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Superior survival with sintilimab in squamous NSCLC
Sintilimab improved both overall survival (OS) and progression-free survival (PFS), according to Yuankai Shi, MD, of the Chinese Academy of Medical Sciences & Peking Union Medical College in Beijing.
Dr. Shi presented these findings, from the ORIENT-3 study, at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract CT041).
ORIENT-3 enrolled and randomized 290 patients with stage IIIB/IIIC or IV sqNSCLC and disease progression during or after first-line platimum-based chemotherapy. They were randomized 1:1 to receive sintilimab at 200 mg or docetaxel at 75 mg/m2intravenously every 3 weeks until disease progression or intolerable toxicity.
The median age was 60 years in the sintilimab arm and 61 years in the docetaxel arm. A majority of patients were men (94% in the sintilimab arm and 90% in the docetaxel arm), most were current or former smokers (90% and 80%, respectively), and more than three-quarters had an ECOG performance status of 1 (76% and 77%, respectively). More than half of patients had a PD-L1 tumor proportion score (TPS) of 1% or greater (57% and 47%, respectively), and 81% of patients in both arms had stage IV disease.
Results: Survival and safety
Patients in the sintilimab arm received a median of 8.0 cycles of therapy (range, 1-45), and those in the docetaxel arm received a median of 2.0 cycles of therapy (range, 1-15).
At a median follow-up of 23.56 months, the median OS was significantly longer in the sintilimab arm than in the docetaxel arm – 11.79 months and 8.25 months, respectively (hazard ratio, 0.74; P = .02489). OS benefits were generally consistent across subgroups.
The secondary endpoints of PFS and objective response rate also favored sintilimab, Dr. Shi reported.
The median PFS was 4.30 months in the sintilimab arm and 2.79 months in the docetaxel arm (HR, 0.52; P < .00001). Confirmed objective response rates were 25.5% and 2.2%, respectively; the median duration of response was 12.45 months and 4.14 months, respectively; and disease control rates were 65.5% and 37.8%, respectively.
“Sintilimab had a favorable safety profile over docetaxel, with a lower frequency of grade 3 or higher treatment-related adverse events, with no new safety signals observed,” Dr. Shi said.
Treatment-related adverse events (TRAEs) occurred in 84.7% of patients receiving sintilimab and 83.1% of those receiving docetaxel. Hypothyroidism was the most common TRAE in the sintilimab arm (18.1%), and alopecia was the most common TRAE in the docetaxel arm (34.6%).
Grade 3 or higher TRAEs were less frequent in the sintilimab arm than in the docetaxel arm (18.1% vs. 36.2%). Rates of discontinuation because of TRAEs were 12.5% and 5.4% in the sintilimab and docetaxel arms, respectively. TRAEs leading to death occurred in five patients in the sintilimab arm and one in the docetaxel arm.
Use in the real world
Noting sintilimab’s significant OS and PFS benefits as well as superior response rate and duration of response, Dr. Shi concluded, “Sintilimab might provide an alternative second-line treatment option for advanced and metastatic sqNSCLC.”
AACR moderator Marina Garassino, MD, of the University of Chicago, commented on the potential utility of sintilimab and tislelizumab, another checkpoint inhibitor that was evaluated in NSCLC in the RATIONALE 303 trial (AACR 2021, Abstract CT039). Dr. Garassino observed that both drugs have demonstrated superiority to docetaxel as second-line therapy in NSCLC.
Although there have been no head-to-head trials, sintilimab and tislelizumab appear to be very similar to the already approved immune checkpoint inhibitors, which are currently being used as first-line treatment.
“That similarity would make them inappropriate for second-line treatment, except in countries where immune checkpoint inhibitors are not yet approved for first-line therapy,” Dr. Garassino noted.
When asked to comment on the higher treatment-related death rate observed with sintilimab, Dr. Garassino said, “We need to remember that these drugs were developed in China with a population that may have a side effect profile differing from that of a Western population. Also, we are very familiar with this class of drugs and know how to treat their side effects. Similar drugs but different populations and different trials, so it’s very hard to judge.”
Dr. Garassino speculated that with the “super expensive” price tags on the new checkpoint inhibitors, having additional agents that could provide choice and drive prices down would be welcome.
ORIENT-3 was funded by Innovent Biologics and Eli Lilly. Dr. Shi disclosed consultancy for Innovent Biologics. Dr. Garassino disclosed relationships with Eli Lilly, AstraZeneca, Novartis, and several other companies, not including Innovent Biologics.
Sintilimab improved both overall survival (OS) and progression-free survival (PFS), according to Yuankai Shi, MD, of the Chinese Academy of Medical Sciences & Peking Union Medical College in Beijing.
Dr. Shi presented these findings, from the ORIENT-3 study, at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract CT041).
ORIENT-3 enrolled and randomized 290 patients with stage IIIB/IIIC or IV sqNSCLC and disease progression during or after first-line platimum-based chemotherapy. They were randomized 1:1 to receive sintilimab at 200 mg or docetaxel at 75 mg/m2intravenously every 3 weeks until disease progression or intolerable toxicity.
The median age was 60 years in the sintilimab arm and 61 years in the docetaxel arm. A majority of patients were men (94% in the sintilimab arm and 90% in the docetaxel arm), most were current or former smokers (90% and 80%, respectively), and more than three-quarters had an ECOG performance status of 1 (76% and 77%, respectively). More than half of patients had a PD-L1 tumor proportion score (TPS) of 1% or greater (57% and 47%, respectively), and 81% of patients in both arms had stage IV disease.
Results: Survival and safety
Patients in the sintilimab arm received a median of 8.0 cycles of therapy (range, 1-45), and those in the docetaxel arm received a median of 2.0 cycles of therapy (range, 1-15).
At a median follow-up of 23.56 months, the median OS was significantly longer in the sintilimab arm than in the docetaxel arm – 11.79 months and 8.25 months, respectively (hazard ratio, 0.74; P = .02489). OS benefits were generally consistent across subgroups.
The secondary endpoints of PFS and objective response rate also favored sintilimab, Dr. Shi reported.
The median PFS was 4.30 months in the sintilimab arm and 2.79 months in the docetaxel arm (HR, 0.52; P < .00001). Confirmed objective response rates were 25.5% and 2.2%, respectively; the median duration of response was 12.45 months and 4.14 months, respectively; and disease control rates were 65.5% and 37.8%, respectively.
“Sintilimab had a favorable safety profile over docetaxel, with a lower frequency of grade 3 or higher treatment-related adverse events, with no new safety signals observed,” Dr. Shi said.
Treatment-related adverse events (TRAEs) occurred in 84.7% of patients receiving sintilimab and 83.1% of those receiving docetaxel. Hypothyroidism was the most common TRAE in the sintilimab arm (18.1%), and alopecia was the most common TRAE in the docetaxel arm (34.6%).
Grade 3 or higher TRAEs were less frequent in the sintilimab arm than in the docetaxel arm (18.1% vs. 36.2%). Rates of discontinuation because of TRAEs were 12.5% and 5.4% in the sintilimab and docetaxel arms, respectively. TRAEs leading to death occurred in five patients in the sintilimab arm and one in the docetaxel arm.
Use in the real world
Noting sintilimab’s significant OS and PFS benefits as well as superior response rate and duration of response, Dr. Shi concluded, “Sintilimab might provide an alternative second-line treatment option for advanced and metastatic sqNSCLC.”
AACR moderator Marina Garassino, MD, of the University of Chicago, commented on the potential utility of sintilimab and tislelizumab, another checkpoint inhibitor that was evaluated in NSCLC in the RATIONALE 303 trial (AACR 2021, Abstract CT039). Dr. Garassino observed that both drugs have demonstrated superiority to docetaxel as second-line therapy in NSCLC.
Although there have been no head-to-head trials, sintilimab and tislelizumab appear to be very similar to the already approved immune checkpoint inhibitors, which are currently being used as first-line treatment.
“That similarity would make them inappropriate for second-line treatment, except in countries where immune checkpoint inhibitors are not yet approved for first-line therapy,” Dr. Garassino noted.
When asked to comment on the higher treatment-related death rate observed with sintilimab, Dr. Garassino said, “We need to remember that these drugs were developed in China with a population that may have a side effect profile differing from that of a Western population. Also, we are very familiar with this class of drugs and know how to treat their side effects. Similar drugs but different populations and different trials, so it’s very hard to judge.”
Dr. Garassino speculated that with the “super expensive” price tags on the new checkpoint inhibitors, having additional agents that could provide choice and drive prices down would be welcome.
ORIENT-3 was funded by Innovent Biologics and Eli Lilly. Dr. Shi disclosed consultancy for Innovent Biologics. Dr. Garassino disclosed relationships with Eli Lilly, AstraZeneca, Novartis, and several other companies, not including Innovent Biologics.
Sintilimab improved both overall survival (OS) and progression-free survival (PFS), according to Yuankai Shi, MD, of the Chinese Academy of Medical Sciences & Peking Union Medical College in Beijing.
Dr. Shi presented these findings, from the ORIENT-3 study, at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract CT041).
ORIENT-3 enrolled and randomized 290 patients with stage IIIB/IIIC or IV sqNSCLC and disease progression during or after first-line platimum-based chemotherapy. They were randomized 1:1 to receive sintilimab at 200 mg or docetaxel at 75 mg/m2intravenously every 3 weeks until disease progression or intolerable toxicity.
The median age was 60 years in the sintilimab arm and 61 years in the docetaxel arm. A majority of patients were men (94% in the sintilimab arm and 90% in the docetaxel arm), most were current or former smokers (90% and 80%, respectively), and more than three-quarters had an ECOG performance status of 1 (76% and 77%, respectively). More than half of patients had a PD-L1 tumor proportion score (TPS) of 1% or greater (57% and 47%, respectively), and 81% of patients in both arms had stage IV disease.
Results: Survival and safety
Patients in the sintilimab arm received a median of 8.0 cycles of therapy (range, 1-45), and those in the docetaxel arm received a median of 2.0 cycles of therapy (range, 1-15).
At a median follow-up of 23.56 months, the median OS was significantly longer in the sintilimab arm than in the docetaxel arm – 11.79 months and 8.25 months, respectively (hazard ratio, 0.74; P = .02489). OS benefits were generally consistent across subgroups.
The secondary endpoints of PFS and objective response rate also favored sintilimab, Dr. Shi reported.
The median PFS was 4.30 months in the sintilimab arm and 2.79 months in the docetaxel arm (HR, 0.52; P < .00001). Confirmed objective response rates were 25.5% and 2.2%, respectively; the median duration of response was 12.45 months and 4.14 months, respectively; and disease control rates were 65.5% and 37.8%, respectively.
“Sintilimab had a favorable safety profile over docetaxel, with a lower frequency of grade 3 or higher treatment-related adverse events, with no new safety signals observed,” Dr. Shi said.
Treatment-related adverse events (TRAEs) occurred in 84.7% of patients receiving sintilimab and 83.1% of those receiving docetaxel. Hypothyroidism was the most common TRAE in the sintilimab arm (18.1%), and alopecia was the most common TRAE in the docetaxel arm (34.6%).
Grade 3 or higher TRAEs were less frequent in the sintilimab arm than in the docetaxel arm (18.1% vs. 36.2%). Rates of discontinuation because of TRAEs were 12.5% and 5.4% in the sintilimab and docetaxel arms, respectively. TRAEs leading to death occurred in five patients in the sintilimab arm and one in the docetaxel arm.
Use in the real world
Noting sintilimab’s significant OS and PFS benefits as well as superior response rate and duration of response, Dr. Shi concluded, “Sintilimab might provide an alternative second-line treatment option for advanced and metastatic sqNSCLC.”
AACR moderator Marina Garassino, MD, of the University of Chicago, commented on the potential utility of sintilimab and tislelizumab, another checkpoint inhibitor that was evaluated in NSCLC in the RATIONALE 303 trial (AACR 2021, Abstract CT039). Dr. Garassino observed that both drugs have demonstrated superiority to docetaxel as second-line therapy in NSCLC.
Although there have been no head-to-head trials, sintilimab and tislelizumab appear to be very similar to the already approved immune checkpoint inhibitors, which are currently being used as first-line treatment.
“That similarity would make them inappropriate for second-line treatment, except in countries where immune checkpoint inhibitors are not yet approved for first-line therapy,” Dr. Garassino noted.
When asked to comment on the higher treatment-related death rate observed with sintilimab, Dr. Garassino said, “We need to remember that these drugs were developed in China with a population that may have a side effect profile differing from that of a Western population. Also, we are very familiar with this class of drugs and know how to treat their side effects. Similar drugs but different populations and different trials, so it’s very hard to judge.”
Dr. Garassino speculated that with the “super expensive” price tags on the new checkpoint inhibitors, having additional agents that could provide choice and drive prices down would be welcome.
ORIENT-3 was funded by Innovent Biologics and Eli Lilly. Dr. Shi disclosed consultancy for Innovent Biologics. Dr. Garassino disclosed relationships with Eli Lilly, AstraZeneca, Novartis, and several other companies, not including Innovent Biologics.
FROM AACR 2021
IMvigor130: A treasure trove of data for urothelial carcinoma
A second interim overall survival (OS) analysis suggested that atezolizumab monotherapy provides a clinical benefit as first-line treatment for mUC patients with PD-L1–expressing immune cells representing at least 5% of the tumor area (IC2/3), including patients who are cisplatin ineligible.
The analysis also suggested that atezolizumab plus chemotherapy produces similar OS results as chemotherapy plus placebo, but patients receiving atezolizumab may do better with cisplatin-based chemotherapy than with carboplatin-based chemotherapy.
These results were reported in two presentations at the American Association for Cancer Research Annual Meeting 2021: Week 1.
Current guidelines from the National Comprehensive Cancer Network and the European Society for Medical Oncology recommend atezolizumab monotherapy for cisplatin-ineligible patients with mUC and PD-L1 IC2/3.
