LENVATINIB CAN OVERCOME IMMUNOTHERAPY RESISTANCE IN MELANOMA

Patients with advanced melanoma who have progressed on anti-programmed death (PD)-1/PD ligand 1 (PD-L1) immunotherapy could substantially extend their overall survival (OS) with a combination of the tyrosine kinase inhibitor lenvatinib (Lenvima) and pembrolizumab (Keytruda), suggests an open-label, single arm study.

The research was presented September 19 at the European Society for Medical Oncology Virtual Congress 2020.

In LEAP-004 trial, over 100 patients with stage 3 or 4 melanoma who had progressed after immunotherapy were given lenvatinib plus pembrolizumab, which yielded a median progression-free survival (PFS) of more than 4 months and a median OS of more than a year. Median follow-up was 12 months.

Presenting the findings, Ana Maria Arance Fernandez, MD, PhD, Hospital Clínic de Barcelona, Spain, said lenvatinib plus pembrolizumab has "promising" antitumor activity in patients with advanced melanoma with confirmed progression on a PD-1 inhibitor given alone or in combination. "These results are encouraging given the stringent definition of progression on prior anti-PD-1 therapy and the enrollment of poor-risk patients."

Arance Fernandez added that "these data support lenvatinib plus pembrolizumab as a potential treatment regimen for this population of high unmet medical need."

Bartosz Chmielowski, MD, PhD, Jonsson Comprehensive Cancer Center at the University of California, Los Angeles, who was not involved in the study, discussed the findings.

He highlighted that the patients were not randomly assigned in LEAP-004, with all of them receiving the same therapy.

Nevertheless, the response rate was "quite impressive for this patient population."

He also drew comparison with previous data with nivolumab (Opdivo) alone or in combination with ipilimumab (Yervoy) in a similar population, noting that the overall survival was less than half that seen in the current trial, "which makes these results even more important."

"It tells us that this combination might be an option with disease progression on anti-PD-1," Chmielowski noted.

Investigator Arance Fernandez pointed out that patients with advanced melanoma who progress on standard-of-care treatment with anti-PD-1 therapy or a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor plus anti-PD-1 "have very limited therapeutic options available and there is no approved regimen in this indication."

Response Rate, PFS, and OS

Previous studies have indicated that adding an anti-PD-1 drug to lenvatinib achieves superior antitumor activity than either treatment alone, with promising results in phase 1/2b data in pretreated metastatic melanoma.

LEAP-004 therefore enrolled patients with unresectable stage 3 or 4 melanoma, who had disease progression within 12 weeks of their last dose of anti-PD-(L)1 therapy either alone or with a CTLA-4 inhibitor. There was no limit on the number of prior treatments.

The patients received pembrolizumab 200 mg IV for up to 35 cycles plus lenvatinib 20 mg daily until progression, unacceptable toxicity, or patient or physician decision.

They were imaged at baseline and every 9 weeks through to week 54, then every 12 weeks until week 102, and then every 24 weeks.

From February to September 2019, 103 patients were enrolled, all of whom received at least one dose of lenvatinib plus pembrolizumab. The median age of the patients was 63 years, and 53.4% were male.

Arance Fernandez pointed out that this was a high-risk population, with 20.4% having a lactate dehydrogenase level twice the upper limit of normal and 14.6% brain metastasis, while the median sum of target lesions was 100 mm.

A BRAFv600 mutation was identified in 36.9% of patients and 64.1% were PD-L1 positive.

Nearly one third (28.2%) had received a prior anti-CTLA-4 plus anti-PD-(L)1 combination, and 19.5% had undergone four or more prior lines of therapy.

The overall response rate to lenvatinib plus pembrolizumab was 21.4%, with 1.9% having a complete response, and 19.4% a partial response. This was seen across subgroups, including by age and disease stage.

Arance Fernandez said that the overall response rate was even higher in patients who had previously been treated with an anti-CTLA-4 plus anti-PD-(L)1 combination, at 31%.

However, Chmielowski warned that "we must interpret this result with caution since only 29 patients were in this subpopulation."

The median duration of blinded independent committee review-confirmed response across the study population was 6.3 months, with 72.6% still responding at 6 months.

The median PFS was 4.2 months with the combination therapy, with 41.7% of patients progression-free at 6 months, and 26.2% at 9 months.

Median overall survival was 13.9 months, with 77.3% of patients still alive at 6 months, and 65.4% alive at 9 months.

Although 96.1% of patients experienced at least one treatment-related adverse event of any grade, only 44.7% had grade 3 or higher events, and only in 7.8% of cases did that lead to treatment discontinuation.

The most common adverse events were hypertension (56.3%), diarrhea (35.9%), nausea (34%), and hypothyroidism (33%), although in the vast majority of cases these were grade 1 or 2.

LEAP Presents Challenges

UCLA's Chmielowski would like to see treatment in this setting individualized somehow.

"It will be also important to come up with personalized immunotherapy, so that based on the mechanism of resistance in patient populations, we would be able to choose the subsequent treatments," he commented.

Investigator Arance Fernandez explained that lenvatinib inhibits multiple tyrosine kinases involved in angiogenesis, cell proliferation, and immune modulation, and has demonstrated immunomodulatory activity in the tumor microenvironment.

However, Arance Fernandez noted that, as resistance to immunotherapy is "multifactorial," it may be that a combination treatment will be more effective in these patients.

The study was funded by Merck. Arance Fernandez has financial ties to Merck and multiple other drug companies. Chmielowski has financial ties to Merck Serono and multiple other companies.  

ESMO Virtual Congress 2020: Abstract LBA44. Presented September 19, 2020.

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NO BENEFIT OF MAINTENACE IMMUNOTHEARPY IN LIMITED SCLC

Giving nivolumab (Opdivo, Bristol-Myers Squibb) plus ipilimumab (Yervoy, Bristol-Myers Squibb) to small cell lung cancer (SCLC) patients after chemoradiotherapy does not offer a progression-free or overall survival benefit, suggests top-line data from a phase II trial.

However, there were signals that a longer follow-up period and a focus on patient subgroups could reveal a biomarker-driven population who will benefit from the treatment combination.

The research was presented at the ESMO Virtual Congress 2020 on September 19, which was held digitally this year due to the COVID-19 pandemic.

No Survival Benefits

For the STIMULI study more than 150 limited stage SCLC patients who had undergone chemoradiotherapy were randomised to either nivolumab plus ipilimumab induction followed by nivolumab maintenance monotherapy, or to the observation group.

Professor Solange Peters, ESMO president, and Oncology Department, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland reported that the immunotherapy combination did not significantly improve progression-free survival (PFS) or overall survival.

Prof Peters said that the study "did not meet its primary endpoint of improving PFS", adding that "a very short period on active treatment observed in the study, related to toxicity and subsequent treatment discontinuation, has certainly impacted the efficacy results".

"A longer follow-up...will allow the exploration of a possible late effect of immunotherapy consolidation on survival, which is already apparent" despite the short follow-up.

