.5% and a median confirmed duration of response (DoR) of 11.3 months versus 3.9 months with chemotherapy.

Summary of results:i

SD, stable disease
i. Data cut-off was 8 November 2019.
ii. Enhertu 6.4mg/kg.
iii. As assessed by independent central review.
iv. ORR is (CR + PR).
v. Confirmed ORR represents responses confirmed by a follow-up scan ≥four weeks after initial CR/PR; unconfirmed ORR is the primary endpoint of the trial (51.3% [95% CI 41.9–60.5] versus 14.3% [95% CI 6.4–26.2]; p<0.0001). Both confirmed and unconfirmed ORR were assessed by independent central review.
vi. DCR is (CR + PR + SD).

The safety and tolerability profile of Enhertu in DESTINY-Gastric01 was consistent with that observed in the Phase I gastric cancer trial and previously reported Enhertu trials.5 The most common Grade 3 or higher treatment-emergent adverse events were decreased neutrophil count (51.2%), anaemia (37.6%), decreased white blood cell count (20.8%) and decreased appetite (16.8%). There were 12 cases (9.6%) of confirmed treatment-related interstitial lung disease (ILD) and pneumonitis as determined by an independent review. The majority were Grade 1 or 2 with two Grade 3, one Grade 4 and no Grade 5 (ILD-related deaths).

The results were presented during the 2020 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) ASCO (Free ASCO Whitepaper)20 Virtual Scientific Program and simultaneously published online in The New England Journal of Medicine.6

Enhertu was recently granted Breakthrough Therapy Designation (BTD) in the US for the treatment of patients with HER2-positive unresectable or metastatic gastric cancer based on data from DESTINY-Gastric01 trial and Orphan Drug Designation (ODD) for patients with gastric cancer, including gastroesophageal junction cancer.

Gastric cancer

Gastric (stomach) cancer is the fifth most common cancer worldwide and the third leading cause of cancer mortality with a five-year survival rate of 5% for metastatic disease; there were approximately one million new cases reported in 2018 and 783,000 deaths.1,2

Approximately one in five gastric cancers are HER2 positive.3,4 HER2 is a tyrosine kinase receptor growth-promoting protein expressed on the surface of many types of tumours including breast, gastric, lung and colorectal cancers. Gastric cancer is usually diagnosed in the advanced stage, but even when diagnosed in earlier stages of the disease the survival rate remains modest.7 Recommended 1st-line treatment for HER2-positive advanced or metastatic gastric cancer is combination chemotherapy plus trastuzumab, an anti-HER2 medicine, which has been shown to improve survival outcomes when added to chemotherapy. For gastric cancer that progresses on 1st-line treatment, there are no other approved HER2-targeted medicines.8

DESTINY-Gastric01

DESTINY-Gastric01 is a registrational Phase II, open-label, multi-centre, randomised controlled trial testing the safety and efficacy of Enhertu versus investigator’s choice of chemotherapy in a primary cohort of 188 patients from Japan and South Korea with HER2-expressing, advanced gastric cancer or gastroesophageal junction adenocarcinoma (defined as IHC3+ or IHC2+/ISH+) who have progressed on two or more prior treatment regimens including fluoropyrimidine and platinum chemotherapy and trastuzumab. Patients were randomised 2:1 to receive Enhertu or investigator’s choice of chemotherapy (paclitaxel or irinotecan monotherapy). Patients were treated with Enhertu 6.4mg/kg once every three weeks or chemotherapy.

The primary endpoint of the trial is ORR, as assessed by independent central review. ORR, or tumour response rate, represents the percentage of patients whose disease decreased and/or disappears. OS was a key secondary endpoint to be statistically evaluated hierarchically at a prespecified interim analysis if the primary endpoint was statistically significant. Other secondary endpoints include progression-free survival, DoR, DCR and confirmed ORR assessed in those responses confirmed by a follow-up scan of at least four weeks after initial independent central review.9

Enhertu

Enhertu (trastuzumab deruxtecan; fam-trastuzumab deruxtecan-nxki in the US) is a HER2-directed antibody drug conjugate (ADC) and is the lead ADC in the oncology portfolio of Daiichi Sankyo and the most advanced programme in AstraZeneca’s ADC scientific platform. ADCs are targeted cancer medicines that deliver cytotoxic chemotherapy ("payload") to cancer cells via a linker attached to a monoclonal antibody that binds to a specific target expressed on cancer cells.