The ongoing phase 3 IMvigor130 trial was designed to compare atezolizumab plus gemcitabine/platinum chemotherapy, atezolizumab monotherapy, and placebo plus chemotherapy. Platinum-based chemotherapy included either cisplatin or carboplatin, per investigator choice.
Coprimary endpoints for IMvigor130 were progression-free survival (PFS) and OS for atezolizumab plus chemotherapy versus placebo plus chemotherapy. The hierarchical study design dictated that OS would only be assessed for the comparison of atezolizumab monotherapy versus placebo-chemotherapy in the overall and PD-L1 IC2/3 populations if there was statistical improvement in OS for the atezolizumab-chemotherapy arm over the placebo-chemotherapy arm.
Secondary endpoints were overall response rate (ORR; per RECIST 1.1), duration of response (DOR) for all patients, and PFS for the comparison between atezolizumab monotherapy and placebo-chemotherapy. Exploratory analyses were performed on cisplatin-ineligible patients by PD-L1 status.
At the time of the primary analysis, an OS benefit for atezolizumab-chemotherapy over placebo-chemotherapy was not observed. Therefore, the OS benefit of atezolizumab monotherapy versus placebo-chemotherapy was not assessed. However, a trend toward improved OS was noted with atezolizumab for PD-L1 IC2/3 patients, including cisplatin-ineligible patients.
Atezolizumab vs. placebo-chemo
Ian D. Davis, MBBS, PhD, of Monash University in Melbourne, presented the second interim analysis of OS with atezolizumab monotherapy versus placebo plus chemotherapy (Abstract CT040).
The median follow-up was 14.9 months for atezolizumab monotherapy (n = 360) and 11.8 months for placebo-chemotherapy (n = 359). The median OS was 15.2 months and 13.1 months, respectively (hazard ratio, 0.99; 95% confidence interval, 0.83-1.19). There was no apparent OS benefit of atezolizumab for any clinically selected subgroup.
The ORR was 23.4% for atezolizumab monotherapy and 44.1% for placebo-chemotherapy. The median DOR was more than 3.5 times longer for atezolizumab monotherapy than for placebo-chemotherapy – 29.6 months and 8.1 months, respectively.
Although there was no formal statistical comparison, exploratory subgroup analyses demonstrated that the median OS for the PD-L1 IC2/3 patients appeared higher in the atezolizumab monotherapy arm than in the placebo-chemotherapy arm – 27.5 months and 16.7 months, respectively.
Similarly, the median OS for cisplatin-ineligible PD-L1 IC2/3 patients appeared higher for atezolizumab monotherapy than for placebo-chemotherapy – 18.6 months and 10.0 months, respectively.
In terms of safety, atezolizumab monotherapy compared favorably with placebo plus chemotherapy. There were similar numbers of grade 3/4 adverse events and comparable adverse events leading to discontinuation of treatment in both arms.
The atezolizumab monotherapy arm had fewer adverse events leading to withdrawal from any treatment, when compared with the placebo-chemotherapy arm – 7% and 34%, respectively. Two patients in the atezolizumab arm and one in the placebo-chemotherapy died of treatment-related causes.
Atezolizumab-chemo vs. placebo-chemo
Matthew D. Galsky, MD, of Mount Sinai Health System and Icahn School of Medicine at Mount Sinai in New York, presented the second interim OS comparison of atezolizumab plus chemotherapy with placebo plus chemotherapy (Abstract CT042).
The primary analysis had shown a statistically significant improvement in PFS for patients on atezolizumab-chemotherapy, in comparison with placebo-chemotherapy, with encouraging OS improvement, but the boundary for declaring significance for the OS endpoint was not crossed (Lancet. 2020 May 16;395[10236]:1547-1557).
Because IMvigor130 included both patients who received cisplatin and patients who investigators deemed cisplatin ineligible, the second interim analysis included an exploratory analysis of whether there was a difference in outcome between patients who received or did not receive cisplatin.
At a median follow-up of 13.3 months, the median OS was not significantly different in the atezolizumab-chemotherapy arm (n = 451) and the placebo-chemotherapy arm (n = 400) – 16.1 months and 13.4 months, respectively (HR, 0.84; 95% CI, 0.71-1.00; P = .026).
There were no clinically or pathologically defined subgroups that experienced an OS benefit from atezolizumab-chemotherapy over placebo-chemotherapy.
As for subsequent nonprotocol therapy, 24% of the placebo-chemotherapy arm received an immune checkpoint inhibitor at progression, as did 7% of the atezolizumab-chemotherapy arm. There was no difference in receipt of an immune checkpoint inhibitor post progression among patients treated with cisplatin versus carboplatin.
The benefit of combining atezolizumab with chemotherapy appeared more substantial with cisplatin-based chemotherapy than with carboplatin-based treatment. With cisplatin, the median OS was 21.6 months for the atezolizumab-chemotherapy arm and 14.6 months for the placebo-chemotherapy arm. With carboplatin, the median OS was 14.3 months and 13.0 months, respectively.
PD-L1 status was prognostic for patients who received cisplatin, with lower OS being observed for patients with PD-L1 IC0/1 status and higher OS observed for patients with PD-L1 IC2/3 status. Atezolizumab plus cisplatin-based chemotherapy appeared superior to cisplatin-based chemotherapy alone in both PD-L1–low and –high groups.
Atezolizumab did not seem to benefit patients who were treated with carboplatin, and PD-L1 status did not seem to influence OS among the carboplatin-treated patients.
Although similar ORR results were seen with cisplatin and carboplatin, there appeared to be a longer median DOR among cisplatin-treated patients who received atezolizumab than among those who did not – 13.2 months and 8.3 months, respectively.
No such benefit from atezolizumab was seen in carboplatin-treated patients. The median DOR was 8.1 months among patients who received atezolizumab and 7.1 months among those who did not.
The overall safety profile for atezolizumab plus chemotherapy was consistent with prior reports of the combination. Treatment-related grade 3-5 adverse events were similar on the atezolizumab-chemotherapy arm and the placebo-chemotherapy arm.
The present and future
The investigators who presented the second interim analysis for OS of the IMvigor130 trial were appropriately modest in their conclusions. After all, the prespecified boundary for significant improvement in OS for the addition of atezolizumab to chemotherapy was not crossed. No change in guideline-based clinical practice would be appropriate at the present time.
The various exploratory analyses are hypothesis generating and invite potential mechanistic explanations. However, given the nonrandom allocation of patients to cisplatin- or carboplatin-based chemotherapy, unrecognized variables may have influenced any appearance of a difference in OS between the regimens.
In IMvigor130, treatment was given until unacceptable toxicity or disease progression. It is uncertain whether the current National Comprehensive Cancer Network category 1 recommendation of chemotherapy induction followed by immune checkpoint inhibitor maintenance therapy will prove superior to the IMvigor130 strategy.
Clearly – and concordant with current treatment guidelines – atezolizumab monotherapy can benefit some patients, though the response rate for atezolizumab monotherapy was lower than for chemotherapy (23.4% vs. 44.1%).
As noted by the session chair, Marina Chiara Garassino, MD, of the University of Chicago, the OS curves were initially superior for chemotherapy over atezolizumab. However, the apparent early OS benefit for chemotherapy dissipated over time and, among responders to atezolizumab, response duration was considerably longer than for chemotherapy.
IMvigor130 will ultimately have a final OS analysis to clarify the relative benefits of the various treatment strategies. Fortunately, this large phase 3 study will yield a treasure trove of data to inform future research and build on the advances of recent years for patients with advanced urothelial cancer.
IMvigor130 is sponsored by Hoffmann-La Roche. Dr. Davis, Dr. Galsky, and Dr. Garassino disclosed relationships with Hoffmann-La Roche and many other companies.
Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers, as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.
A second interim overall survival (OS) analysis suggested that atezolizumab monotherapy provides a clinical benefit as first-line treatment for mUC patients with PD-L1–expressing immune cells representing at least 5% of the tumor area (IC2/3), including patients who are cisplatin ineligible.
The analysis also suggested that atezolizumab plus chemotherapy produces similar OS results as chemotherapy plus placebo, but patients receiving atezolizumab may do better with cisplatin-based chemotherapy than with carboplatin-based chemotherapy.
These results were reported in two presentations at the American Association for Cancer Research Annual Meeting 2021: Week 1.
Current guidelines from the National Comprehensive Cancer Network and the European Society for Medical Oncology recommend atezolizumab monotherapy for cisplatin-ineligible patients with mUC and PD-L1 IC2/3.
The ongoing phase 3 IMvigor130 trial was designed to compare atezolizumab plus gemcitabine/platinum chemotherapy, atezolizumab monotherapy, and placebo plus chemotherapy. Platinum-based chemotherapy included either cisplatin or carboplatin, per investigator choice.
Coprimary endpoints for IMvigor130 were progression-free survival (PFS) and OS for atezolizumab plus chemotherapy versus placebo plus chemotherapy. The hierarchical study design dictated that OS would only be assessed for the comparison of atezolizumab monotherapy versus placebo-chemotherapy in the overall and PD-L1 IC2/3 populations if there was statistical improvement in OS for the atezolizumab-chemotherapy arm over the placebo-chemotherapy arm.
Secondary endpoints were overall response rate (ORR; per RECIST 1.1), duration of response (DOR) for all patients, and PFS for the comparison between atezolizumab monotherapy and placebo-chemotherapy. Exploratory analyses were performed on cisplatin-ineligible patients by PD-L1 status.
At the time of the primary analysis, an OS benefit for atezolizumab-chemotherapy over placebo-chemotherapy was not observed. Therefore, the OS benefit of atezolizumab monotherapy versus placebo-chemotherapy was not assessed. However, a trend toward improved OS was noted with atezolizumab for PD-L1 IC2/3 patients, including cisplatin-ineligible patients.
Atezolizumab vs. placebo-chemo
Ian D. Davis, MBBS, PhD, of Monash University in Melbourne, presented the second interim analysis of OS with atezolizumab monotherapy versus placebo plus chemotherapy (Abstract CT040).
The median follow-up was 14.9 months for atezolizumab monotherapy (n = 360) and 11.8 months for placebo-chemotherapy (n = 359). The median OS was 15.2 months and 13.1 months, respectively (hazard ratio, 0.99; 95% confidence interval, 0.83-1.19). There was no apparent OS benefit of atezolizumab for any clinically selected subgroup.
The ORR was 23.4% for atezolizumab monotherapy and 44.1% for placebo-chemotherapy. The median DOR was more than 3.5 times longer for atezolizumab monotherapy than for placebo-chemotherapy – 29.6 months and 8.1 months, respectively.
Although there was no formal statistical comparison, exploratory subgroup analyses demonstrated that the median OS for the PD-L1 IC2/3 patients appeared higher in the atezolizumab monotherapy arm than in the placebo-chemotherapy arm – 27.5 months and 16.7 months, respectively.
Similarly, the median OS for cisplatin-ineligible PD-L1 IC2/3 patients appeared higher for atezolizumab monotherapy than for placebo-chemotherapy – 18.6 months and 10.0 months, respectively.
In terms of safety, atezolizumab monotherapy compared favorably with placebo plus chemotherapy. There were similar numbers of grade 3/4 adverse events and comparable adverse events leading to discontinuation of treatment in both arms.
The atezolizumab monotherapy arm had fewer adverse events leading to withdrawal from any treatment, when compared with the placebo-chemotherapy arm – 7% and 34%, respectively. Two patients in the atezolizumab arm and one in the placebo-chemotherapy died of treatment-related causes.
Atezolizumab-chemo vs. placebo-chemo
Matthew D. Galsky, MD, of Mount Sinai Health System and Icahn School of Medicine at Mount Sinai in New York, presented the second interim OS comparison of atezolizumab plus chemotherapy with placebo plus chemotherapy (Abstract CT042).
The primary analysis had shown a statistically significant improvement in PFS for patients on atezolizumab-chemotherapy, in comparison with placebo-chemotherapy, with encouraging OS improvement, but the boundary for declaring significance for the OS endpoint was not crossed (Lancet. 2020 May 16;395[10236]:1547-1557).
Because IMvigor130 included both patients who received cisplatin and patients who investigators deemed cisplatin ineligible, the second interim analysis included an exploratory analysis of whether there was a difference in outcome between patients who received or did not receive cisplatin.
At a median follow-up of 13.3 months, the median OS was not significantly different in the atezolizumab-chemotherapy arm (n = 451) and the placebo-chemotherapy arm (n = 400) – 16.1 months and 13.4 months, respectively (HR, 0.84; 95% CI, 0.71-1.00; P = .026).
There were no clinically or pathologically defined subgroups that experienced an OS benefit from atezolizumab-chemotherapy over placebo-chemotherapy.
As for subsequent nonprotocol therapy, 24% of the placebo-chemotherapy arm received an immune checkpoint inhibitor at progression, as did 7% of the atezolizumab-chemotherapy arm. There was no difference in receipt of an immune checkpoint inhibitor post progression among patients treated with cisplatin versus carboplatin.
The benefit of combining atezolizumab with chemotherapy appeared more substantial with cisplatin-based chemotherapy than with carboplatin-based treatment. With cisplatin, the median OS was 21.6 months for the atezolizumab-chemotherapy arm and 14.6 months for the placebo-chemotherapy arm. With carboplatin, the median OS was 14.3 months and 13.0 months, respectively.
PD-L1 status was prognostic for patients who received cisplatin, with lower OS being observed for patients with PD-L1 IC0/1 status and higher OS observed for patients with PD-L1 IC2/3 status. Atezolizumab plus cisplatin-based chemotherapy appeared superior to cisplatin-based chemotherapy alone in both PD-L1–low and –high groups.
Atezolizumab did not seem to benefit patients who were treated with carboplatin, and PD-L1 status did not seem to influence OS among the carboplatin-treated patients.