Noting the differential benefits of immunotherapy in certain subgroups, notably women and those who received twice daily radiotherapy fractions, Prof Peters said that exploratory work to identify potential biomarkers for response "is ongoing".

Study co-author Professor Sanjay Popat, Royal Marsden Hospital NHS Foundation Trust, London, told Medscape News UK that they were "of course" disappointed to see no improvement in survival.

"Nevertheless, this is an advance in the field because we’ve already showed this is not perhaps the best schedule" of immunotherapy due to the "relatively high rate of grade 3 and more adverse events".

But with greater understanding of the subgroups who showed a benefit and biomarker evaluation and several other trials ongoing, he has "no doubt that in the future we will be showing that checkpoint inhibitors are active in limited state SCLC".

Prof Popat added: "We just have to prove that benefit, and that’s why it’s absolutely important we continue to generate the evidence and ensure that our patients get access to clinical trials."

Disappointment

The results were described as "disappointing" by many on Twitter.

However, Stephen V. Liu director of thoracic oncology at Georgetown University, Washington DC, USA, said that, while STIMULI showed that the immunotherapy combination "did not improve" survival outcomes, the crossing of the curves pointed to the "statistical challenges" of the study.

https://twitter.com/stephenvliu/status/1307289636805513216?s=21

Dr Jonathan Lim, a PhD candidate at The Francis Crick Institute, London, highlighted the "interesting difference" in PFS between patients receiving twice daily and once daily radiotherapy.

"Are we potentially seeing the effect of immunogenic radiotherapy?" he asked.

https://twitter.com/drjonlim/status/1307281921941135360?s=21

 

'Frontline Standard of Care'

Prof Peters began her presentation by noting that the combination of nivolumab and ipilimumab has become a "frontline standard of care" in a number of metastatic cancers, including renal cell carcinoma and non-small cell lung cancer.

Moreover, CheckMate 032 showed that nivolumab monotherapy achieves durable responses and is well tolerated as a third or later line treatment in recurrent SCLC.

This did not translate into a longer PFS and overall survival, although there were signals for improved response in patients with a high tumour mutational burden.

For the phase II STIMULI trial, patients with treatment-naïve stage I–IIIB SCLC and a good performance status were given chemoradiotherapy followed by prophylactic cranial irradiation.

If they did not progress, they were randomised in a 1:1 fashion to immunotherapy consolidation or observation, with no further treatment.

Immunotherapy consisted of four cycles of induction treatment with nivolumab plus ipilimumab 3 times a week for four cycles, followed by nivolumab twice weekly for up to 12 months.

From an initial enrolment of 222 patients, 78 patients were assigned to immunotherapy consolidation and 75 to observation.

The median age of the patients was approximately 62 years. The majority (84%) had stage IIIA or IIIB disease, and between 80% and 83% had a partial response to chemoradiotherapy.

After a median follow-up of 22.7 months, 51 immunotherapy and 48 observation patients were still in the trial.

Prof Peters noted that most of the treatment failures in the observation group were due to disease progression, "while importantly in the nivolumab and ipilimumab arm most treatment failures were related not to disease progression but to toxicity, or to patient or investigator decision".

Trial Data

There was no significant difference between the immunotherapy and observation arms in terms of PFS, at 10.7 months and 14.5 months, respectively, or a hazard ratio of 1.02 (p=0.93).

Interestingly, patients with an ECOG performance status of 1 did better on immunotherapy than those with a status of 0, at a hazard ratio for PFS of 0.67 versus 2.06 (p for interaction=0.022).

A similar split was seen for patients who were treated with 2 radiotherapy fractions per day versus those who received one, at hazard ratios for PFS with immunotherapy of 0.63 and 1.34, respectively (p for interaction=0.096).

Overall survival was again not significantly different between the immunotherapy and observation arms, with the median not reached in the immunotherapy group, whilst it was 31.6 months - hazard ratio of 1.06 (p=0.83) – in the observation group.

However, and "very importantly in this secondary endpoint," she said, the curves crossed, suggesting that a survival benefit with immunotherapy accrued over time.

Indeed, the hazard ratio for survival for immunotherapy versus observation fell from 1.91 (p=0.14) between months 0 and 12 to 0.97 (p=0.95) between months 12 and 24, to 0.25 (p=0.087) from month 24.

There were also certain patients who appeared to benefit with immunotherapy, with women having a hazard ratio for overall survival of 0.34 versus 1.55 for men (p for interaction=0.034).

Patients with an ECOG status of 1 had a hazard ratio for overall survival with immunotherapy of 0.44 versus 4.62 versus those with a status of 0 (p for interaction=0.0009).

Two radiotherapy fractions per day was also associated with an overall survival benefit, at a hazard ratio with immunotherapy of 0.41 versus 1.75 for 2 fractions per day (p for interaction=0.015).

The combination treatment resulted in "significant toxicity" versus observation, Prof Peters said, with any cause adverse events of grade ≥3 seen in 62% versus 25%.

She said that most of the adverse events recorded for immunotherapy "unfortunately" led to treatment discontinuation, at 55% for any cause events.

The most common adverse events reported for immunotherapy were fatigue (49%), anorexia (32%), diarrhoea (28%), and vomiting (27%).
 

'Too Toxic'

Invited discussant Professor Corinne Faivre-Finn, professor of thoracic radiation oncology at the University of Manchester, said that, based on the current results, the combination nivolumab and ipilimumab therapy must be considered "too toxic" for this setting.

Moreover, results from phase 2 studies with less than 200 patients "cannot be considered definitive and practice-changing".

With a lack of more details on the radiotherapy regimens used in the study, and a lack of biomarker data to predict response to immunotherapy, she said that the standard of care in limited stage SCLC patients therefore remains radiotherapy at 45 Gy twice daily.

Prof Faivre-Finn nevertheless said that, with other trials of immunotherapy and chemoradiotherapy combinations currently recruiting, the message is: "watch this space".

The STIMULI trial was sponsored by the European Thoracic Oncology Platform (ETOP) and financed by a grant from Bristol Myers Squibb.

Prof Peters declares consultation/advisory role: Abbvie, Amgen, AstraZeneca, Bayer, Biocartis, Bioinvent, Blueprint Medicines, Boehringer-Ingelheim, Bristol-Myers Squibb, Clovia, Daiichi Sankyo, Debiopharm, Eli Lilly, F. Hoffman La Roche, Foundation Medicine, Illumina, Janssen, Merck Sharp and Dohme, Merck Serono, Merrimack, Mirati, Novartis, Pharma Mar, Regeneron, Sanofi, Seattle Genetics, Takeda and Vaccibody; Talk’s: AztraZeneca, Boehringer-Ingelheim, Bristol Myers Squibb, Eli Lilly, F. Hoffman La Roche, Illumina, Merck Sharp and Dohme, Novartis, Pfizer, Sanofi, Takeda; Grants/research support: Amgen, AstraZeneca, Biodesix, Boehringer-Ingelheim, Bristol Myers Squibb, Clovis, F. Hoffman La Roche, Illumina, Merck Sharp and Dohme, Merck Serono, Novartis, and Pfizer.