Enhertu (5.4mg/kg) is approved in the US and Japan for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2-based regimens based on the DESTINY-Breast01 trial.

Enhertu clinical development

A comprehensive development programme is underway globally with six registrational trials evaluating the efficacy and safety of Enhertu monotherapy across multiple HER2-targetable cancers including breast, gastric and lung cancers. Trials in combination with other anticancer treatments, such as immunotherapy, are also underway.

In May 2020, Enhertu received BTD from the US FDA for the treatment of patients with HER2-positive unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma who have received two or more prior regimens including trastuzumab and ODD for patients with gastric cancer, including gastroesophageal junction cancer. In March 2018, Enhertu received a SAKIGAKE designation for potential use in the same HER2-positive gastric cancer patient population and a supplemental New Drug Application was recently submitted to the Japan Ministry of Health, Labour and Welfare.

In May 2020, Enhertu also received a BTD for the treatment of patients with metastatic non-small cell lung cancer whose tumours have a HER2 mutation and with disease progression on or after platinum-based therapy.

Collaboration between AstraZeneca and Daiichi Sankyo

In March 2019, AstraZeneca and Daiichi Sankyo entered into a global collaboration to jointly develop and commercialise Enhertu worldwide, except in Japan where Daiichi Sankyo maintains exclusive rights. Daiichi Sankyo is solely responsible for manufacturing and supply.

AstraZeneca in oncology

AstraZeneca has a deep-rooted heritage in oncology and offers a quickly growing portfolio of new medicines that has the potential to transform patients’ lives and the Company’s future. With six new medicines launched between 2014 and 2020, and a broad pipeline of small molecules and biologics in development, the Company is committed to advance oncology as a key growth driver for AstraZeneca focused on lung, ovarian, breast and blood cancers. In addition to AstraZeneca’s main capabilities, the Company is actively pursuing innovative partnerships and investment that accelerate the delivery of our strategy, as illustrated by the investment in Acerta Pharma in haematology.

By harnessing the power of four scientific platforms – Immuno-Oncology, Tumour Drivers and Resistance, DNA Damage Response and ADCs – and by championing the development of personalised combinations, AstraZeneca has the vision to redefine cancer treatment and, one day, eliminate cancer as a cause of death.

On May 29, 2020 AstraZeneca reported Detailed results from an updated analysis of the Phase III CASPIAN trial showed Imfinzi (durvalumab) in combination with a choice of chemotherapies, etoposide plus either carboplatin or cisplatin, demonstrated a sustained, clinically meaningful overall survival (OS) benefit for adults with extensive-stage small cell lung cancer (ES-SCLC) treated in the 1st-line setting (Press release, AstraZeneca, MAY 29, 2020, View Source [SID1234558677]).

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The CASPIAN trial met the primary endpoint of OS in June 2019, reducing the risk of death by 27% (based on a hazard ratio [HR] of 0.73; 95% confidence interval [CI] 0.59-0.91; p=0.0047) which formed the basis of the US FDA approval in March 2020.

After a median follow up of more than two years, the latest results for Imfinzi plus chemotherapy showed sustained efficacy, maintaining a 25% reduction in the risk of death versus chemotherapy alone (based on an HR of 0.75; 95% CI 0.62, 0.91; nominal p=0.0032). Updated median OS was 12.9 months versus 10.5 for chemotherapy. In a post-hoc analysis, an estimated 22.2% of patients treated with Imfinzi plus chemotherapy were alive at 24 months versus 14.4% for chemotherapy.

For Imfinzi plus chemotherapy, 11% of patients were alive and progression-free at 24 months versus 2.9% for chemotherapy alone (post-hoc). Imfinzi plus chemotherapy maintained a high confirmed objective response rate (ORR) (68% versus 58%) and in a post-hoc analysis, duration of response (DoR) for Imfinzi at 24 months was 13.5% versus 3.9% for chemotherapy. At 24 months, 12% of patients in the Imfinzi plus chemotherapy arm remained on Imfinzi treatment.