Although similar ORR results were seen with cisplatin and carboplatin, there appeared to be a longer median DOR among cisplatin-treated patients who received atezolizumab than among those who did not – 13.2 months and 8.3 months, respectively.
No such benefit from atezolizumab was seen in carboplatin-treated patients. The median DOR was 8.1 months among patients who received atezolizumab and 7.1 months among those who did not.
The overall safety profile for atezolizumab plus chemotherapy was consistent with prior reports of the combination. Treatment-related grade 3-5 adverse events were similar on the atezolizumab-chemotherapy arm and the placebo-chemotherapy arm.
The present and future
The investigators who presented the second interim analysis for OS of the IMvigor130 trial were appropriately modest in their conclusions. After all, the prespecified boundary for significant improvement in OS for the addition of atezolizumab to chemotherapy was not crossed. No change in guideline-based clinical practice would be appropriate at the present time.
The various exploratory analyses are hypothesis generating and invite potential mechanistic explanations. However, given the nonrandom allocation of patients to cisplatin- or carboplatin-based chemotherapy, unrecognized variables may have influenced any appearance of a difference in OS between the regimens.
In IMvigor130, treatment was given until unacceptable toxicity or disease progression. It is uncertain whether the current National Comprehensive Cancer Network category 1 recommendation of chemotherapy induction followed by immune checkpoint inhibitor maintenance therapy will prove superior to the IMvigor130 strategy.
Clearly – and concordant with current treatment guidelines – atezolizumab monotherapy can benefit some patients, though the response rate for atezolizumab monotherapy was lower than for chemotherapy (23.4% vs. 44.1%).
As noted by the session chair, Marina Chiara Garassino, MD, of the University of Chicago, the OS curves were initially superior for chemotherapy over atezolizumab. However, the apparent early OS benefit for chemotherapy dissipated over time and, among responders to atezolizumab, response duration was considerably longer than for chemotherapy.
IMvigor130 will ultimately have a final OS analysis to clarify the relative benefits of the various treatment strategies. Fortunately, this large phase 3 study will yield a treasure trove of data to inform future research and build on the advances of recent years for patients with advanced urothelial cancer.
IMvigor130 is sponsored by Hoffmann-La Roche. Dr. Davis, Dr. Galsky, and Dr. Garassino disclosed relationships with Hoffmann-La Roche and many other companies.
Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers, as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.
A second interim overall survival (OS) analysis suggested that atezolizumab monotherapy provides a clinical benefit as first-line treatment for mUC patients with PD-L1–expressing immune cells representing at least 5% of the tumor area (IC2/3), including patients who are cisplatin ineligible.
The analysis also suggested that atezolizumab plus chemotherapy produces similar OS results as chemotherapy plus placebo, but patients receiving atezolizumab may do better with cisplatin-based chemotherapy than with carboplatin-based chemotherapy.
These results were reported in two presentations at the American Association for Cancer Research Annual Meeting 2021: Week 1.
Current guidelines from the National Comprehensive Cancer Network and the European Society for Medical Oncology recommend atezolizumab monotherapy for cisplatin-ineligible patients with mUC and PD-L1 IC2/3.
The ongoing phase 3 IMvigor130 trial was designed to compare atezolizumab plus gemcitabine/platinum chemotherapy, atezolizumab monotherapy, and placebo plus chemotherapy. Platinum-based chemotherapy included either cisplatin or carboplatin, per investigator choice.
Coprimary endpoints for IMvigor130 were progression-free survival (PFS) and OS for atezolizumab plus chemotherapy versus placebo plus chemotherapy. The hierarchical study design dictated that OS would only be assessed for the comparison of atezolizumab monotherapy versus placebo-chemotherapy in the overall and PD-L1 IC2/3 populations if there was statistical improvement in OS for the atezolizumab-chemotherapy arm over the placebo-chemotherapy arm.
Secondary endpoints were overall response rate (ORR; per RECIST 1.1), duration of response (DOR) for all patients, and PFS for the comparison between atezolizumab monotherapy and placebo-chemotherapy. Exploratory analyses were performed on cisplatin-ineligible patients by PD-L1 status.
At the time of the primary analysis, an OS benefit for atezolizumab-chemotherapy over placebo-chemotherapy was not observed. Therefore, the OS benefit of atezolizumab monotherapy versus placebo-chemotherapy was not assessed. However, a trend toward improved OS was noted with atezolizumab for PD-L1 IC2/3 patients, including cisplatin-ineligible patients.
Atezolizumab vs. placebo-chemo
Ian D. Davis, MBBS, PhD, of Monash University in Melbourne, presented the second interim analysis of OS with atezolizumab monotherapy versus placebo plus chemotherapy (Abstract CT040).
The median follow-up was 14.9 months for atezolizumab monotherapy (n = 360) and 11.8 months for placebo-chemotherapy (n = 359). The median OS was 15.2 months and 13.1 months, respectively (hazard ratio, 0.99; 95% confidence interval, 0.83-1.19). There was no apparent OS benefit of atezolizumab for any clinically selected subgroup.
The ORR was 23.4% for atezolizumab monotherapy and 44.1% for placebo-chemotherapy. The median DOR was more than 3.5 times longer for atezolizumab monotherapy than for placebo-chemotherapy – 29.6 months and 8.1 months, respectively.
Although there was no formal statistical comparison, exploratory subgroup analyses demonstrated that the median OS for the PD-L1 IC2/3 patients appeared higher in the atezolizumab monotherapy arm than in the placebo-chemotherapy arm – 27.5 months and 16.7 months, respectively.
Similarly, the median OS for cisplatin-ineligible PD-L1 IC2/3 patients appeared higher for atezolizumab monotherapy than for placebo-chemotherapy – 18.6 months and 10.0 months, respectively.
In terms of safety, atezolizumab monotherapy compared favorably with placebo plus chemotherapy. There were similar numbers of grade 3/4 adverse events and comparable adverse events leading to discontinuation of treatment in both arms.
The atezolizumab monotherapy arm had fewer adverse events leading to withdrawal from any treatment, when compared with the placebo-chemotherapy arm – 7% and 34%, respectively. Two patients in the atezolizumab arm and one in the placebo-chemotherapy died of treatment-related causes.
Atezolizumab-chemo vs. placebo-chemo
Matthew D. Galsky, MD, of Mount Sinai Health System and Icahn School of Medicine at Mount Sinai in New York, presented the second interim OS comparison of atezolizumab plus chemotherapy with placebo plus chemotherapy (Abstract CT042).
The primary analysis had shown a statistically significant improvement in PFS for patients on atezolizumab-chemotherapy, in comparison with placebo-chemotherapy, with encouraging OS improvement, but the boundary for declaring significance for the OS endpoint was not crossed (Lancet. 2020 May 16;395[10236]:1547-1557).
Because IMvigor130 included both patients who received cisplatin and patients who investigators deemed cisplatin ineligible, the second interim analysis included an exploratory analysis of whether there was a difference in outcome between patients who received or did not receive cisplatin.
At a median follow-up of 13.3 months, the median OS was not significantly different in the atezolizumab-chemotherapy arm (n = 451) and the placebo-chemotherapy arm (n = 400) – 16.1 months and 13.4 months, respectively (HR, 0.84; 95% CI, 0.71-1.00; P = .026).
There were no clinically or pathologically defined subgroups that experienced an OS benefit from atezolizumab-chemotherapy over placebo-chemotherapy.
As for subsequent nonprotocol therapy, 24% of the placebo-chemotherapy arm received an immune checkpoint inhibitor at progression, as did 7% of the atezolizumab-chemotherapy arm. There was no difference in receipt of an immune checkpoint inhibitor post progression among patients treated with cisplatin versus carboplatin.
The benefit of combining atezolizumab with chemotherapy appeared more substantial with cisplatin-based chemotherapy than with carboplatin-based treatment. With cisplatin, the median OS was 21.6 months for the atezolizumab-chemotherapy arm and 14.6 months for the placebo-chemotherapy arm. With carboplatin, the median OS was 14.3 months and 13.0 months, respectively.
PD-L1 status was prognostic for patients who received cisplatin, with lower OS being observed for patients with PD-L1 IC0/1 status and higher OS observed for patients with PD-L1 IC2/3 status. Atezolizumab plus cisplatin-based chemotherapy appeared superior to cisplatin-based chemotherapy alone in both PD-L1–low and –high groups.
Atezolizumab did not seem to benefit patients who were treated with carboplatin, and PD-L1 status did not seem to influence OS among the carboplatin-treated patients.
Although similar ORR results were seen with cisplatin and carboplatin, there appeared to be a longer median DOR among cisplatin-treated patients who received atezolizumab than among those who did not – 13.2 months and 8.3 months, respectively.
No such benefit from atezolizumab was seen in carboplatin-treated patients. The median DOR was 8.1 months among patients who received atezolizumab and 7.1 months among those who did not.
The overall safety profile for atezolizumab plus chemotherapy was consistent with prior reports of the combination. Treatment-related grade 3-5 adverse events were similar on the atezolizumab-chemotherapy arm and the placebo-chemotherapy arm.
The present and future
The investigators who presented the second interim analysis for OS of the IMvigor130 trial were appropriately modest in their conclusions. After all, the prespecified boundary for significant improvement in OS for the addition of atezolizumab to chemotherapy was not crossed. No change in guideline-based clinical practice would be appropriate at the present time.
The various exploratory analyses are hypothesis generating and invite potential mechanistic explanations. However, given the nonrandom allocation of patients to cisplatin- or carboplatin-based chemotherapy, unrecognized variables may have influenced any appearance of a difference in OS between the regimens.
In IMvigor130, treatment was given until unacceptable toxicity or disease progression. It is uncertain whether the current National Comprehensive Cancer Network category 1 recommendation of chemotherapy induction followed by immune checkpoint inhibitor maintenance therapy will prove superior to the IMvigor130 strategy.
Clearly – and concordant with current treatment guidelines – atezolizumab monotherapy can benefit some patients, though the response rate for atezolizumab monotherapy was lower than for chemotherapy (23.4% vs. 44.1%).
As noted by the session chair, Marina Chiara Garassino, MD, of the University of Chicago, the OS curves were initially superior for chemotherapy over atezolizumab. However, the apparent early OS benefit for chemotherapy dissipated over time and, among responders to atezolizumab, response duration was considerably longer than for chemotherapy.
IMvigor130 will ultimately have a final OS analysis to clarify the relative benefits of the various treatment strategies. Fortunately, this large phase 3 study will yield a treasure trove of data to inform future research and build on the advances of recent years for patients with advanced urothelial cancer.
IMvigor130 is sponsored by Hoffmann-La Roche. Dr. Davis, Dr. Galsky, and Dr. Garassino disclosed relationships with Hoffmann-La Roche and many other companies.
Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers, as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.
AACR 2021
Cell-free DNA improves response prediction in breast cancer
When the two techniques were in agreement, the accuracy of response prediction was 92.6% in the study, with a predictive value for complete response of 87.5% and a predictive value for absence of complete response of 94.7%, which was substantially better than either method alone.
“Our work identifies a new parameter that is easily combinable with MRI for a more accurate prediction of response following neoadjuvant treatment, with possible implications for current protocols for the evaluation of nodal residual disease,” researcher Francesco Ravera, MD, PhD, of the University of Genoa (Italy), said in a press release.
Dr. Ravera and colleagues presented their research in a poster at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract LB063).
Accurate response prediction is important because it guides subsequent surgical management, Dr. Ravera and colleagues noted. Pathological complete responders – generally about 25% of patients after neoadjuvant therapy – typically undergo a sentinel lymph node biopsy to ensure cancer hasn’t spread, while incomplete responders often have a complete axillary lymph node dissection.
Response is currently assessed by MRI, but accuracy is suboptimal, the researchers noted. A more accurate method might “allow the omission of sentinel lymph node biopsy in complete responders, which could be replaced by longitudinal radiologic monitoring. This would represent substantial progress in the pursuit of an effective, minimally invasive treatment,” Dr. Ravera said.
He and his colleagues turned to plasma cfDNA because it has shown potential for providing useful diagnostic, recurrence, and treatment response information in neoplastic patients.
When healthy cells die, they release similarly sized DNA fragments into the blood, but cancer cells release fragments of varying sizes. The heart of the research was using electrophoresis to assess the degree of fragmentation – called cfDNA integrity – in plasma samples from 38 patients after anthracycline/taxane-based regimens.
The researchers compared how well cfDNA, preoperative MRI, and the combination of the two methods predicted response according to surgical histology.
A total of 11 patients had pathological complete responses to neoadjuvant therapy.
The ratio of large 321-1,000 base pair sized fragments to smaller 150-220 base pair sized fragments, which the team dubbed the “cfDNA integrity index,” best predicted response. At a cutoff above 2.71, the index was 81.6% accurate in predicting pathological complete response, with a sensitivity of 81.8% and specificity of 81.5%.
The predictive power wasn’t much better than MRI, which was 77.1% accurate, with a sensitivity of 72.7% and a specificity of 81.5%.
The two techniques were concordant in their prediction in over two-thirds of patients. When the techniques agreed, accuracy was over 90%.
Prospective studies are needed to evaluate the cfDNA integrity index in combination with MRI, the researchers concluded.
The study was sponsored by the University of Genoa and others. Dr. Ravera disclosed no conflicts of interest.
When the two techniques were in agreement, the accuracy of response prediction was 92.6% in the study, with a predictive value for complete response of 87.5% and a predictive value for absence of complete response of 94.7%, which was substantially better than either method alone.
“Our work identifies a new parameter that is easily combinable with MRI for a more accurate prediction of response following neoadjuvant treatment, with possible implications for current protocols for the evaluation of nodal residual disease,” researcher Francesco Ravera, MD, PhD, of the University of Genoa (Italy), said in a press release.
Dr. Ravera and colleagues presented their research in a poster at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract LB063).