Prof Popat declares Honoraria (self): BMS; Honoraria (self): Roche; Honoraria (self): Takeda; Honoraria (self): AstraZeneca; Honoraria (self): Pfizer; Honoraria (self): MSD; Honoraria (self): EMD Serono; Honoraria (self): Guardant Health; Honoraria (self): AbbVie; Honoraria (self): Boehringer-Ingelheim; Honoraria (self): OncLive; Honoraria (self): Medscape; Honoraria (self): Incyte; Honoraria (self): Paradox Pharmaceuticals; Honoraria (self): Eli Lilly.

Prof Faivre-Finn declares research funding: AZ, MSD, Elekta; Advisory Board: AZ, Pfizer, Boehringer Ingelheim (institutional).

No other relevant financial relationships declared.

ESMO Virtual Congress 2020: Abstract LBA84. Presented September 19.

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Cite this: Liam Davenport. A Glimmer of Hope for Immunotherapy in SCLC? - Medscape - Sep 23, 2020.

KRAS INHIBITORS N NSCLC-SOTORASIB

KRAS, one of the most frequently mutated oncogenes in human cancer, has long been thought to be "undruggable," but early results from a clinical trial of the experimental KRAS-inhibitor sotorasib (Amgen) suggest that at least one KRAS mutation common in non-small cell lung cancers (NSCLC) has a soft underbelly.

In the phase 1 CodeBreaK 100 trial, sotorasib, an investigational first-in-class inhibitor of the KRAS p.G12C mutation, showed encouraging activity against advanced NSCLC and other solid tumors.

Among patients with NSCLC, 19 (32.2%) of 59 had a confirmed objective response to sotorasib monotherapy, and 52 (88.1%) had disease control, reported David S. Hong, MD, from the University of Texas MD Anderson Cancer Center in Houston.

"Sotorasib also demonstrated durable disease control in heavily pretreated patients with non-small cell lung cancer," said Hong.

He presented secondary efficacy endpoint results from the trial in an online presentation during the European Society of Medical Oncology (ESMO) Virtual Congress 2020.

The study was also published simultaneously online in the New England Journal of Medicine.

The trial met its primary endpoint of safety of sotorasib, with no dose-limiting toxicities or treatment-related fatal adverse events, and treatment-emergent grade 3 or higher adverse events occurring in less than 20% of patients.

"The safety profile is more favorable than that of other targeted agents, and I think the reason why you have a quite safe compound here is that sotorasib is very specific in its binding to KRAS G12C, and KRAS G12C is only present in the tumor," co-investigator Marwan G. Fakih, MD, a medical oncologist at City of Hope Comprehensive Cancer Center in Duarte, California, told Medscape Medical News. Fakih was co-lead author of the report in NEJM.

A Real "Triumph"

Sotorasib is "a triumph of drug discovery," commented Colin Lindsay, MD, from the University of Manchester, UK, the invited discussant.

"We know that KRAS, over many years, over three decades, has been very difficult to target," he said.

"The early development of KRAS G12C-targeted agents is just the beginning, lending hope that the ability to target not only other KRAS mutations but also other targets previously thought to be undruggable may be within reach," write Patricia M. LoRusso, DO, from the Yale Cancer Center in New Haven, Connecticut, and Judith S. Sebolt‑Leopold, PhD, from the University of Michigan Rogel Cancer Center in Ann Arbor, in an accompanying editorial.

The KRAS, which stands for Kristen rat sarcoma viral oncogene homologue, p.G12C mutation is a glycine-to-cysteine substitution that results in the oncogene being switched on in its active form. The mutation has been identified in approximately 13% of NSCLC tumors, in 1% to 7% of colorectal cancers, and in other solid tumors.

But the mutation has been considered too difficult to target because of KRAS' strong binding affinity for guanosine triphosphate (GTP), an essential building block of RNA synthesis, and by a lack of accessible drug binding sites.

Sotorasib is a small-molecule, specific and irreversible inhibitor of KRAS that interacts with a "pocket" on the gene's surface that is present only in an inactive conformation of KRAS. The drug inhibits oncogenic signaling and tumorigenesis by preventing cycling of the oncogene into its active form, investigator Fakih explained.

Study Details

The CodeBreaK 100 investigators enrolled patients with 13 different locally advanced or metastatic solid tumor types, all bearing the KRAS p.G12C mutation.

The trial began with a dose-escalation phase, with two to four patients per cohort assigned to receive daily oral sotorasib at doses of 180, 360, 720, or 960 mg. The 960 mg dose was selected for expansion cohorts and for planned phase 2 studies, based on the safety profile and the lack of dose-limiting toxicities.

Hong and colleagues reported results for 129 patients treated in the dose-escalation and expansion cohorts, including 59 with NSCLC, 42 with colorectal cancer and 28 with other tumor types, but focused primarily on patients with NSCLC.

After a median follow-up of 11.7 months, 59 patients with NSCLC had been treated, 3 at the 180 mg dose, 16 at 360 mg, 6 at 720 mg, and 34 at 960 mg. At the time of data cutoff in June of this year, 14 patients were still on treatment and 45 had discontinued, either from disease progression (35 patients), death (5), patient request (4) or adverse events (1).

As noted, there were no dose-limiting toxicities or treatment-related fatalities reported.

Grade 3 or 4 treatment-related adverse events were reported in 18.6% of patients. The only grade 4 treatment-related event was elevated alanine aminotransferase (ALT) in one patient (1.7%). Grade 3 events included elevated liver transaminases in 9 patients, increased alkaline phosphatase in 2, anemia in 1, and increased gamma-glutamyl transferase levels, decreased lymphocyte count, hepatitis, and hyponatremia in 1 patient each.

Fakih told Medscape Medical News that given sotorasib's high degree of specificity, it's unclear what might be causing the observed adverse events.

Responses at All Dose Levels

The confirmed partial response rate was 32.2% for patients with NSCLC treated at all dose levels, and 35.3% for patients who received the 960 mg dose.

Among all NSCLC patients, and all treated at the highest 960 mg dose level, the stable disease rates were 55.9%. The respective disease control rates were 88.1% and 91.2%.

Tumor reductions occurred across all dose levels in patients with NSCLC. The median progression-free survival was 6.3 months.

Hong reported results for one patient, a 59-year-old man with the mutation who had experienced disease progression on five prior therapies including targeted agents, chemotherapy, and a checkpoint inhibitor, and had gamma-knife surgery for brains lesions.

This patient had a complete response in target lesions and a partial response overall, which included shrinkage of central nervous system metastases; he recently had progression in non-target lesions, after 1.5 years in response, Hong said.

The median duration of response was 10.9 months for patients with partial responses, and 4 months for patients with stable disease.

Hong noted that response to sotorasib was seen across a range co-mutational profiles, including several patients with four mutations in addition to KRAS p.G12C.

