A Glimmer of Hope for Immunotherapy in SCLC?

Liam Davenport

September 23, 2020

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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