Accurate response prediction is important because it guides subsequent surgical management, Dr. Ravera and colleagues noted. Pathological complete responders – generally about 25% of patients after neoadjuvant therapy – typically undergo a sentinel lymph node biopsy to ensure cancer hasn’t spread, while incomplete responders often have a complete axillary lymph node dissection.
Response is currently assessed by MRI, but accuracy is suboptimal, the researchers noted. A more accurate method might “allow the omission of sentinel lymph node biopsy in complete responders, which could be replaced by longitudinal radiologic monitoring. This would represent substantial progress in the pursuit of an effective, minimally invasive treatment,” Dr. Ravera said.
He and his colleagues turned to plasma cfDNA because it has shown potential for providing useful diagnostic, recurrence, and treatment response information in neoplastic patients.
When healthy cells die, they release similarly sized DNA fragments into the blood, but cancer cells release fragments of varying sizes. The heart of the research was using electrophoresis to assess the degree of fragmentation – called cfDNA integrity – in plasma samples from 38 patients after anthracycline/taxane-based regimens.
The researchers compared how well cfDNA, preoperative MRI, and the combination of the two methods predicted response according to surgical histology.
A total of 11 patients had pathological complete responses to neoadjuvant therapy.
The ratio of large 321-1,000 base pair sized fragments to smaller 150-220 base pair sized fragments, which the team dubbed the “cfDNA integrity index,” best predicted response. At a cutoff above 2.71, the index was 81.6% accurate in predicting pathological complete response, with a sensitivity of 81.8% and specificity of 81.5%.
The predictive power wasn’t much better than MRI, which was 77.1% accurate, with a sensitivity of 72.7% and a specificity of 81.5%.
The two techniques were concordant in their prediction in over two-thirds of patients. When the techniques agreed, accuracy was over 90%.
Prospective studies are needed to evaluate the cfDNA integrity index in combination with MRI, the researchers concluded.
The study was sponsored by the University of Genoa and others. Dr. Ravera disclosed no conflicts of interest.
When the two techniques were in agreement, the accuracy of response prediction was 92.6% in the study, with a predictive value for complete response of 87.5% and a predictive value for absence of complete response of 94.7%, which was substantially better than either method alone.
“Our work identifies a new parameter that is easily combinable with MRI for a more accurate prediction of response following neoadjuvant treatment, with possible implications for current protocols for the evaluation of nodal residual disease,” researcher Francesco Ravera, MD, PhD, of the University of Genoa (Italy), said in a press release.
Dr. Ravera and colleagues presented their research in a poster at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract LB063).
Accurate response prediction is important because it guides subsequent surgical management, Dr. Ravera and colleagues noted. Pathological complete responders – generally about 25% of patients after neoadjuvant therapy – typically undergo a sentinel lymph node biopsy to ensure cancer hasn’t spread, while incomplete responders often have a complete axillary lymph node dissection.
Response is currently assessed by MRI, but accuracy is suboptimal, the researchers noted. A more accurate method might “allow the omission of sentinel lymph node biopsy in complete responders, which could be replaced by longitudinal radiologic monitoring. This would represent substantial progress in the pursuit of an effective, minimally invasive treatment,” Dr. Ravera said.
He and his colleagues turned to plasma cfDNA because it has shown potential for providing useful diagnostic, recurrence, and treatment response information in neoplastic patients.
When healthy cells die, they release similarly sized DNA fragments into the blood, but cancer cells release fragments of varying sizes. The heart of the research was using electrophoresis to assess the degree of fragmentation – called cfDNA integrity – in plasma samples from 38 patients after anthracycline/taxane-based regimens.
The researchers compared how well cfDNA, preoperative MRI, and the combination of the two methods predicted response according to surgical histology.
A total of 11 patients had pathological complete responses to neoadjuvant therapy.
The ratio of large 321-1,000 base pair sized fragments to smaller 150-220 base pair sized fragments, which the team dubbed the “cfDNA integrity index,” best predicted response. At a cutoff above 2.71, the index was 81.6% accurate in predicting pathological complete response, with a sensitivity of 81.8% and specificity of 81.5%.
The predictive power wasn’t much better than MRI, which was 77.1% accurate, with a sensitivity of 72.7% and a specificity of 81.5%.
The two techniques were concordant in their prediction in over two-thirds of patients. When the techniques agreed, accuracy was over 90%.
Prospective studies are needed to evaluate the cfDNA integrity index in combination with MRI, the researchers concluded.
The study was sponsored by the University of Genoa and others. Dr. Ravera disclosed no conflicts of interest.
FROM AACR 2021
Tislelizumab bests docetaxel in NSCLC
The results were presented at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract CT039).
Tislelizumab is an anti–PD-1 antibody engineered to minimize Fc-gamma receptor binding on macrophages, a mechanism of T-cell clearance and potential anti–PD-1 resistance, according to investigator Caicun Zhou, MD, PhD, of Shanghai (China) Pulmonary Hospital.
Tislelizumab is approved for the treatment of relapsed/refractory classical Hodgkin lymphoma, the second-line treatment of locally advanced or metastatic urothelial carcinoma, and first-line treatment of advanced squamous NSCLC in China.
In patients with locally advanced or metastatic NSCLC whose disease has progressed after initial platinum-based chemotherapy, anti–PD-1/PD-L1 therapies have been shown to improve OS by 2-4 months versus docetaxel, Dr. Zhou said. A phase 1/2 study of second-line tislelizumab demonstrated antitumor activity in multiple advanced solid tumors, including NSCLC.
The phase 3 RATIONALE 303 study (NCT3358875) was designed to investigate the efficacy and safety of tislelizumab, compared with docetaxel in patients with locally advanced or metastatic NSCLC whose disease had progressed during or after platinum-containing doublet chemotherapy.
Study details
RATIONALE 303 enrolled 805 patients who had received up to two prior lines of systemic therapy and had no known EGFR mutations or ALK fusions.
The patients’ median age was 61 years, about 77% were male, about 80% were Asian, and about 70% were current or former smokers. Roughly 46% of patients had squamous histology, and about 43% had PD-L1 expression of 25% or greater.
Patients were stratified according to histology (squamous vs. nonsquamous), lines of prior therapy (second vs. third), and PD-L1 status (<25% vs. ≥25%).
Patients were randomized 2:1 to receive IV tislelizumab at 200 mg every 3 weeks (n = 535) or IV docetaxel at 75 mg/m2 every 3 weeks (n = 270) until unacceptable toxicity or disease progression.
The dual primary endpoints were OS in the intention-to-treat (ITT) population and in patients with PD-L1 expression of 25% or higher.
Survival and safety
In the ITT population, the 1-year OS rate was 61.9% in the tislelizumab arm and 49.8% in the docetaxel arm. At 2 years, the OS rates were 39.4% and 25.0%, respectively.
The median OS was 17.2 months in the tislelizumab arm and 11.9 months in the docetaxel arm (hazard ratio, 0.64; 95% CI, 0.53-0.78; P < .0001).
In the PD-L1–high subgroup, the median OS was 19.1 months with tislelizumab and 11.9 months with docetaxel (HR, 0.52; 95% CI, 0.38-0.71; P < .0001). The 1-year OS rates in this group were 67.5% and 49.1%, respectively, and the 2-year OS rates were 44.7% and 24.5%, respectively.
The OS benefit with tislelizumab was observed across nearly all subgroups, Dr. Zhou noted.
In the ITT population, benefits were seen with tislelizumab over docetaxel for progression-free survival (4.1 months vs. 2.6 months, P < .0001), objective response rate (21.9% vs. 7.1%, P < .0001), and median duration of response (13.5 months vs. 6.2 months, P < .0001).
The rate of treatment-related adverse events (TRAEs) was 73.0% in the tislelizumab arm and 93.8% in the docetaxel arm. Rates of grade 3 or higher TRAEs were 14.4% and 66.3%, respectively. Rates of TRAEs leading to permanent discontinuation of treatment were 6.0% and 9.7%, respectively, and rates of TRAEs leading to death were 1.5% and 1.6%, respectively.
The most common treatment-emergent adverse events were anemia in the tislelizumab arm (28.5%) and alopecia in the docetaxel arm (47.3%). The most common grade 3 or higher treatment-emergent adverse event was neutropenia in the docetaxel arm (27.9% vs. 0.6% with tislelizumab).
‘Very important trial’
“RATIONALE 303 demonstrated that, as second- or third-line therapy in patients with advanced NSCLC, tislelizumab was tolerable and prolonged overall survival by 5-7 months. It also improved progression-free survival and objective response rate versus docetaxel, regardless of histology or PD-L1 expression,” Dr. Zhou concluded.
Session moderator Marina Chiara Garassino, MD, of the University of Chicago called RATIONALE 303 a “very important trial.”
Citing the range of immunotherapies available for NSCLC, Dr. Garassino said, “We have a very crowded space in the treatment of NSCLC. ... It is difficult to do a direct comparison [of immunotherapy trials] because we know that populations can be different and other factors can play a role. In the near future, we have to understand if they are all the same and interchangeable or if they are different.”
RATIONALE 303 was funded by BeiGene. Dr. Zhou disclosed relationships with Lily China, Sanofi, Roche, and several other companies, not including BeiGene. Dr. Garassino disclosed relationships with AstraZeneca, Novartis, Bristol-Myers Squibb, and several other companies, not including BeiGene.
The results were presented at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract CT039).
Tislelizumab is an anti–PD-1 antibody engineered to minimize Fc-gamma receptor binding on macrophages, a mechanism of T-cell clearance and potential anti–PD-1 resistance, according to investigator Caicun Zhou, MD, PhD, of Shanghai (China) Pulmonary Hospital.
Tislelizumab is approved for the treatment of relapsed/refractory classical Hodgkin lymphoma, the second-line treatment of locally advanced or metastatic urothelial carcinoma, and first-line treatment of advanced squamous NSCLC in China.
In patients with locally advanced or metastatic NSCLC whose disease has progressed after initial platinum-based chemotherapy, anti–PD-1/PD-L1 therapies have been shown to improve OS by 2-4 months versus docetaxel, Dr. Zhou said. A phase 1/2 study of second-line tislelizumab demonstrated antitumor activity in multiple advanced solid tumors, including NSCLC.
The phase 3 RATIONALE 303 study (NCT3358875) was designed to investigate the efficacy and safety of tislelizumab, compared with docetaxel in patients with locally advanced or metastatic NSCLC whose disease had progressed during or after platinum-containing doublet chemotherapy.
Study details
RATIONALE 303 enrolled 805 patients who had received up to two prior lines of systemic therapy and had no known EGFR mutations or ALK fusions.
The patients’ median age was 61 years, about 77% were male, about 80% were Asian, and about 70% were current or former smokers. Roughly 46% of patients had squamous histology, and about 43% had PD-L1 expression of 25% or greater.
Patients were stratified according to histology (squamous vs. nonsquamous), lines of prior therapy (second vs. third), and PD-L1 status (<25% vs. ≥25%).
Patients were randomized 2:1 to receive IV tislelizumab at 200 mg every 3 weeks (n = 535) or IV docetaxel at 75 mg/m2 every 3 weeks (n = 270) until unacceptable toxicity or disease progression.
The dual primary endpoints were OS in the intention-to-treat (ITT) population and in patients with PD-L1 expression of 25% or higher.
Survival and safety
In the ITT population, the 1-year OS rate was 61.9% in the tislelizumab arm and 49.8% in the docetaxel arm. At 2 years, the OS rates were 39.4% and 25.0%, respectively.
The median OS was 17.2 months in the tislelizumab arm and 11.9 months in the docetaxel arm (hazard ratio, 0.64; 95% CI, 0.53-0.78; P < .0001).
In the PD-L1–high subgroup, the median OS was 19.1 months with tislelizumab and 11.9 months with docetaxel (HR, 0.52; 95% CI, 0.38-0.71; P < .0001). The 1-year OS rates in this group were 67.5% and 49.1%, respectively, and the 2-year OS rates were 44.7% and 24.5%, respectively.
The OS benefit with tislelizumab was observed across nearly all subgroups, Dr. Zhou noted.
In the ITT population, benefits were seen with tislelizumab over docetaxel for progression-free survival (4.1 months vs. 2.6 months, P < .0001), objective response rate (21.9% vs. 7.1%, P < .0001), and median duration of response (13.5 months vs. 6.2 months, P < .0001).
The rate of treatment-related adverse events (TRAEs) was 73.0% in the tislelizumab arm and 93.8% in the docetaxel arm. Rates of grade 3 or higher TRAEs were 14.4% and 66.3%, respectively. Rates of TRAEs leading to permanent discontinuation of treatment were 6.0% and 9.7%, respectively, and rates of TRAEs leading to death were 1.5% and 1.6%, respectively.
The most common treatment-emergent adverse events were anemia in the tislelizumab arm (28.5%) and alopecia in the docetaxel arm (47.3%). The most common grade 3 or higher treatment-emergent adverse event was neutropenia in the docetaxel arm (27.9% vs. 0.6% with tislelizumab).
‘Very important trial’
“RATIONALE 303 demonstrated that, as second- or third-line therapy in patients with advanced NSCLC, tislelizumab was tolerable and prolonged overall survival by 5-7 months. It also improved progression-free survival and objective response rate versus docetaxel, regardless of histology or PD-L1 expression,” Dr. Zhou concluded.
Session moderator Marina Chiara Garassino, MD, of the University of Chicago called RATIONALE 303 a “very important trial.”
Citing the range of immunotherapies available for NSCLC, Dr. Garassino said, “We have a very crowded space in the treatment of NSCLC. ... It is difficult to do a direct comparison [of immunotherapy trials] because we know that populations can be different and other factors can play a role. In the near future, we have to understand if they are all the same and interchangeable or if they are different.”
RATIONALE 303 was funded by BeiGene. Dr. Zhou disclosed relationships with Lily China, Sanofi, Roche, and several other companies, not including BeiGene. Dr. Garassino disclosed relationships with AstraZeneca, Novartis, Bristol-Myers Squibb, and several other companies, not including BeiGene.