Other Tumors, Possible Combinations

Among 42 patients with colorectal cancers bearing the KRAS p.G12C mutation, 3 (7.1%) had a partial response. There were also partial responses seen in one patient each with melanoma and with appendiceal, endometrial, and pancreatic tumors.

"Overall, the results of this trial are very encouraging, showing the first step in 'drugging the undruggable,' '' LoRusso and Sebolt-Leopold write in their editorial.

They suggested that therapy with sotorasib may be improved by combining it with other agents that could target resistance to KRAS inhibition.

"A recent study showed that KRAS G12C colorectal cancer cells have higher basal epidermal growth factor receptor (EGFR) activity than NSCLC cells, leading to a rapid rebound in mitogen-activated protein (MAP) kinase signaling and resistance to KRAS G12C inhibition," the editorialists write. "This observation is consistent with the weaker observed clinical activity of sotorasib in patients with colorectal cancer, a problem that may be addressed by combining it with an EGFR inhibitor (e.g., cetuximab), as seen preclinically."

"I think this drug is being positioned not only in refractory disease, but we're hoping to see it move up front in non-small cell lung cancer, and we're hoping to improve its efficacy in colorectal cancer," study author Fakih told Medscape Medical News.

The study was sponsored by Amgen and by grants from the National Institutes of Health. Hong disclosed research/grant funding and an advisory/consulting role with Amgen and others. Fakih disclosed a speaking engagement for Amgen and consulting for and grant support from others. Lindsay disclosed consulting for Amgen and institutional research funding from the company and others. LoRusso disclosed fees from multiple companies, not including Amgen. Sebolt-Leopold has disclosed no relevant financial relationships.

N Engl J Med. Published online September 20, 2020. Abstract

ESMO Virtual Annual Meeting: Abstract 1257O. Presented September 20, 2020.

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Cite this: Sotorasib Is a 'Triumph of Drug Discovery'in Cancer - Medscape - Sep 21, 2020.

PEMBROLIZUMAB FOR SOME RARE SARCOMAS

Sarcomas are rare malignancies, and effective therapies, apart from surgery and radiotherapy, are largely limited to chemotherapy and a handful of targeted agents.

But a few rare sarcoma subtypes may respond to therapy with the immune checkpoint inhibitor pembrolizumab (Keytruda), as French investigators demonstrated in the phase 2 AcSé trial.

Results from the study were presented online during the European Society of Medical Oncology (ESMO) Virtual Congress 2020.

"We all know that there is limited single-agent activity of PD-1 antibodies or PD-L1 antibodies as well as CTLA-4 antibodies in unselected sarcoma populations. But we also know that sarcomas are more than 150 different histotypes or molecular subtypes of disease," commented led author Jean-Yves Blay, MD, PhD, from Université Claude Bernard in Lyon, France.

Combinations of checkpoint inhibitors and antiangiogenic agents have been associated with prolonged progression-free survival (PFS) in alveolar soft part sarcomas (ASPSs), and single-agent activity of immunotherapeutic agents has been reported in other rare subtypes, including chordoma and rhabdoid tumors, he said.

But given the rarity and heterogeneity of sarcomas, investigators are increasingly "moving from a one-size-fits-all approach to a basket approach, and this was the intent of this clinical trial," Blay said.

AcSé Study Details

AcSé was a multicenter, open-label study involving patients with metastatic or treatment-refractory rare disease types, including sarcomas.

Patients with histologically confirmed diagnoses of rare sarcomas with metastatic disease or unresectable locally advanced tumors for whom there were no alternative treatment options were eligible.

Although there was no set definition of "rare," for most sarcoma subtypes included in the study, the incidence was less than 1 per one million population.

The cohort included 81 patients: 24 with chordoma, 14 with alveolar ASPS, five with desmoplastic small round cell tumor (DSRCT), six with SMARCA4-malignant rhabdoid tumor (SMBT), and 32 with diseases of other histotypes, including epitheliod sarcoma, myxoid liposarcoma, chondrosarcoma, angiosarcoma, and other unspecified types.

The median age of the patients was 48 years. Patients had received a median of two prior lines of therapy.

Patients received pembrolizumab 200 mg intravenously every 21 days for up to 2 years or until disease progression or unacceptable toxicity or until the physician or the patient decided to withdraw.

Some Objective Responses Seen

The primary endpoint was the objective response rate by intention to treat at 84 days. Among all patients with sarcoma, there were no complete responses, but five patients (6%) had a partial response. An additional 34 patients had stable disease, for a disease control rate of 48%.

The best responses by histotype were seen in 2 of 6 patients with SMBT, 1 of 5 patients with epitheloid sarcoma, 2 of 24 with chordoma, 5 of 14 with ASPS, and 2 of 22 with other types.

There were no objective responses among patients with myxoid liposarcoma, DSRCT, chondosarcoma, or angiosarcoma.

At a median follow-up of 228 days, the median PFS was 7.9 months. Median overall survival was 19.7 months. In all, 33 patients died during follow-up, after a median of three cycles.

In all, 60% of patients who had had an initial response experienced disease progression or withdrew before 84 days. These patients were counted as nonresponders in the intention-to-treat analysis.

PFS was superior among patients with ASPS, chordoma, and DSCRT compared with patients with diseases of other histologies.

Overall survival was also superior among patients with ASPS and chordoma compared with patients with other sarcoma subtypes.

Toxicities were recorded in 28 patients. Grade 3 events occurred in four patients (one case each of cognitive disorder, bullous pemphigus, febrile aplasia, and erysipelas). There was one case of grade-4 lipasemia.

Blay noted that the four subtypes for which pembrolizumab prolonged PFS ― ASPS, chordoma, SMBT, and DSCRT ― are not consistently associated with either PD-L1 expression, high tumor mutational burden, cell infiltrates, or tertiary lymphoid structures that might make them susceptible to a PD-1/PD-L1 inhibitor.

"Therefore, additional translational research is foreseen to understand the determinants of response in these sarcoma histotypes," he said.

Anti-PD-1 Recommended for Some Subtypes

Invited discussant Javier Martin-Broto, MD, PhD, from the Instituto de Biomedicina de Sevilla, Sevilla, Spain, commented that compared with other studies of immunotherapy with pembrolizumab (SARC028) or nivolumab (Opdivo; Alliance A091401), "the longer median progression-free survival observed in the current study could be highly related to the subtypes included in the study."

In other studies with drug combinations, the respective median PFS for chordoma, ASPS, and epithelioid sarcoma was 14 months, 10.9 – 12.4 months, and 5.53 – 6 months, he noted.

"Anti PD-1 agents should be included in the therapeutic arsenal of some subtypes as an example alveolar soft part sarcoma or malignant rhabdoid tumors. Anti-PD-1 immunomodulation deserves further investigations in tumors with misfunctioning SWItch/Sucrose Non-Fermentable complex, such as epithelioid sarcoma, dedifferentiated chordoma, and others," he said.