Luis Paz-Ares MD, Ph.D., Chair, Medical Oncology Department, Hospital Universitario Doce de Octubre, Madrid, Spain and principal investigator in the Phase III CASPIAN trial said: "These updated results from the CASPIAN trial show a remarkable 22% of patients still alive at 24 months, supporting the sustained benefits of treatment with Imfinzi plus chemotherapy. This is an effective 1st-line treatment in the extensive-stage setting, where improving outcomes has been a challenge and so few patients survive five years."

José Baselga, Executive Vice President, Oncology R&D, said: "After two years median follow-up, Imfinzi continues to show sustained and meaningful improvements in survival and prolonged treatment response for patients facing this devastating and aggressive disease. These data reinforce Imfinzi plus chemotherapy as an important new standard of care for extensive-stage small cell lung cancer patients, and this regimen offers patients convenient dosing every four weeks during maintenance. We look forward to bringing the benefits of Imfinzi to patients around the world."

The second experimental arm in the CASPIAN trial testing tremelimumab, an anti-CTLA4 monoclonal antibody, added to Imfinzi and chemotherapy showed a trend towards OS, but did not reach statistical significance compared to chemotherapy alone.

Summary of updated results:

Data cut-off date was 27 January 2020. Formal statistical analysis was completed at the time of the interim analysis per trial protocol. Therefore, no formal testing for statistical significance could be performed in this updated analysis.

i. Etoposide plus investigator choice of carboplatin or cisplatin chemotherapy.
ii. OS rate is an estimated proportion of patients alive at 24 months.
iii. Post-hoc analysis.
iv. Confirmed responses according to investigator assessment per RECIST v1.1.
v. Unconfirmed ORR was a prespecified secondary endpoint per protocol.

The safety and tolerability for Imfinzi plus chemotherapy was consistent with the known safety profile of these medicines. Results showed 62.3% of patients experienced a Grade 3 or 4 adverse event with Imfinzi plus chemotherapy (all causes) versus 62.8% with chemotherapy alone. The percentage of patients discontinuing treatment (all causes) was 10.2% for Imfinzi plus chemotherapy and 9.4% for chemotherapy alone.

Imfinzi in combination with etoposide and either carboplatin or cisplatin is currently under regulatory review for the treatment of ES-SCLC in the 1st-line setting in the EU and Japan.

Updated results from the CASPIAN trial were presented during the 2020 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) ASCO (Free ASCO Whitepaper)20 Virtual Scientific Program on 29 to 31 May 2020. Several presentations featured during the meeting will showcase AstraZeneca’s leadership in lung cancer across early and late-stage disease and reinforce the Company’s biomarker-driven approach.

Small cell lung cancer

Lung cancer is the leading cause of cancer death among both men and women and accounts for about one fifth of all cancer deaths.1 Lung cancer is broadly split into NSCLC and SCLC, with about 15% classified as SCLC.2 SCLC is a highly aggressive, fast-growing form of lung cancer that typically recurs and progresses rapidly despite initial response to chemotherapy.3,4 About two thirds of SCLC patients are diagnosed with extensive-stage disease, in which the cancer has spread widely through the lung or to other parts of the body.5 Prognosis is particularly poor, as only 6% of all SCLC patients will be alive five years after diagnosis.5

CASPIAN

CASPIAN was a randomised, open-label, multi-centre, global, Phase III trial in the 1st-line treatment of 805 patients with ES-SCLC. The trial compared Imfinzi in combination with etoposide and either carboplatin or cisplatin chemotherapy, or Imfinzi and chemotherapy with the addition of a second immunotherapy, tremelimumab, versus chemotherapy alone. In the experimental arms, patients were treated with four cycles of chemotherapy. In comparison, the control arm allowed up to six cycles of chemotherapy and optional prophylactic cranial irradiation. The trial was conducted in more than 200 centres across 23 countries, including the US, in Europe, South America, Asia and the Middle East. The primary endpoint was OS in each of the two experimental arms.

Imfinzi

Imfinzi (durvalumab) is a human monoclonal antibody that binds to PD-L1 and blocks the interaction of PD-L1 with PD-1 and CD80, countering the tumour’s immune-evading tactics and releasing the inhibition of immune responses.

Imfinzi is approved in the curative-intent setting of unresectable, Stage III NSCLC after chemoradiation therapy in the US, Japan, China, across the EU and in many other countries, based on the Phase III PACIFIC trial. Imfinzi is approved for the 1st-line treatment of ES-SCLC in combination with chemotherapy in the US and Singapore. Imfinzi is also approved for previously treated patients with advanced bladder cancer in the US and a small number of other countries.