The results were presented at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract CT039).
Tislelizumab is an anti–PD-1 antibody engineered to minimize Fc-gamma receptor binding on macrophages, a mechanism of T-cell clearance and potential anti–PD-1 resistance, according to investigator Caicun Zhou, MD, PhD, of Shanghai (China) Pulmonary Hospital.
Tislelizumab is approved for the treatment of relapsed/refractory classical Hodgkin lymphoma, the second-line treatment of locally advanced or metastatic urothelial carcinoma, and first-line treatment of advanced squamous NSCLC in China.
In patients with locally advanced or metastatic NSCLC whose disease has progressed after initial platinum-based chemotherapy, anti–PD-1/PD-L1 therapies have been shown to improve OS by 2-4 months versus docetaxel, Dr. Zhou said. A phase 1/2 study of second-line tislelizumab demonstrated antitumor activity in multiple advanced solid tumors, including NSCLC.
The phase 3 RATIONALE 303 study (NCT3358875) was designed to investigate the efficacy and safety of tislelizumab, compared with docetaxel in patients with locally advanced or metastatic NSCLC whose disease had progressed during or after platinum-containing doublet chemotherapy.
Study details
RATIONALE 303 enrolled 805 patients who had received up to two prior lines of systemic therapy and had no known EGFR mutations or ALK fusions.
The patients’ median age was 61 years, about 77% were male, about 80% were Asian, and about 70% were current or former smokers. Roughly 46% of patients had squamous histology, and about 43% had PD-L1 expression of 25% or greater.
Patients were stratified according to histology (squamous vs. nonsquamous), lines of prior therapy (second vs. third), and PD-L1 status (<25% vs. ≥25%).
Patients were randomized 2:1 to receive IV tislelizumab at 200 mg every 3 weeks (n = 535) or IV docetaxel at 75 mg/m2 every 3 weeks (n = 270) until unacceptable toxicity or disease progression.
The dual primary endpoints were OS in the intention-to-treat (ITT) population and in patients with PD-L1 expression of 25% or higher.
Survival and safety
In the ITT population, the 1-year OS rate was 61.9% in the tislelizumab arm and 49.8% in the docetaxel arm. At 2 years, the OS rates were 39.4% and 25.0%, respectively.
The median OS was 17.2 months in the tislelizumab arm and 11.9 months in the docetaxel arm (hazard ratio, 0.64; 95% CI, 0.53-0.78; P < .0001).
In the PD-L1–high subgroup, the median OS was 19.1 months with tislelizumab and 11.9 months with docetaxel (HR, 0.52; 95% CI, 0.38-0.71; P < .0001). The 1-year OS rates in this group were 67.5% and 49.1%, respectively, and the 2-year OS rates were 44.7% and 24.5%, respectively.
The OS benefit with tislelizumab was observed across nearly all subgroups, Dr. Zhou noted.
In the ITT population, benefits were seen with tislelizumab over docetaxel for progression-free survival (4.1 months vs. 2.6 months, P < .0001), objective response rate (21.9% vs. 7.1%, P < .0001), and median duration of response (13.5 months vs. 6.2 months, P < .0001).
The rate of treatment-related adverse events (TRAEs) was 73.0% in the tislelizumab arm and 93.8% in the docetaxel arm. Rates of grade 3 or higher TRAEs were 14.4% and 66.3%, respectively. Rates of TRAEs leading to permanent discontinuation of treatment were 6.0% and 9.7%, respectively, and rates of TRAEs leading to death were 1.5% and 1.6%, respectively.
The most common treatment-emergent adverse events were anemia in the tislelizumab arm (28.5%) and alopecia in the docetaxel arm (47.3%). The most common grade 3 or higher treatment-emergent adverse event was neutropenia in the docetaxel arm (27.9% vs. 0.6% with tislelizumab).
‘Very important trial’
“RATIONALE 303 demonstrated that, as second- or third-line therapy in patients with advanced NSCLC, tislelizumab was tolerable and prolonged overall survival by 5-7 months. It also improved progression-free survival and objective response rate versus docetaxel, regardless of histology or PD-L1 expression,” Dr. Zhou concluded.
Session moderator Marina Chiara Garassino, MD, of the University of Chicago called RATIONALE 303 a “very important trial.”
Citing the range of immunotherapies available for NSCLC, Dr. Garassino said, “We have a very crowded space in the treatment of NSCLC. ... It is difficult to do a direct comparison [of immunotherapy trials] because we know that populations can be different and other factors can play a role. In the near future, we have to understand if they are all the same and interchangeable or if they are different.”
RATIONALE 303 was funded by BeiGene. Dr. Zhou disclosed relationships with Lily China, Sanofi, Roche, and several other companies, not including BeiGene. Dr. Garassino disclosed relationships with AstraZeneca, Novartis, Bristol-Myers Squibb, and several other companies, not including BeiGene.
FROM AACR 2021
Antibiotics may prolong PFS in HCC patients on immunotherapy
Response rates and overall survival (OS), on the other hand, did not seem to be affected by antibiotic administration, according to investigator Petros Fessas, MD, of Imperial College London.
Dr. Fessas and colleagues presented these findings in a poster at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract 485).
Dr. Fessas noted that, in other cancers, antibiotics have been shown to reduce both response and survival rates after ICI.
To assess the impact of early antibiotic exposure on ICI efficacy in HCC, Dr. Fessas and colleagues examined data from 449 patients treated at 12 centers in the United States, Europe, and Asia.
The patients’ median age was 65 years, and 79.1% were men. Nearly three-quarters (73.3%) were cirrhotic (60.4% because of viral hepatitis), 79.9% were Child-Pugh class A, 72.4% were Barcelona Clinic Liver Cancer stage C, and 79% had an Eastern Cooperative Oncology Group performance status of 0-1.
Response and survival results
The investigators compared outcomes between patients with and without antibiotic exposure in the early immunotherapy period (EIOP) 30 days before and after ICI initiation.
In all, 170 patients (37.9%) received antibiotics in the EIOP. There were no differences in response rates, disease control rates, or median OS between patients who received antibiotics and those who did not.
The objective response rate was 20.2% in patients who received antibiotics in the EIOP and 16.1% in patients who did not (P = .2808). Disease control rates were 63.1% and 55.4%, respectively (P = .1144). The median OS was 15.3 months and 15.4 months, respectively (hazard ratio, 0.93; 95% confidence interval, 0.72-1.21; P = .6275).
The median PFS, however, was significantly longer in patients who received antibiotics than in patients who did not – 6.1 months and 3.7 months, respectively (HR, 0.74; 95% CI, 0.60-0.93; P = .0135).
To overcome possible bias introduced by misclassification of patients who received antibiotics but discontinued immunotherapy within 30 days of initiation, the investigators conducted a landmark selection analysis among only those patients with a median follow-up for PFS of 30 days or longer (n = 402). This analysis confirmed the prior findings.
“Antibiotic exposure in the 30 days before or after immune checkpoint initiation in hepatocellular carcinoma is associated with prolonged progression-free survival,” Dr. Fessas concluded.
He added that a key question for future research is to discover the immune-microbiologic determinants of response to initiation of ICIs.
Positive effect surprising
“My group has shown that antibiotic therapy is normally detrimental in patients with cancer,” investigator David J. Pinato, MD, PhD, of Imperial College London, said in an interview. “So we were very surprised to see a positive effect on PFS.”
He added that the new findings should be interpreted with caution.
“My feeling is that, unlike with many other malignancies, the gut microbiome is heavily involved in the progression of the cirrhosis that pre-dates HCC onset,” he said.
That would suggest the relationship between antibiotics and perturbation of the gut microbiome is dictated by something more than changes in antitumor immune tolerance, he added.
“Overall, I think the interplay is more complex in HCC: cirrhosis/cancer/microbiome, not just microbiome/cancer as in many other tumors,” Dr. Pinato said. “So we are looking at microbial determinants of response in HCC patients undergoing ICI therapy, and we are hopeful to see some more mechanistic evidence behind this association.”
Dr. Pinato disclosed relationships with ViiV Healthcare, Bayer Healthcare, Bristol Myers Squibb, Mina Therapeutics, Eisai, Roche, and AstraZeneca. Dr. Fessas reported having no conflicts of interest. No funding source for the study was disclosed.
Response rates and overall survival (OS), on the other hand, did not seem to be affected by antibiotic administration, according to investigator Petros Fessas, MD, of Imperial College London.
Dr. Fessas and colleagues presented these findings in a poster at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract 485).
Dr. Fessas noted that, in other cancers, antibiotics have been shown to reduce both response and survival rates after ICI.
To assess the impact of early antibiotic exposure on ICI efficacy in HCC, Dr. Fessas and colleagues examined data from 449 patients treated at 12 centers in the United States, Europe, and Asia.
The patients’ median age was 65 years, and 79.1% were men. Nearly three-quarters (73.3%) were cirrhotic (60.4% because of viral hepatitis), 79.9% were Child-Pugh class A, 72.4% were Barcelona Clinic Liver Cancer stage C, and 79% had an Eastern Cooperative Oncology Group performance status of 0-1.
Response and survival results
The investigators compared outcomes between patients with and without antibiotic exposure in the early immunotherapy period (EIOP) 30 days before and after ICI initiation.
In all, 170 patients (37.9%) received antibiotics in the EIOP. There were no differences in response rates, disease control rates, or median OS between patients who received antibiotics and those who did not.
The objective response rate was 20.2% in patients who received antibiotics in the EIOP and 16.1% in patients who did not (P = .2808). Disease control rates were 63.1% and 55.4%, respectively (P = .1144). The median OS was 15.3 months and 15.4 months, respectively (hazard ratio, 0.93; 95% confidence interval, 0.72-1.21; P = .6275).
The median PFS, however, was significantly longer in patients who received antibiotics than in patients who did not – 6.1 months and 3.7 months, respectively (HR, 0.74; 95% CI, 0.60-0.93; P = .0135).
To overcome possible bias introduced by misclassification of patients who received antibiotics but discontinued immunotherapy within 30 days of initiation, the investigators conducted a landmark selection analysis among only those patients with a median follow-up for PFS of 30 days or longer (n = 402). This analysis confirmed the prior findings.
“Antibiotic exposure in the 30 days before or after immune checkpoint initiation in hepatocellular carcinoma is associated with prolonged progression-free survival,” Dr. Fessas concluded.
He added that a key question for future research is to discover the immune-microbiologic determinants of response to initiation of ICIs.
Positive effect surprising
“My group has shown that antibiotic therapy is normally detrimental in patients with cancer,” investigator David J. Pinato, MD, PhD, of Imperial College London, said in an interview. “So we were very surprised to see a positive effect on PFS.”
He added that the new findings should be interpreted with caution.
“My feeling is that, unlike with many other malignancies, the gut microbiome is heavily involved in the progression of the cirrhosis that pre-dates HCC onset,” he said.
That would suggest the relationship between antibiotics and perturbation of the gut microbiome is dictated by something more than changes in antitumor immune tolerance, he added.
“Overall, I think the interplay is more complex in HCC: cirrhosis/cancer/microbiome, not just microbiome/cancer as in many other tumors,” Dr. Pinato said. “So we are looking at microbial determinants of response in HCC patients undergoing ICI therapy, and we are hopeful to see some more mechanistic evidence behind this association.”
Dr. Pinato disclosed relationships with ViiV Healthcare, Bayer Healthcare, Bristol Myers Squibb, Mina Therapeutics, Eisai, Roche, and AstraZeneca. Dr. Fessas reported having no conflicts of interest. No funding source for the study was disclosed.
Response rates and overall survival (OS), on the other hand, did not seem to be affected by antibiotic administration, according to investigator Petros Fessas, MD, of Imperial College London.
Dr. Fessas and colleagues presented these findings in a poster at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract 485).
Dr. Fessas noted that, in other cancers, antibiotics have been shown to reduce both response and survival rates after ICI.
To assess the impact of early antibiotic exposure on ICI efficacy in HCC, Dr. Fessas and colleagues examined data from 449 patients treated at 12 centers in the United States, Europe, and Asia.
The patients’ median age was 65 years, and 79.1% were men. Nearly three-quarters (73.3%) were cirrhotic (60.4% because of viral hepatitis), 79.9% were Child-Pugh class A, 72.4% were Barcelona Clinic Liver Cancer stage C, and 79% had an Eastern Cooperative Oncology Group performance status of 0-1.
Response and survival results
The investigators compared outcomes between patients with and without antibiotic exposure in the early immunotherapy period (EIOP) 30 days before and after ICI initiation.
In all, 170 patients (37.9%) received antibiotics in the EIOP. There were no differences in response rates, disease control rates, or median OS between patients who received antibiotics and those who did not.
The objective response rate was 20.2% in patients who received antibiotics in the EIOP and 16.1% in patients who did not (P = .2808). Disease control rates were 63.1% and 55.4%, respectively (P = .1144). The median OS was 15.3 months and 15.4 months, respectively (hazard ratio, 0.93; 95% confidence interval, 0.72-1.21; P = .6275).
The median PFS, however, was significantly longer in patients who received antibiotics than in patients who did not – 6.1 months and 3.7 months, respectively (HR, 0.74; 95% CI, 0.60-0.93; P = .0135).
To overcome possible bias introduced by misclassification of patients who received antibiotics but discontinued immunotherapy within 30 days of initiation, the investigators conducted a landmark selection analysis among only those patients with a median follow-up for PFS of 30 days or longer (n = 402). This analysis confirmed the prior findings.
“Antibiotic exposure in the 30 days before or after immune checkpoint initiation in hepatocellular carcinoma is associated with prolonged progression-free survival,” Dr. Fessas concluded.
He added that a key question for future research is to discover the immune-microbiologic determinants of response to initiation of ICIs.