Martin-Broto also recommended that clinical research be conducted into regimens for sarcomas that combine chemotherapy with immunomodulators.

The study was supported by Merck Sharp & Dohme. Blay disclosed honoraria, consulting/advising, and research funding from MSD and others. Martin-Broto disclosed consulting/advising, speakers bureau participation, and research funding from several companies, not including MSD.

European Society for Medical Oncology (ESMO) Annual Meeting 2020: Abstract 1691O, presented September 21, 2020.

IMPASSION 131- A NEGATIVE TRIAL OF PEMBRO-PACLITAXEL IN TNBC

Certain patients with triple-negative breast cancer (TNBC) may benefit when atezolizumab is combined with nab-paclitaxel but not with paclitaxel, a pair of phase 3 trials suggest.

The trials, IMpassion130 and IMpassion131, both enrolled patients with metastatic or unresectable, locally advanced TNBC.

In IMpassion131, adding atezolizumab to paclitaxel did not improve progression-free survival (PFS) or overall survival (OS), regardless of programmed death–ligand 1 (PD-L1) expression.

In IMpassion130, adding atezolizumab to nab-paclitaxel did not improve OS in the intention-to-treat (ITT) population but did provide a "clinically meaningful" improvement in OS among PD-L1-positive patients, according to investigators.

IMpassion130 and IMpassion131 were presented during the same session at the European Society for Medical Oncology (ESMO) Virtual Congress 2020.

Potential reasons for the different outcomes in the two studies require further exploration, according to David Miles, MD, of Mount Vernon Cancer Centre in Northwood, England, who presented the findings from IMpassion131.

ESMO discussant Lisa A. Carey, MD, of the University of North Carolina at Chapel Hill, posited three possible explanations for the divergent findings. The steroids necessary with paclitaxel dosing may have had a negative effect on immune checkpoint inhibitor activity, differences in study populations may have played a role, or the divergent findings could be caused by chance.

Steroid use in IMpassion131 could have played a negative role because of its lympholytic activity, but other indications with steroid use have not demonstrated attenuated benefits, said Leisha A. Emens, MD, PhD, of the University of Pittsburgh Medical Center, who presented the findings from IMpassion130 at ESMO 2020.

"If I were a patient, based on the data to date, I would want nab-paclitaxel with atezolizumab," Dr. Emens said.

Trial Details

Both trials are phase 3, double-blind, placebo-controlled studies of women with metastatic or unresectable locally advanced TNBC who had received no prior therapy for advanced TNBC.

IMpassion130 included 451 patients randomized to atezolizumab plus nab-paclitaxel and 451 randomized to placebo plus nab-paclitaxel. Patients received nab-paclitaxel at a starting dose of 100 mg/m2 via IV infusion on days 1, 8, and 15 of each 28-day cycle for at least six cycles.

In both studies, patients received atezolizumab at 840 mg on days 1 and 15 of a 28-day cycle in their active treatment arms.

IMpassion131 included 651 patients randomized 2:1 to atezolizumab plus paclitaxel (n = 431) or placebo plus paclitaxel (n = 220). Patients received paclitaxel at 90 mg/m2 on days 1, 8, and 15 every 28 days until disease progression or unacceptable toxicity.

Baseline characteristics were well balanced between the treatment arms in both studies. Less than half of patients – 45% in IMpassion131 and 41% in IMpassion130 – were PD-L1 positive.

Results of IMpassion131

The primary endpoint in IMpassion131 was PFS, and there was no significant difference in PFS between the treatment arms.

"The primary objective of IMpassion131 was not met," Dr. Miles said. "[The] addition of atezolizumab to paclitaxel did not significantly improve PFS in patients with PD-L1-positive metastatic triple-negative breast cancer."

In the PD-L1-positive population, the median PFS was 5.7 months in the placebo arm and 6.0 months in the atezolizumab arm (stratified hazard ratio, 0.82, P = .20).

In the ITT population, the median PFS was 5.6 months in the control arm and 5.7 months in the atezolizumab arm (HR, 0.86).

In subgroup analyses, Dr. Miles noted, "There was no clue about adverse or beneficial effects in any subgroup."

The updated OS analysis demonstrated no benefit with atezolizumab in the ITT population or the PD-L1-positive population. In fact, there was a trend toward better OS for the control group in the latter analysis.

In the PD-L1-positive population, the median OS was 28.3 months in the control arm and 22.1 months in the atezolizumab arm (HR, 1.12). The 2-year OS rates were 51% and 49%, respectively.

In the ITT population, the median OS was 22.8 months in the control arm and 19.2 months in the atezolizumab arm (HR, 1.11). The 2-year OS rates were 45% and 42%, respectively.

The safety profile of the atezolizumab-paclitaxel combination was consistent with known side effects of the individual drugs, Dr. Miles said. There were four fatal treatment-related adverse events in the atezolizumab arm.

Results of IMpassion130

Presenting the final OS analysis from IMpassion130, Dr. Emens noted that the study's findings have led to recommendations for atezolizumab plus nab-paclitaxel as first-line treatment of PD-L1-positive TNBC in international guidelines.

The median OS in the ITT population was 18.7 months in the placebo arm and 21.0 months in the atezolizumab arm (stratified HR, 0.87, P = .077). The 3-year OS rates were 25% and 28%, respectively.

The median OS in the PD-L1-positive population was 17.9 months in the placebo arm and 25.4 months in the atezolizumab arm (HR, 0.67). The 3-year OS rates were 22% and 36%, respectively.

A P value is not available for the between-arm OS comparison in the PD-L1-positive population. OS was not formally tested in this group because the OS boundary for statistical significance was not crossed in the ITT population. However, Dr. Emens said there was a "clinically meaningful" OS benefit observed with atezolizumab in the PD-L1-positive patients.

Treatment withdrawals caused by adverse events were more common in the atezolizumab arm (19% vs. 8%). The most common of these was neuropathy, Dr. Emens said. However, she noted that atezolizumab-related adverse events were generally low grade and easily managed.

"These results support a positive benefit-risk profile for atezolizumab plus nab-paclitaxel as first-line therapy in patients with PD-L1-positive metastatic triple-negative breast cancer," Dr. Emens concluded.

Both studies were funded by F. Hoffman–La Roche. Dr. Miles, Dr. Emens, and Dr. Carey disclosed financial relationships with Roche and other companies.

SOURCES: Miles D et al. ESMO 2020, Abstract LBA15; Emens LA et al. ESMO 2020, Abstract LBA16.

This article originally appeared on MDedge.com, part of the Medscape Professional Network.

ADJUVANT ABEMACICLIB IN BREAST CANCER

Adding the CDK4/6 inhibitor abemaciclib (Verzenio) to endocrine therapy significantly reduces the risk of early recurrence in high-risk hormone receptor positive (HR+), human epidermal growth factor receptor 2 (HER2)-negative breast cancer, suggests a preplanned interim analysis of a phase 3 trial.

The research was presented September 19 at the ESMO Virtual Congress 2020 and simultaneously published in the Journal of Clinical Oncology.