As part of a broad development programme, Imfinzi is also being tested as a monotherapy and in combination with tremelimumab, an anti-CTLA4 monoclonal antibody and potential new medicine, as a treatment for patients with NSCLC, SCLC, bladder cancer, head and neck cancer, liver cancer, biliary tract cancer, cervical cancer and other solid tumours.

Tremelimumab

Tremelimumab is a human monoclonal antibody and potential new medicine that targets the activity of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). Tremelimumab blocks the activity of CTLA-4, contributing to T-cell activation, priming the immune response to cancer and fostering cancer cell death. Tremelimumab is being tested in a clinical trial programme in combination with Imfinzi in NSCLC, SCLC, bladder cancer, head and neck cancer and liver cancer.

AstraZeneca in lung cancer

AstraZeneca has a comprehensive portfolio of approved and potential new medicines in late-stage development for the treatment of different forms of lung cancer spanning different histologies, several stages of disease, lines of therapy and modes of action. We aim to address the unmet needs of patients with EGFR-mutated tumours as a genetic driver of disease, which occur in 10-15% of NSCLC patients in the US and EU and 30-40% of NSCLC patients in Asia, with the approved medicines Iressa (gefitinib) and Tagrisso and its ongoing Phase III trials LAURA, and FLAURA2.6-8 We are also committed to addressing tumour mechanisms of resistance through the ongoing Phase II trials SAVANNAH and ORCHARD which test Tagrisso in combination with savolitinib, a selective inhibitor of c-MET receptor tyrosine kinase, along with other potential new medicines. Enhertu a HER2-directed antibody drug conjugate is in development for metastatic non-squamous HER2-overexpressing or HER2-mutated NSCLC including trials in combination with other anticancer treatments.

An extensive Immuno-Oncology development programme focuses on lung cancer patients without a targetable genetic mutation which represents up to three-quarters of all patients with lung cancer.9 Imfinzi, an anti-PDL1 antibody, is in development for patients with advanced disease (Phase III trials POSEIDON and PEARL) and for patients in earlier stages of disease including potentially-curative settings (Phase III trials MERMAID-1, AEGEAN, ADJUVANT BR.31, PACIFIC-2, PACIFIC-4, PACIFIC-5, and ADRIATIC) both as monotherapy and in combination with tremelimumab and/or chemotherapy. Imfinzi is also in development in the Phase II trials NeoCOAST, COAST and HUDSON in combination with potential new medicines from the early-stage pipeline including Enhertu.

AstraZeneca’s approach to Immuno-Oncology

Immuno-oncology (IO) is a therapeutic approach designed to stimulate the body’s immune system to attack tumours. The Company’s IO portfolio is anchored by immunotherapies that have been designed to overcome anti-tumour immune suppression. AstraZeneca is invested in using IO approaches that deliver long-term survival for new groups of patients across tumour types.

The Company is pursuing a comprehensive clinical-trial programme that includes Imfinzi as a monotherapy and in combination with tremelimumab in multiple tumour types, stages of disease, and lines of therapy, and where relevant using the PD-L1 biomarker as a decision-making tool to define the best potential treatment path for a patient. In addition, the ability to combine the IO portfolio with radiation, chemotherapy, small targeted molecules from across AstraZeneca’s Oncology pipeline, and from research partners, may provide new treatment options across a broad range of tumours.

AstraZeneca in oncology

AstraZeneca has a deep-rooted heritage in oncology and offers a quickly growing portfolio of new medicines that has the potential to transform patients’ lives and the Company’s future. With six new medicines launched between 2014 and 2020, and a broad pipeline of small molecules and biologics in development, the Company is committed to advance oncology as a key growth driver for AstraZeneca focused on lung, ovarian, breast and blood cancers. In addition to AstraZeneca’s main capabilities, the Company is actively pursuing innovative partnerships and investment that accelerate the delivery of our strategy, as illustrated by the investment in Acerta Pharma in haematology.

By harnessing the power of four scientific platforms – Immuno-Oncology, Tumour Drivers and Resistance, DNA Damage Response and Antibody Drug Conjugates – and by championing the development of personalised combinations, AstraZeneca has the vision to redefine cancer treatment and, one day, eliminate cancer as a cause of death.