Positive effect surprising
“My group has shown that antibiotic therapy is normally detrimental in patients with cancer,” investigator David J. Pinato, MD, PhD, of Imperial College London, said in an interview. “So we were very surprised to see a positive effect on PFS.”
He added that the new findings should be interpreted with caution.
“My feeling is that, unlike with many other malignancies, the gut microbiome is heavily involved in the progression of the cirrhosis that pre-dates HCC onset,” he said.
That would suggest the relationship between antibiotics and perturbation of the gut microbiome is dictated by something more than changes in antitumor immune tolerance, he added.
“Overall, I think the interplay is more complex in HCC: cirrhosis/cancer/microbiome, not just microbiome/cancer as in many other tumors,” Dr. Pinato said. “So we are looking at microbial determinants of response in HCC patients undergoing ICI therapy, and we are hopeful to see some more mechanistic evidence behind this association.”
Dr. Pinato disclosed relationships with ViiV Healthcare, Bayer Healthcare, Bristol Myers Squibb, Mina Therapeutics, Eisai, Roche, and AstraZeneca. Dr. Fessas reported having no conflicts of interest. No funding source for the study was disclosed.
FROM AACR 2021
Made-to-order TILs effective against metastatic melanoma
In just over one-third of patients with metastatic melanoma who had experienced disease progression while receiving multiple prior lines of therapy, including immunotherapy and targeted agents, objective clinical responses occurred with a customized cell therapy based on T cells extracted directly from tumor tissue.
The product, called lifileucel, is custom made for each patient and utilizes tumor-infiltrating lymphocytes (TILs) extracted from tumor lesions. This approach differs from other cell-based therapies that utilize T cells collected from the patient’s blood.
The new results come from a phase 2 trial conducted in 66 patients with previously treated unresectable or metastatic melanoma who received a single dose of the product. The objective response rate was 36.4%.
“Lifileucel has demonstrated efficacy and durability of response for patients with metastatic melanoma and represents a viable therapeutic option warranting further investigation,” said Jason Alan Chesney, MD, PhD, of the James Graham Brown Cancer Center at the University of Louisville (Ky.)
He presented the new data at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract CT008).
Customized cell therapy with TILs has been explored for the treatment of melanoma for more than a decade. Some researchers have reported durable response in 25% of patients.
However, “generalizing TIL therapy has been hampered by the complex and really not absolutely defined process for generating cells,” commented Philip Greenberg, MD, professor and head of the program in immunology in the clinical research division of the Fred Hutchinson Cancer Center, Seattle, who was the invited discussant.
The current study demonstrates that cell generation can be performed at a centralized facility that has the required technical expertise. The patient-specific products are then disseminated to multiple centers, he said. The study also demonstrates that TILs can be successfully generated from tumor sites other than skin or lymph nodes.
“Toxicity was, however, significant, although it was generally manageable, and it did occur early, generally within the first 2 weeks,” he noted.
Patient-derived product
Lifileucel is a tailor-made immunotherapy product created from melanoma tumor tissues resected from lesions in skin, lymph nodes, liver, lung, peritoneum, musculoskeletal system, breast, or other visceral organs. The cells are shipped to a central manufacturing facility, where the TILs are isolated, cultured, expanded, and reinvigorated. The cells are then harvested and cryopreserved. The process takes about 22 days. The cryopreserved product is then shipped back to the treating facility.
Prior to receiving the expanded and rejuvenated TILs, patients undergo myeloablative conditioning with cyclophosphamide followed by fludarabine. The TILs are then delivered in a single infusion, followed by administration of up to six doses of interleukin-2.
Details from clinical trial
At the meeting, Dr. Chesney reported details on the 66 patients in the trial. They had metastatic melanoma that was progressing on treatment. The had received a mean of 3.3 prior lines of therapy. All patients had received prior anti–PD-1/PD-L1 agents; 53 had received a CTLA4 inhibitor; and 15 had received a BRAF/MEK inhibitor.
These patients had a mean of six baseline target and nontarget lesions, and 28 patients had liver and/or brain metastases.
In all, 24 patients (36.4%) had an objective response, 3 patients had a complete response, and 21 had a partial response. There were 29 patients who had stable disease and 9 who progressed. Four patients had not undergone the first assessment at the time of data cutoff.
After a median follow-up of 28.1 months, the median duration of response was not reached. It ranged from 2.2 to more than 35.2 months.
Since the data cutoff in April 2020, reduction of tumor burden has occurred in 50 of 62 evaluable patients. Reductions in the target lesion sum of diameters has occurred in 11 patients. In one patient, a partial response converted to a complete response 24 months after infusion, Dr. Chesney noted.
The mean number of TILs infused was 27.3 billion (27.3 x 109). Appropriate amounts of TILs were manufactured from tumor samples acquired across all sites, and reductions in target lesion sum of diameter were seen across the range of TIL total cell doses.
All patients experienced at least one adverse event of any grade. All but two patients experienced grade 3 or 4 adverse events. Two patients died, one as a result of intra-abdominal hemorrhage considered possibly related to TIL therapy and one from acute respiratory failure deemed not related to TILs.
The most common grade 3 or 4 adverse events were thrombocytopenia, anemia, febrile neutropenia, hypophosphatemia, and lymphopenia.
“The adverse-event profile was manageable and was consistent with the underlying and the known profiles of the nonmyeloablative depletion regimen and IL-2,” Dr. Chesney said.
The decreasing frequency of adverse events over time reflects the potential benefit of the one-time infusion, and no new safety risks have been identified during more than 2 years of follow-up, he added.
Remaining questions, next steps
Dr. Greenberg said one of the study’s limitations is that the investigators did not characterize the TIL product.
“Studies have predicted that there’s a particular type of cell, a stem-like T cell, that’s responsible for mediating the efficacy,” he commented. He referred to research from Steven Rosenberg, MD, PhD, and colleagues at the National Cancer Institute, where TILs were first used in 2002.
Dr. Greenberg also raised the question of whether high-dose IL-2 was required post infusion, given that the patients were lymphodepleted before receiving lifileucel.
Future steps for TIL therapy, he said, should include identification of biomarkers for success or failure; strategies to enhance generation and expansion of tumor-reactive T cells; postinfusion strategies, such as using vaccines and/or checkpoint inhibitors to increase therapeutic activity; genetic modifications to enhance the function of TILs in the tumor microenvironment; and research into other tumor types that may be effectively treated with TILs.
The study was supported by Iovance Biotherapeutics. Dr. Chesney has received research funding from Iovance and other companies and has consulted for Amgen and Replimune. Dr. Greenberg has served on scientific advisory boards, has received grant/research support, and owns stock in several companies that do not include Iovance.
A version of this article first appeared on Medscape.com.
In just over one-third of patients with metastatic melanoma who had experienced disease progression while receiving multiple prior lines of therapy, including immunotherapy and targeted agents, objective clinical responses occurred with a customized cell therapy based on T cells extracted directly from tumor tissue.
The product, called lifileucel, is custom made for each patient and utilizes tumor-infiltrating lymphocytes (TILs) extracted from tumor lesions. This approach differs from other cell-based therapies that utilize T cells collected from the patient’s blood.
The new results come from a phase 2 trial conducted in 66 patients with previously treated unresectable or metastatic melanoma who received a single dose of the product. The objective response rate was 36.4%.
“Lifileucel has demonstrated efficacy and durability of response for patients with metastatic melanoma and represents a viable therapeutic option warranting further investigation,” said Jason Alan Chesney, MD, PhD, of the James Graham Brown Cancer Center at the University of Louisville (Ky.)
He presented the new data at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract CT008).
Customized cell therapy with TILs has been explored for the treatment of melanoma for more than a decade. Some researchers have reported durable response in 25% of patients.
However, “generalizing TIL therapy has been hampered by the complex and really not absolutely defined process for generating cells,” commented Philip Greenberg, MD, professor and head of the program in immunology in the clinical research division of the Fred Hutchinson Cancer Center, Seattle, who was the invited discussant.
The current study demonstrates that cell generation can be performed at a centralized facility that has the required technical expertise. The patient-specific products are then disseminated to multiple centers, he said. The study also demonstrates that TILs can be successfully generated from tumor sites other than skin or lymph nodes.
“Toxicity was, however, significant, although it was generally manageable, and it did occur early, generally within the first 2 weeks,” he noted.
Patient-derived product
Lifileucel is a tailor-made immunotherapy product created from melanoma tumor tissues resected from lesions in skin, lymph nodes, liver, lung, peritoneum, musculoskeletal system, breast, or other visceral organs. The cells are shipped to a central manufacturing facility, where the TILs are isolated, cultured, expanded, and reinvigorated. The cells are then harvested and cryopreserved. The process takes about 22 days. The cryopreserved product is then shipped back to the treating facility.
Prior to receiving the expanded and rejuvenated TILs, patients undergo myeloablative conditioning with cyclophosphamide followed by fludarabine. The TILs are then delivered in a single infusion, followed by administration of up to six doses of interleukin-2.
Details from clinical trial
At the meeting, Dr. Chesney reported details on the 66 patients in the trial. They had metastatic melanoma that was progressing on treatment. The had received a mean of 3.3 prior lines of therapy. All patients had received prior anti–PD-1/PD-L1 agents; 53 had received a CTLA4 inhibitor; and 15 had received a BRAF/MEK inhibitor.
These patients had a mean of six baseline target and nontarget lesions, and 28 patients had liver and/or brain metastases.
In all, 24 patients (36.4%) had an objective response, 3 patients had a complete response, and 21 had a partial response. There were 29 patients who had stable disease and 9 who progressed. Four patients had not undergone the first assessment at the time of data cutoff.
After a median follow-up of 28.1 months, the median duration of response was not reached. It ranged from 2.2 to more than 35.2 months.
Since the data cutoff in April 2020, reduction of tumor burden has occurred in 50 of 62 evaluable patients. Reductions in the target lesion sum of diameters has occurred in 11 patients. In one patient, a partial response converted to a complete response 24 months after infusion, Dr. Chesney noted.
The mean number of TILs infused was 27.3 billion (27.3 x 109). Appropriate amounts of TILs were manufactured from tumor samples acquired across all sites, and reductions in target lesion sum of diameter were seen across the range of TIL total cell doses.
All patients experienced at least one adverse event of any grade. All but two patients experienced grade 3 or 4 adverse events. Two patients died, one as a result of intra-abdominal hemorrhage considered possibly related to TIL therapy and one from acute respiratory failure deemed not related to TILs.
The most common grade 3 or 4 adverse events were thrombocytopenia, anemia, febrile neutropenia, hypophosphatemia, and lymphopenia.
“The adverse-event profile was manageable and was consistent with the underlying and the known profiles of the nonmyeloablative depletion regimen and IL-2,” Dr. Chesney said.
The decreasing frequency of adverse events over time reflects the potential benefit of the one-time infusion, and no new safety risks have been identified during more than 2 years of follow-up, he added.
Remaining questions, next steps
Dr. Greenberg said one of the study’s limitations is that the investigators did not characterize the TIL product.
“Studies have predicted that there’s a particular type of cell, a stem-like T cell, that’s responsible for mediating the efficacy,” he commented. He referred to research from Steven Rosenberg, MD, PhD, and colleagues at the National Cancer Institute, where TILs were first used in 2002.
Dr. Greenberg also raised the question of whether high-dose IL-2 was required post infusion, given that the patients were lymphodepleted before receiving lifileucel.
Future steps for TIL therapy, he said, should include identification of biomarkers for success or failure; strategies to enhance generation and expansion of tumor-reactive T cells; postinfusion strategies, such as using vaccines and/or checkpoint inhibitors to increase therapeutic activity; genetic modifications to enhance the function of TILs in the tumor microenvironment; and research into other tumor types that may be effectively treated with TILs.
The study was supported by Iovance Biotherapeutics. Dr. Chesney has received research funding from Iovance and other companies and has consulted for Amgen and Replimune. Dr. Greenberg has served on scientific advisory boards, has received grant/research support, and owns stock in several companies that do not include Iovance.
A version of this article first appeared on Medscape.com.
In just over one-third of patients with metastatic melanoma who had experienced disease progression while receiving multiple prior lines of therapy, including immunotherapy and targeted agents, objective clinical responses occurred with a customized cell therapy based on T cells extracted directly from tumor tissue.
The product, called lifileucel, is custom made for each patient and utilizes tumor-infiltrating lymphocytes (TILs) extracted from tumor lesions. This approach differs from other cell-based therapies that utilize T cells collected from the patient’s blood.
The new results come from a phase 2 trial conducted in 66 patients with previously treated unresectable or metastatic melanoma who received a single dose of the product. The objective response rate was 36.4%.
“Lifileucel has demonstrated efficacy and durability of response for patients with metastatic melanoma and represents a viable therapeutic option warranting further investigation,” said Jason Alan Chesney, MD, PhD, of the James Graham Brown Cancer Center at the University of Louisville (Ky.)
He presented the new data at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract CT008).
Customized cell therapy with TILs has been explored for the treatment of melanoma for more than a decade. Some researchers have reported durable response in 25% of patients.
However, “generalizing TIL therapy has been hampered by the complex and really not absolutely defined process for generating cells,” commented Philip Greenberg, MD, professor and head of the program in immunology in the clinical research division of the Fred Hutchinson Cancer Center, Seattle, who was the invited discussant.
The current study demonstrates that cell generation can be performed at a centralized facility that has the required technical expertise. The patient-specific products are then disseminated to multiple centers, he said. The study also demonstrates that TILs can be successfully generated from tumor sites other than skin or lymph nodes.
“Toxicity was, however, significant, although it was generally manageable, and it did occur early, generally within the first 2 weeks,” he noted.
Patient-derived product
Lifileucel is a tailor-made immunotherapy product created from melanoma tumor tissues resected from lesions in skin, lymph nodes, liver, lung, peritoneum, musculoskeletal system, breast, or other visceral organs. The cells are shipped to a central manufacturing facility, where the TILs are isolated, cultured, expanded, and reinvigorated. The cells are then harvested and cryopreserved. The process takes about 22 days. The cryopreserved product is then shipped back to the treating facility.