The monarchE trial compared 2 years of abemaciclib plus endocrine therapy vs endocrine therapy alone among 5600 patients and found that the combination was associated with a 25% relative risk reduction in the primary endpoint — invasive disease-free survival (P =.0096; HR, 0.75; 95% CI, 0.60 - 0.93)

At 2 years, the rate of invasive disease-free survival was 92.2% in the abemaciclib arm vs 88.7% in the group that took endocrine therapy alone.

"This is the first time in more than 20 years that we have seen an advance in the adjuvant treatment of this form of breast cancer," said lead investigator Stephen Johnston, MD, PhD, from the Royal Marsden Hospital NHS Foundation Trust in London, UK, in a meeting press release.

Dr Stephen Johnston

He told Medscape Medical News that the high-risk patients in their study "are predicted to relapse quite quickly," as a result of having a degree of endocrine resistance, "and by intervening early we are stopping these recurrences within the first 2 years."

He continued: "The key issue…is whether you need 2 years of treatment or perhaps even longer. One other trial is looking at 3 years with another drug and we'll just have to await further follow-up of the data to see if the [monarchE] curves continue to separate while on treatment."

According to Giuseppe Curigliano, MD, PhD, head of the Division of Early Drug Development at the European Institute of Oncology, Milan, Italy, "This is a very important trial and the findings will change practice. Once approved for high risk HR+ HER2-negative early breast cancer, the new standard of care for these patients will be to add two years of abemaciclib to endocrine therapy."

Curigliano, who was not involved with the study, further commented during a meeting press conference that a randomized trial will be needed to answer a new important question: Can these high-risk patients treated with a CDK4/6 inhibitor be spared chemotherapy?

Investigator Johnston pointed out that many patients diagnosed with HR+, HER-2 breast cancer will not experience recurrence with standard-of-care therapies.

But he also explained "that up to 20% may develop recurrence or distant relapse in the first 10 years," and that the risk of recurrence is "much greater" for patients who have high-risk clinical or pathological features, "especially during the first few years on their adjuvant endocrine therapy."

Study Details

Abemaciclib was approved by the US Food and Drug Administration in 2017 and is approved in combination with the endocrine therapy fulvestrant for the treatment of HR+, HER2-negative advanced or metastatic breast cancer that has progressed after endocrine therapy.

The approval was in-part based on data from the MONARCH-2 trial, which showed consistent overall survival benefits with the combination.

MonarchE, on the other hand, examined the impact of abemaciclib in the first-line adjuvant setting, enrolling patients with HR+, HER2-negative, node-positive early breast cancer who had a tumor size of ≥5 cm, histologic grade 3 disease, and/or Ki67 index of ≥20%.

They were randomly assigned in a 1:1 fashion to abemaciclib 150 mg twice daily for up to two years plus standard of care endocrine therapy or standard of care endocrine therapy alone.

The choice of endocrine therapy was left to the physician and was continued for 5-10 years, as clinically indicated.

The trial included 5637 patients. An efficacy interim analysis was planned for when 75% of the estimated invasive disease-free survival events had occurred, which equated to 323 events in the intention-to-treat population.

This occurred after approximately 15.5 months of follow-up in each arm, when 12.5% of patients had completed the two-year treatment period, leaving 70% still in treatment.

The intention-to-treat population included 2808 patients from the abemaciclib plus endocrine therapy group and 2829 in the group taking endocrine therapy alone.

The two groups were well balanced in terms of their baseline characteristics. The vast majority (approximately 85%) of patients were younger than age 65 years, and 56.5% were postmenopausal.

Also, 37% had previously received neoadjuvant chemotherapy and approximately 58% adjuvant chemotherapy.

Distant relapse-free survival was also significantly reduced with abemaciclib plus endocrine therapy vs endocrine therapy alone, at a hazard ratio of 0.72 (P = .0085), and a two-year rate of 93.6% and 90.3%, respectively.

Johnston highlighted that not only was the number of patients with distant recurrences reduced with the combination therapy, at 92 vs 142 with endocrine therapy alone, but also the reductions were in key locations.

The number of patients with recurrences in the bone were 32 with abemaciclib and 81 with endocrine therapy alone; 29 patients with abemaciclib and 42 with endocrine therapy alone had recurrences in the liver.

The results show that the most frequent adverse events in the abemaciclib arm were diarrhea (82%), neutropenia (45%), and fatigue (38%), whereas arthralgia (31%), hot flush (21%), and fatigue (15%) were seen most often in the control group.

A venous thromboembolic event was recorded in 2.3% of patients in the abemaciclib group versus 0.5% of those on endocrine therapy alone; interstitial lung disease was seen in 2.7% and 1.2%, respectively.

Despite the protocol allowing dose reductions from 150 mg to 100 mg twice daily if required, 463 (16.6%) patients discontinued abemaciclib as a result of adverse events. Of those, 306 continued on endocrine therapy.

"Adherence to treatment will be an important issue to be considered in the real-life population of patients when this treatment is approved and used in clinical practice," Johnston said.

Nevertheless, diarrhea frequency and severity decreased significantly over time and only 4.8% of the abemaciclib group discontinued use as a result of this adverse event.

Questions Remain

George W. Sledge Jr, MD, professor of medicine (oncology) at Stanford University Medical Center, Palo Alto, California, was the invited discussant after the presentation.

He said that "positive trails raise as many questions as they answer, and monarchE is no exception."

For example, there is the conundrum posed by the negative results of the very similar PALLAS trial, which looked at the addition of palbociclib to adjuvant endocrine therapy for HR+, HER2-negative early breast cancer, and was also presented at the ESMO meeting.

Returning to monarchE, Sledge asked what the ultimate increase in invasive disease- and distant relapse-free survival will be with the drug combination, noting that the trial has "very, very short follow-up."

"Second, will the improvements seen in disease-free survival lead to what we really care about: improved overall survival? Again, time will tell, but healthcare systems and patients care deeply about the answer to this question."

Sledge continued: "How about late recurrence? Do CDK4/6 inhibitors kill off dormant or slow-growing micro-mets that lead to recurrences 5 or more years out?"

He also asked what the optimum duration therapy would be: "Is it more than we need, or not enough?"

Sledge wondered whether it is possible to determine who benefits "and why the drug fails some patients."

Finally, Sledge said, "These drugs are expensive…2 years of adjuvant therapy is simply out of reach for the majority of patients around the globe who might be candidates for adjuvant CDK4/6 inhibitor therapy."

And he observed an important truism: "A patient cannot benefit from a drug she cannot take."

The study was funded by Eli Lilly and Company. Johnston, Sledge, and Curigliano have financial ties to Eli Lilly and multiple other drug companies.

ESMO Virtual Congress 2020: Abstract LBA5_PR. Presented September 19, 2020.

J Clin Oncol. Published online September 19, 2020. Full text

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Cite this: Abemaciclib Cuts Early Recurrence in High-risk Breast Cancer - Medscape - Sep 21, 2020.

SACITUZUMAB FOR TRIPLE NEGATIVE BREAST CANCER

The antibody–drug conjugate sacituzumab govitecan (SG) (Trodelvy) significantly extends both progression-free survival (PFS) and overall survival (OS) for patients with metastatic triple-negative breast cancer (TNBC) that has progressed after multiple lines of therapy, phase 3 trial data show.

The first-in-class drug is directed at trophoblast cell surface antigen 2 (Trop-2), which is highly expressed in breast cancer. Research on the drug was presented at the ESMO Virtual Congress 2020 on September 19.

ASCENT randomly assigned more than 500 patients who had metastatic TNBC and who had experienced disease progression after a median of four lines of therapy to receive either SG or physician's choice of chemotherapy. SG significantly improved median PFS (5.6 vs 1.7 months; hazard ratio [HR], 0.41; P < .0001) and median OS (12.1 vs 6.7 months; HR, 0.48; P < .0001).

The response rate was 35% for SG vs 5% for chemotherapy (P < .0001).

The study was presented by Aditya Bardia, MD, MPH, a medical oncologist at Massachusetts General Hospital, Boston, Massachusetts.

He said that because the safety profile of SG is consistent with previous reports and that the treatment discontinuation rate was low, the clinical benefit "confirms the use of sacituzumab govitecan" in metastatic TNBC. This was a reference to the fact that the drug previously received accelerated approval on the basis of early data.

Bardia added that ongoing studies are evaluating the use of SG in earlier lines of therapy, including neoadjuvant settings in combination with other targeted agents, as well as in hormone receptor–positive metastatic breast cancer. One such study is the phase 3 TROPiCS-02 study, which is actively accruing patients.

Invited discussant Fatima Cardoso, MD, director of the Breast Unit at Champalimaud Clinical Center, Lisbon, Portugal, said that the treatment algorithm for the management of TNBC will need to be updated in light of these results.

"In my opinion, we should now add sacituzumab govitecan as a new treatment option for patients treated with two or more lines of therapy," she said.

She noted that the study design raised some questions over the way such trials should be conducted and the future sequencing of treatments.

Objections to Study Design and Execution

Discussant Cardoso said that the choice of PFS as the primary endpoint for the trial was not ideal.

"In the metastatic setting, and particularly for triple-negative breast cancer, where the median survival is quite low and where each line of treatment, particularly after the second line, has a short duration, the primary endpoint should have been overall survival," she commented.

"Luckily, we saw some results, but we could have missed it," Cardoso said. She made "a plea to make sure that overall survival is at least the co-primary endpoint" in the future.

Cardoso also said it was not clear to her why the trial had to be stopped. "For the current patients, if there is no crossover, there is no benefit in stopping the trial," she said.

She went on: "For future patients, it's better to have the final results sufficiently powered." She noted that the benefit seen in ASCENT was "moderate" and "so not a substantial breakthrough." She noted that it was "important not to stop trials too early."

On the positive side, Cardoso said that the median number of previous lines of therapy that the patients had received was "quite remarkable for this subtype, and it is important then for us to discuss sequencing," particularly given that so many patients received checkpoint inhibitors before entering the trial.

Safety and a Focus on Diarrhea

Investigator Bardia explained that SG is an antibody–drug conjugate directed at trophoblast cell surface antigen 2 (Trop-2), which is highly expressed in breast cancer.

The antibody is linked to SN-38, the active metabolite of irinotecan, via a hydrolyzable linker that makes internalization and enzymatic cleavage by tumor cells unnecessary.

Hydrolysis of the linker releases SN-38 both within the tumor cell and extracellularly to induce a so-called bystander effect, in which neighboring tumors cells may be killed even if they do not express Trop-2.

On the basis of positive results from phase 1/2 trial data, SG was granted accelerated approval by the US Food and Drug Administration for patients with metastatic TNBC who experience disease progression after at least two prior therapies.

ASCENT was therefore a phase 3 confirmatory study. Patients with metastatic TNBC who had received at least two prior chemotherapy regimens were randomly assigned in a 1:1 ratio to receive intravenous SG on days 1 and 8 of a 21-day cycle or to receive physician's choice of treatment.

Physicians could choose eribulin, vinorelbine, gemcitabine, or capecitabine.

The patients continued receiving treatment until disease progression or unacceptable toxicity occurred. On the unanimous recommendation of the data safety monitoring committee, the trial was ended early because of "compelling evidence of efficacy."

In all, 267 patients were randomly assigned to receive SG. Of those patients, 15 remain on treatment. Treatment was discontinued for 199 patients who experienced disease progression. In the control arm, 262 patients were included, none of whom are still on treatment; 166 discontinued because of disease progression.

The current analysis is limited to 235 patients in the SG group and, in the control arm, 233 patients who did not have brain metastases. Patients with brain metastases will be the subject of a later analysis.

All but one patient in both treatment groups were women. The median age was approximately 54 years. The median number of prior treatment regimens was four. All patients had previously received chemotherapy, and between 26% and 29% have taken checkpoint inhibitors.

By the data cutoff of March 11, 2020, patients had received a median of seven treatment cycles with SG. PFS was adjudicated by blind, independent central review. The median duration of response was of borderline significance, at 6.3 months vs 3.6 months (P = .057).

Bardia showed that the results were consistent among all subgroups, including subgroups determined on the basis of age, number of prior therapies, whether patients had received prior immune checkpoint therapy, and the presence of liver metastases.

With respect to safety, the important grade ≥3 treatment-related adverse events were neutropenia, seen in 51% of SG patients vs 33% of patients in the control arm; diarrhea, at 10% vs <1%; leukopenia, at 10% vs 5%; anemia, at 8% vs 5%; and febrile neutropenia, at 6% vs 2%.

Despite the fact that the adverse event rate was higher with SG than with physician's choice of chemotherapy, the percentage of such events that led to treatment discontinuation was numerically lower, at 4.7% vs 5.4%.

Cardoso highlighted the "substantial percentage" of patients with diarrhea and nausea in the trial and noted that "all grades" of these adverse events "affect quality of life."

The focus therefore should be on patient education, prophylaxis, and "the early management of side effects," she said.

This point was taken up in the post-presentation debate. Bardia said that the high rate of diarrhea "likely relates to the toxic payload, which is SN-38, which is known to cause diarrhea.

"Loperamide or immodium prophylaxis can be used in patients who receive this drug, and in general, our experience with the use of sacituzumab govitecan is you can control the diarrhea," Bardia said.

He added: "There is also a different side effect that occurs during the infusion of SG, which is abdominal cramping and diarrhea, and that's more of a cholinergic reaction. For that, atropine is the best medication to use."

The study was funded by Immunomedics Inc. Bardia has disclosed financial ties with Immunomedics and multiple other pharmaceutical companies. Cardoso has disclosed financial ties to multiple drug companies.

European Society for Medical Oncology (ESMO) Annual Meeting 2020: Presented September 19, 2020.