Prior to receiving the expanded and rejuvenated TILs, patients undergo myeloablative conditioning with cyclophosphamide followed by fludarabine. The TILs are then delivered in a single infusion, followed by administration of up to six doses of interleukin-2.
Details from clinical trial
At the meeting, Dr. Chesney reported details on the 66 patients in the trial. They had metastatic melanoma that was progressing on treatment. The had received a mean of 3.3 prior lines of therapy. All patients had received prior anti–PD-1/PD-L1 agents; 53 had received a CTLA4 inhibitor; and 15 had received a BRAF/MEK inhibitor.
These patients had a mean of six baseline target and nontarget lesions, and 28 patients had liver and/or brain metastases.
In all, 24 patients (36.4%) had an objective response, 3 patients had a complete response, and 21 had a partial response. There were 29 patients who had stable disease and 9 who progressed. Four patients had not undergone the first assessment at the time of data cutoff.
After a median follow-up of 28.1 months, the median duration of response was not reached. It ranged from 2.2 to more than 35.2 months.
Since the data cutoff in April 2020, reduction of tumor burden has occurred in 50 of 62 evaluable patients. Reductions in the target lesion sum of diameters has occurred in 11 patients. In one patient, a partial response converted to a complete response 24 months after infusion, Dr. Chesney noted.
The mean number of TILs infused was 27.3 billion (27.3 x 109). Appropriate amounts of TILs were manufactured from tumor samples acquired across all sites, and reductions in target lesion sum of diameter were seen across the range of TIL total cell doses.
All patients experienced at least one adverse event of any grade. All but two patients experienced grade 3 or 4 adverse events. Two patients died, one as a result of intra-abdominal hemorrhage considered possibly related to TIL therapy and one from acute respiratory failure deemed not related to TILs.
The most common grade 3 or 4 adverse events were thrombocytopenia, anemia, febrile neutropenia, hypophosphatemia, and lymphopenia.
“The adverse-event profile was manageable and was consistent with the underlying and the known profiles of the nonmyeloablative depletion regimen and IL-2,” Dr. Chesney said.
The decreasing frequency of adverse events over time reflects the potential benefit of the one-time infusion, and no new safety risks have been identified during more than 2 years of follow-up, he added.
Remaining questions, next steps
Dr. Greenberg said one of the study’s limitations is that the investigators did not characterize the TIL product.
“Studies have predicted that there’s a particular type of cell, a stem-like T cell, that’s responsible for mediating the efficacy,” he commented. He referred to research from Steven Rosenberg, MD, PhD, and colleagues at the National Cancer Institute, where TILs were first used in 2002.
Dr. Greenberg also raised the question of whether high-dose IL-2 was required post infusion, given that the patients were lymphodepleted before receiving lifileucel.
Future steps for TIL therapy, he said, should include identification of biomarkers for success or failure; strategies to enhance generation and expansion of tumor-reactive T cells; postinfusion strategies, such as using vaccines and/or checkpoint inhibitors to increase therapeutic activity; genetic modifications to enhance the function of TILs in the tumor microenvironment; and research into other tumor types that may be effectively treated with TILs.
The study was supported by Iovance Biotherapeutics. Dr. Chesney has received research funding from Iovance and other companies and has consulted for Amgen and Replimune. Dr. Greenberg has served on scientific advisory boards, has received grant/research support, and owns stock in several companies that do not include Iovance.
A version of this article first appeared on Medscape.com.
Tebentafusp improves OS: A first in metastatic uveal melanoma
Tebentafusp is the first investigational therapy in a phase 3 trial to improve OS in metastatic uveal melanoma, said Jessica Hassel, MD, of University Hospital Heidelberg in Germany, when presenting the results at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract CT002).
Dr. Hassel explained that tebentafusp is a bispecific fusion protein designed to target gp100 through a high affinity T-cell receptor binding domain and an anti-CD3 T-cell engaging domain, which redirects T cells to kill gp100-expressing tumor cells. Because the T-cell receptor binding domain only recognizes a specific gp100-derived peptide presented on HLA-A*02:01, tebentafusp can only be used to treat patients with this HLA type.
In the phase 3 trial, investigators enrolled 378 treatment-naive HLA-A*02:01-positive patients with metastatic uveal melanoma. Their median age was 65 years, and 50% were men.
Patients were assigned 2:1 to receive tebentafusp (n = 252) or investigator’s choice of pembrolizumab (n = 103), ipilimumab (n = 16), or dacarbazine (n = 7).
Prolonged OS despite low response rate
At a median follow-up of 14.1 months, patients receiving tebentafusp had significantly longer OS than that of patients in the investigator’s choice arm – 21.7 months and 16.0 months, respectively. The estimated 1-year OS rate was 73.2% in the tebentafusp arm and 58.5% in the standard therapy arm (hazard ratio, 0.51; 95% confidence interval, 0.37-0.71; P < .0001). The OS benefit was consistent across subgroups, Dr. Hassel said.
At a median follow-up of 11.4 months, the median progression-free survival was 3.3 months in the tebentafusp arm and 2.9 months in the investigator’s choice arm (HR, 0.73; 95% CI, 0.58-0.94; P = .0139).
The objective response rate was 9% in the tebentafusp arm and 5% in the investigator’s choice arm. There was only one complete response, and it was in the tebentafusp arm.
The disease control rate, defined as response or stable disease for 12 or more weeks, was 46% in the tebentafusp arm and 27% in the investigator’s choice arm. Rates of progressive disease were 52% and 62%, respectively.
Dr. Hassel pointed out that a landmark analysis of OS in patients with a best response of progressive disease, with patients continuing to receive treatment after progression, showed a hazard ratio of 0.4 (95% CI, 0.248-0.642) for those receiving tebentafusp vs. investigator’s choice. The OS benefit, despite low response rates, suggests that patients progress but are then stabilized with tebentafusp treatment.
“So this drug is slowing down developing disease,” she said.
‘Manageable’ adverse events
Target-mediated or cytokine-mediated adverse events were the most common side effects with tebentafusp. These included pyrexia (76%), pruritus (69%), and rash (83%), which decreased in frequency and severity after the first three to four doses.
While cytokine release syndrome was common (89%), the rate of grade 3-4 cytokine release syndrome was very low (1%). Adverse events were generally manageable with standard interventions, Dr. Hassel said.
The discontinuation rate was lower in the tebentafusp arm than in the investigator’s choice arm – 2% and 4.5%, respectively. There were no tebentafusp-related deaths.
‘Practice-changing’ results
“This is the first randomized controlled trial to be positive for overall survival in uveal melanoma. These are seminal and practice-changing results,” said AACR discussant Caroline Robert, MD, PhD, of Gustave Roussy and Paris-Saclay University in France.
She observed that the biology of uveal melanoma is distinct from that of cutaneous melanoma, and future research will have to address why tebentafusp doesn’t work as well in cutaneous melanoma. Tebentafusp will be evaluated in combination with immune checkpoint inhibitors as well, she added.
The major limitation of tebentafusp, Dr. Hassel observed, is that it can be used only in HLA-A*02:01-positive patients. “There still remains an unmet need for patients who do not have this particular surface protein,” she said.
The study was sponsored by Immunocore. Dr. Hassel disclosed relationships with Immunocore and other companies. Dr. Robert disclosed relationships with Bristol Myers Squibb, Pierre Fabre, Novartis, and other companies.
Tebentafusp is the first investigational therapy in a phase 3 trial to improve OS in metastatic uveal melanoma, said Jessica Hassel, MD, of University Hospital Heidelberg in Germany, when presenting the results at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract CT002).
Dr. Hassel explained that tebentafusp is a bispecific fusion protein designed to target gp100 through a high affinity T-cell receptor binding domain and an anti-CD3 T-cell engaging domain, which redirects T cells to kill gp100-expressing tumor cells. Because the T-cell receptor binding domain only recognizes a specific gp100-derived peptide presented on HLA-A*02:01, tebentafusp can only be used to treat patients with this HLA type.
In the phase 3 trial, investigators enrolled 378 treatment-naive HLA-A*02:01-positive patients with metastatic uveal melanoma. Their median age was 65 years, and 50% were men.
Patients were assigned 2:1 to receive tebentafusp (n = 252) or investigator’s choice of pembrolizumab (n = 103), ipilimumab (n = 16), or dacarbazine (n = 7).
Prolonged OS despite low response rate
At a median follow-up of 14.1 months, patients receiving tebentafusp had significantly longer OS than that of patients in the investigator’s choice arm – 21.7 months and 16.0 months, respectively. The estimated 1-year OS rate was 73.2% in the tebentafusp arm and 58.5% in the standard therapy arm (hazard ratio, 0.51; 95% confidence interval, 0.37-0.71; P < .0001). The OS benefit was consistent across subgroups, Dr. Hassel said.
At a median follow-up of 11.4 months, the median progression-free survival was 3.3 months in the tebentafusp arm and 2.9 months in the investigator’s choice arm (HR, 0.73; 95% CI, 0.58-0.94; P = .0139).
The objective response rate was 9% in the tebentafusp arm and 5% in the investigator’s choice arm. There was only one complete response, and it was in the tebentafusp arm.
The disease control rate, defined as response or stable disease for 12 or more weeks, was 46% in the tebentafusp arm and 27% in the investigator’s choice arm. Rates of progressive disease were 52% and 62%, respectively.
Dr. Hassel pointed out that a landmark analysis of OS in patients with a best response of progressive disease, with patients continuing to receive treatment after progression, showed a hazard ratio of 0.4 (95% CI, 0.248-0.642) for those receiving tebentafusp vs. investigator’s choice. The OS benefit, despite low response rates, suggests that patients progress but are then stabilized with tebentafusp treatment.
“So this drug is slowing down developing disease,” she said.
‘Manageable’ adverse events
Target-mediated or cytokine-mediated adverse events were the most common side effects with tebentafusp. These included pyrexia (76%), pruritus (69%), and rash (83%), which decreased in frequency and severity after the first three to four doses.
While cytokine release syndrome was common (89%), the rate of grade 3-4 cytokine release syndrome was very low (1%). Adverse events were generally manageable with standard interventions, Dr. Hassel said.
The discontinuation rate was lower in the tebentafusp arm than in the investigator’s choice arm – 2% and 4.5%, respectively. There were no tebentafusp-related deaths.
‘Practice-changing’ results
“This is the first randomized controlled trial to be positive for overall survival in uveal melanoma. These are seminal and practice-changing results,” said AACR discussant Caroline Robert, MD, PhD, of Gustave Roussy and Paris-Saclay University in France.
She observed that the biology of uveal melanoma is distinct from that of cutaneous melanoma, and future research will have to address why tebentafusp doesn’t work as well in cutaneous melanoma. Tebentafusp will be evaluated in combination with immune checkpoint inhibitors as well, she added.
The major limitation of tebentafusp, Dr. Hassel observed, is that it can be used only in HLA-A*02:01-positive patients. “There still remains an unmet need for patients who do not have this particular surface protein,” she said.
The study was sponsored by Immunocore. Dr. Hassel disclosed relationships with Immunocore and other companies. Dr. Robert disclosed relationships with Bristol Myers Squibb, Pierre Fabre, Novartis, and other companies.
Tebentafusp is the first investigational therapy in a phase 3 trial to improve OS in metastatic uveal melanoma, said Jessica Hassel, MD, of University Hospital Heidelberg in Germany, when presenting the results at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract CT002).
Dr. Hassel explained that tebentafusp is a bispecific fusion protein designed to target gp100 through a high affinity T-cell receptor binding domain and an anti-CD3 T-cell engaging domain, which redirects T cells to kill gp100-expressing tumor cells. Because the T-cell receptor binding domain only recognizes a specific gp100-derived peptide presented on HLA-A*02:01, tebentafusp can only be used to treat patients with this HLA type.
In the phase 3 trial, investigators enrolled 378 treatment-naive HLA-A*02:01-positive patients with metastatic uveal melanoma. Their median age was 65 years, and 50% were men.
Patients were assigned 2:1 to receive tebentafusp (n = 252) or investigator’s choice of pembrolizumab (n = 103), ipilimumab (n = 16), or dacarbazine (n = 7).
Prolonged OS despite low response rate
At a median follow-up of 14.1 months, patients receiving tebentafusp had significantly longer OS than that of patients in the investigator’s choice arm – 21.7 months and 16.0 months, respectively. The estimated 1-year OS rate was 73.2% in the tebentafusp arm and 58.5% in the standard therapy arm (hazard ratio, 0.51; 95% confidence interval, 0.37-0.71; P < .0001). The OS benefit was consistent across subgroups, Dr. Hassel said.
At a median follow-up of 11.4 months, the median progression-free survival was 3.3 months in the tebentafusp arm and 2.9 months in the investigator’s choice arm (HR, 0.73; 95% CI, 0.58-0.94; P = .0139).
The objective response rate was 9% in the tebentafusp arm and 5% in the investigator’s choice arm. There was only one complete response, and it was in the tebentafusp arm.
The disease control rate, defined as response or stable disease for 12 or more weeks, was 46% in the tebentafusp arm and 27% in the investigator’s choice arm. Rates of progressive disease were 52% and 62%, respectively.
Dr. Hassel pointed out that a landmark analysis of OS in patients with a best response of progressive disease, with patients continuing to receive treatment after progression, showed a hazard ratio of 0.4 (95% CI, 0.248-0.642) for those receiving tebentafusp vs. investigator’s choice. The OS benefit, despite low response rates, suggests that patients progress but are then stabilized with tebentafusp treatment.
“So this drug is slowing down developing disease,” she said.