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Cite this: First-in-Class ADC Ups Survival in mTNBC - Medscape - Sep 21, 2020.

NIVOLUMAB IN FIRST LINE TREATMENT OF GASTROESOPHAGEAL CANCER

Patients with gastric cancer or gastroesophageal junction cancer (GEJ) could experience significantly improved progression-free survival, and maybe also overall survival, with nivolumab (Opdivo) in the first-line and neoadjuvant settings, suggest data from three phase 3 trials.

However, contrasting results between the trials and question marks over the effect of the drug in all-comers leaves some questions yet to be answered, despite the "practice-changing" findings, said experts discussing the new data.

The research was presented September 21 at the ESMO Virtual Congress 2020, held online due to the COVID-19 pandemic.

Gastric cancer and GEJ have been an area of interest for immunotherapy in recent years, as standard first-line chemotherapy is associated with poor overall survival at a median of less than 1 year.

Previous smaller studies have suggested that nivolumab has promising activity in the first-line setting, improving survival particularly in individuals with a combined positive score (CPS) for programmed death ligand 1 (PD-L1) expression ≥5.

The new results come from the largest phase 3 trial of its kind to date, CheckMate 649 , which involved 1581 previously untreated patients with unresectable HER2-negative gastric cancer, GEJ, or esophageal adenocarcinoma.

Among these patients, 60% had a PD-L1 CPS ≥5.

Patients were randomly assigned to one of three treatment groups:

• nivolumab plus ipilimumab (Yervoy)

• nivolumab plus oxaliplatin-based chemotherapy

• chemotherapy alone

Results, after a minimum follow up of 12 months, show that nivolumab plus chemotherapy was associated with significantly better overall survival (OS) than chemotherapy alone, reported Markus Moehler, MD, PhD, Johannes-Gutenberg University Clinic, Mainz, Germany.

In patients with PD-L1 CPS ≥5, median OS was 14.4 months vs 11.1 months for chemotherapy alone (hazard ratio 0.71, P < .0001).

The figures were similar for patients with a PD-L1 CPS ≥1, at 14.0 months and 11.3 months (HR, 0.77, P = .0001), and also across the whole study population (13.8 months vs 11.6 months, HR, 0.80, P = .0002).

Progression-free survival (PFS), however, was significantly improved with the nivolumab chemotherapy combination only in patients with a PD-L1 CPS ≥5, at a median of 7.7 months vs 6.0 months (HR, 0.68, P < .0001).

The proportion of patients with treatment-related adverse events leading to discontinuation were 36% with nivolumab plus chemotherapy and 24% for chemotherapy alone.

At a press conference, Moehler said the benefits seen with nivolumab plus chemotherapy are "highly clinically meaningful" and the combination "represents a new potential standard first-line treatment" for these patients.

These results are "practice changing" and are "clearly significant," commented Salah-Eddin Al-Batran, MD, Krankenhaus Nordwest-University Cancer Center, Frankfurt, Germany, who was not involved with the study.

"However, as a physician," he continued, "I am treating an individual patient and, for me, it's important to know the efficacy in the patients with a CPS of 1 to 4, or of 0."

"We have to be sure that we do not inflate the results for the all-comers by the very responsive group of high-expressers," he said, adding that other factors to consider will be microsatellite instability, and tumor mutational burden. "I think these questions have to be addressed to give us a clear picture of how to treat the patient sitting in front of us."

Surprisingly, the results from ATTRACTION-4 , a very similar phase 3 trial conducted in Japan, Korea, and Taiwan, did not follow the same pattern.

This trial involved 724 previously untreated patients with HER2-negative gastric cancer or GEJ randomly assigned to receive nivolumab plus chemotherapy or chemotherapy alone.

Lead author Narikazu Boku, MD, PhD, National Cancer Center Hospital, Tokyo, Japan, said that, after a median follow-up of 11.6 months, the combination treatment was associated with a significant improvement in PFS, at a median 10.5 months vs 8.3 months with chemotherapy alone (HR, 0.68, P = .0007).

In contrast, there was no significant difference in overall survival between the nivolumab and placebo arms, at a median of 17.5 months and 17.2 months, respectively (HR, 0.90; P = .257).

Invited discussant Elizabeth Smyth, MD, from Addenbrooke's Hospital in Cambridge, UK, suggested that the lack of overall survival benefit seen in ATTRACTION-4 could be the result of a number of factors, including that PD-L1 status was assessed on tumor cells only and there were no key endpoints based around PD-L1 status.

Moreover, the post-trial therapy could have affected the overall results, as Asian patients typically receive more subsequent therapies than those elsewhere.

Smyth also commented that both CheckMate 649 and ATTRACTION-4 represent a "paradigm shift" in the first-line treatment of gastroesophageal adenocarcinoma.

Nivolumab in Adjuvant Setting

The results of a third trial presented at the ESMO meeting suggest a role for nivolumab in the adjuvant setting, following neoadjuvant chemoradiation therapy in patients with resected esophageal or GEJ cancer.

This was the CheckMate 577 trial, which compared adjuvant nivolumab with placebo in 794 patients from across the globe.

Nivolumab significantly increased median disease-free survival to 22.4 months vs 11.0 months with placebo (HR, 0.69, P = .0003).

Treatment-related adverse events leading to discontinuation were reported in 9% of nivolumab patients vs 3% on placebo, reported Ronan J. Kelly, MD, chief of oncology at Baylor Scott & White Health in Dallas, Texas.

Interestingly, patient-reported health status on the EQ-5D-3L visual analogue scale (VAS) and utility index were similar between nivolumab- and placebo-treated patients, with both groups experiencing clinically meaningful improvements.

Kelly said that this is "the first adjuvant therapy to provide a statistically significant and clinically meaningful improvement" in patients with esophageal cancer or GEJ cancer following neoadjuvant chemoradiation.

Consequently, the results "represent the first advance in years for this group of patients, potentially establishing adjuvant nivolumab as a new standard of care."

However, the invited discussant raised several issues with the trial design. Preoperative chemoradiation is not "universally accepted" as the standard of care in this setting, disease-free survival is not currently validated as a major endpoint in gastroesophageal cancers, and the median follow-up was short, commented Andrés Cervantes, MD, PhD, University of Valencia, Spain, and president-elect of ESMO.

In addition, there was no differentiation between esophageal squamous cell and adenocarcinoma histologies.

Nevertheless, CheckMate 577 is the first positive adjuvant study for checkpoint inhibitors in gastrointestinal tumors and, crucially, the results "are independent of PD-L1 status," Cervantes said.

CheckMate 649 was funded by Bristol-Myers Squibb Company. ATTRACTION-4 was funded by Ono Pharmaceutical Co, Ltd and Bristol-Myers Squibb. CheckMate 577 was funded by Bristol-Myers Squibb Company. Many of the presenters report relationships with pharmaceutical companies; see abstracts for details.

ESMO Virtual Congress 2020: Abstracts LBA6, LBA7, LBA9. Presented September 21, 2020.

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