‘Manageable’ adverse events
Target-mediated or cytokine-mediated adverse events were the most common side effects with tebentafusp. These included pyrexia (76%), pruritus (69%), and rash (83%), which decreased in frequency and severity after the first three to four doses.
While cytokine release syndrome was common (89%), the rate of grade 3-4 cytokine release syndrome was very low (1%). Adverse events were generally manageable with standard interventions, Dr. Hassel said.
The discontinuation rate was lower in the tebentafusp arm than in the investigator’s choice arm – 2% and 4.5%, respectively. There were no tebentafusp-related deaths.
‘Practice-changing’ results
“This is the first randomized controlled trial to be positive for overall survival in uveal melanoma. These are seminal and practice-changing results,” said AACR discussant Caroline Robert, MD, PhD, of Gustave Roussy and Paris-Saclay University in France.
She observed that the biology of uveal melanoma is distinct from that of cutaneous melanoma, and future research will have to address why tebentafusp doesn’t work as well in cutaneous melanoma. Tebentafusp will be evaluated in combination with immune checkpoint inhibitors as well, she added.
The major limitation of tebentafusp, Dr. Hassel observed, is that it can be used only in HLA-A*02:01-positive patients. “There still remains an unmet need for patients who do not have this particular surface protein,” she said.
The study was sponsored by Immunocore. Dr. Hassel disclosed relationships with Immunocore and other companies. Dr. Robert disclosed relationships with Bristol Myers Squibb, Pierre Fabre, Novartis, and other companies.
FROM AACR 2021
New combo shows benefit even in patients with high-risk HCC
Updated data continue to show significant clinical benefits for patients with unresectable hepatocellular carcinoma (HCC) with the combination of the immune checkpoint inhibitor atezolizumab and the angiogenesis inhibitor bevacizumab.
The new analysis shows benefit even in patients with high-risk disease.
The findings come from the practice-changing IMBRave150 trial, and the new data are from a median follow-up of 15.6 months. They show that median overall survival in the intention-to-treat (ITT) population, which included both high-risk and non–high-risk patients, was 19.2 months for patients randomized to atezolizumab-bevacizumab vs. 13.4 months for patients on sorafenib (P = .0009).
Jennifer J. Knox, MD, of Princess Margaret Cancer Centre at the University of Toronto, said that the updated data confirm her first impressions of the atezolizumab-bevacizumab combination.
“As a clinician who treats HCC, I can’t tell you how exciting it was to see these [survival] curves, now published in The New England Journal of Medicine, where you can see the superiority of the atezolizumab-bevacizumab combination over sorafenib, with early separation of the curves that last in both overall survival and progression-free survival,” she said.
Dr. Knox was acting as a discussant for the presentation, where the new data were reported by Richard S. Finn, MD, of Jonsson Comprehensive Cancer Center at the University of California, Los Angeles, at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract CT009).
Benefit seen also in high-risk group
At the meeting, Dr. Finn reported results from a subgroup of 101 patients who had high-risk disease (from 501 patients in the ITT population).
High-risk disease included tumor invasion of the main trunk of the portal vein of the liver and/or the portal vein branch contralateral to the primarily involved lobe (Vp4), and/or bile duct invasion, and/or tumor occupancy of at least 50% of the liver. Many of these patients would have been excluded from contemporary trials in HCC, Dr. Finn noted.
In this subgroup of patients with high-risk disease, the median overall survival with atezolizumab-bevacizumab was 7.6 months, compared with 5.5 months with sorafenib. This difference translated into a hazard ratio (HR) for death of 0.62 for the combination, although the upper limit of the 95% confidence was 1.00, and therefore statistically not significant.
The overall survival benefit for high-risk patients was similar to that in the non–high-risk population of 400 patients (HR, 0.68; 95% CI 0.51 - 0.91), Dr. Finn said.
Median progression-free survival (PFS) among high-risk patients was 5.4 months vs. 2.8 months with sorafenib, although this difference too was not significant, possibly because of the relatively small sample size.
“The data in this high-risk group is generally consistent with what we saw in the intent-to-treat population, and that is to say that atezo-bev has improved overall survival and PFS as compared to sorafenib, and a very similar objective response rate in this high-risk group as in the intent-to-treat population,” he said.
However, there were five fatal upper gastrointestinal bleeding events among high-risk patients treated with the combination, compared with none in the sorafenib arm. None of the deaths were considered by investigators to be treatment related, Dr. Finn said. All five patients who died had microvascular invasion, suggesting that patients with these features are at especially elevated risk for adverse events, he noted.
Overall, there were 23 on-study deaths among patients who received the combination (10 high-risk and 13 non–high-risk patients), compared with 9 patients treated with sorafenib (3 high-risk and 6 non–high-risk). Six of the deaths in the combination arm were attributed to treatment vs. one in the sorafenib arm.
Treatment-related adverse events of any grade, and grade 3 or 4 adverse events, occurred more frequently with sorafenib than with the combination in both high-risk and non–high-risk patients.
In both treatment groups, however, the incidence of serious adverse events was higher with the combination. Dr. Finn noted that the duration of therapy was longer with atezolizumab-bevacizumab than with sorafenib, which could account for the higher incidence of serious adverse events with the combination.
What’s next?
In her discussion, Dr. Knox noted that several other combinations are currently being explored for first-line treatment of HCC, including two trials with dual checkpoint inhibitors, and two comparing a tyrosine kinase inhibitor plus checkpoint inhibitor with tyrosine kinase inhibitors alone.
“There’s a lot of excitement about seeing these results, and I think when they read out in the next year or two, there will be a lot of cross-trial comparisons with patient groups and outcomes with the IMBRave150 data, which will be informative in choosing treatments for our patients,” she said.
“This abstract has shown that there is real benefit across both the high- and the lower-risk patients, and that clinicians need to be careful about the risk of hemorrhage in portal vein thrombosis,” Dr. Knox summarized.
The IMBRave150 trial is sponsored by F. Hoffmann–La Roche. Dr. Finn disclosed consulting activities for F. Hoffmann–La Roche, and institutional grant/research support from Roche and others. Dr. Knox disclosed grant/research support from F. Hoffmann–La Roche and others, and consulting for Merck, Pfizer, and Esai.
A version of this article first appeared on Medscape.com.
Updated data continue to show significant clinical benefits for patients with unresectable hepatocellular carcinoma (HCC) with the combination of the immune checkpoint inhibitor atezolizumab and the angiogenesis inhibitor bevacizumab.
The new analysis shows benefit even in patients with high-risk disease.
The findings come from the practice-changing IMBRave150 trial, and the new data are from a median follow-up of 15.6 months. They show that median overall survival in the intention-to-treat (ITT) population, which included both high-risk and non–high-risk patients, was 19.2 months for patients randomized to atezolizumab-bevacizumab vs. 13.4 months for patients on sorafenib (P = .0009).
Jennifer J. Knox, MD, of Princess Margaret Cancer Centre at the University of Toronto, said that the updated data confirm her first impressions of the atezolizumab-bevacizumab combination.
“As a clinician who treats HCC, I can’t tell you how exciting it was to see these [survival] curves, now published in The New England Journal of Medicine, where you can see the superiority of the atezolizumab-bevacizumab combination over sorafenib, with early separation of the curves that last in both overall survival and progression-free survival,” she said.
Dr. Knox was acting as a discussant for the presentation, where the new data were reported by Richard S. Finn, MD, of Jonsson Comprehensive Cancer Center at the University of California, Los Angeles, at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract CT009).
Benefit seen also in high-risk group
At the meeting, Dr. Finn reported results from a subgroup of 101 patients who had high-risk disease (from 501 patients in the ITT population).
High-risk disease included tumor invasion of the main trunk of the portal vein of the liver and/or the portal vein branch contralateral to the primarily involved lobe (Vp4), and/or bile duct invasion, and/or tumor occupancy of at least 50% of the liver. Many of these patients would have been excluded from contemporary trials in HCC, Dr. Finn noted.
In this subgroup of patients with high-risk disease, the median overall survival with atezolizumab-bevacizumab was 7.6 months, compared with 5.5 months with sorafenib. This difference translated into a hazard ratio (HR) for death of 0.62 for the combination, although the upper limit of the 95% confidence was 1.00, and therefore statistically not significant.
The overall survival benefit for high-risk patients was similar to that in the non–high-risk population of 400 patients (HR, 0.68; 95% CI 0.51 - 0.91), Dr. Finn said.
Median progression-free survival (PFS) among high-risk patients was 5.4 months vs. 2.8 months with sorafenib, although this difference too was not significant, possibly because of the relatively small sample size.
“The data in this high-risk group is generally consistent with what we saw in the intent-to-treat population, and that is to say that atezo-bev has improved overall survival and PFS as compared to sorafenib, and a very similar objective response rate in this high-risk group as in the intent-to-treat population,” he said.
However, there were five fatal upper gastrointestinal bleeding events among high-risk patients treated with the combination, compared with none in the sorafenib arm. None of the deaths were considered by investigators to be treatment related, Dr. Finn said. All five patients who died had microvascular invasion, suggesting that patients with these features are at especially elevated risk for adverse events, he noted.
Overall, there were 23 on-study deaths among patients who received the combination (10 high-risk and 13 non–high-risk patients), compared with 9 patients treated with sorafenib (3 high-risk and 6 non–high-risk). Six of the deaths in the combination arm were attributed to treatment vs. one in the sorafenib arm.
Treatment-related adverse events of any grade, and grade 3 or 4 adverse events, occurred more frequently with sorafenib than with the combination in both high-risk and non–high-risk patients.
In both treatment groups, however, the incidence of serious adverse events was higher with the combination. Dr. Finn noted that the duration of therapy was longer with atezolizumab-bevacizumab than with sorafenib, which could account for the higher incidence of serious adverse events with the combination.
What’s next?
In her discussion, Dr. Knox noted that several other combinations are currently being explored for first-line treatment of HCC, including two trials with dual checkpoint inhibitors, and two comparing a tyrosine kinase inhibitor plus checkpoint inhibitor with tyrosine kinase inhibitors alone.
“There’s a lot of excitement about seeing these results, and I think when they read out in the next year or two, there will be a lot of cross-trial comparisons with patient groups and outcomes with the IMBRave150 data, which will be informative in choosing treatments for our patients,” she said.
“This abstract has shown that there is real benefit across both the high- and the lower-risk patients, and that clinicians need to be careful about the risk of hemorrhage in portal vein thrombosis,” Dr. Knox summarized.
The IMBRave150 trial is sponsored by F. Hoffmann–La Roche. Dr. Finn disclosed consulting activities for F. Hoffmann–La Roche, and institutional grant/research support from Roche and others. Dr. Knox disclosed grant/research support from F. Hoffmann–La Roche and others, and consulting for Merck, Pfizer, and Esai.
A version of this article first appeared on Medscape.com.
Updated data continue to show significant clinical benefits for patients with unresectable hepatocellular carcinoma (HCC) with the combination of the immune checkpoint inhibitor atezolizumab and the angiogenesis inhibitor bevacizumab.
The new analysis shows benefit even in patients with high-risk disease.
The findings come from the practice-changing IMBRave150 trial, and the new data are from a median follow-up of 15.6 months. They show that median overall survival in the intention-to-treat (ITT) population, which included both high-risk and non–high-risk patients, was 19.2 months for patients randomized to atezolizumab-bevacizumab vs. 13.4 months for patients on sorafenib (P = .0009).
Jennifer J. Knox, MD, of Princess Margaret Cancer Centre at the University of Toronto, said that the updated data confirm her first impressions of the atezolizumab-bevacizumab combination.
“As a clinician who treats HCC, I can’t tell you how exciting it was to see these [survival] curves, now published in The New England Journal of Medicine, where you can see the superiority of the atezolizumab-bevacizumab combination over sorafenib, with early separation of the curves that last in both overall survival and progression-free survival,” she said.
Dr. Knox was acting as a discussant for the presentation, where the new data were reported by Richard S. Finn, MD, of Jonsson Comprehensive Cancer Center at the University of California, Los Angeles, at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract CT009).
Benefit seen also in high-risk group
At the meeting, Dr. Finn reported results from a subgroup of 101 patients who had high-risk disease (from 501 patients in the ITT population).
High-risk disease included tumor invasion of the main trunk of the portal vein of the liver and/or the portal vein branch contralateral to the primarily involved lobe (Vp4), and/or bile duct invasion, and/or tumor occupancy of at least 50% of the liver. Many of these patients would have been excluded from contemporary trials in HCC, Dr. Finn noted.
In this subgroup of patients with high-risk disease, the median overall survival with atezolizumab-bevacizumab was 7.6 months, compared with 5.5 months with sorafenib. This difference translated into a hazard ratio (HR) for death of 0.62 for the combination, although the upper limit of the 95% confidence was 1.00, and therefore statistically not significant.
The overall survival benefit for high-risk patients was similar to that in the non–high-risk population of 400 patients (HR, 0.68; 95% CI 0.51 - 0.91), Dr. Finn said.
Median progression-free survival (PFS) among high-risk patients was 5.4 months vs. 2.8 months with sorafenib, although this difference too was not significant, possibly because of the relatively small sample size.
“The data in this high-risk group is generally consistent with what we saw in the intent-to-treat population, and that is to say that atezo-bev has improved overall survival and PFS as compared to sorafenib, and a very similar objective response rate in this high-risk group as in the intent-to-treat population,” he said.
However, there were five fatal upper gastrointestinal bleeding events among high-risk patients treated with the combination, compared with none in the sorafenib arm. None of the deaths were considered by investigators to be treatment related, Dr. Finn said. All five patients who died had microvascular invasion, suggesting that patients with these features are at especially elevated risk for adverse events, he noted.
Overall, there were 23 on-study deaths among patients who received the combination (10 high-risk and 13 non–high-risk patients), compared with 9 patients treated with sorafenib (3 high-risk and 6 non–high-risk). Six of the deaths in the combination arm were attributed to treatment vs. one in the sorafenib arm.
Treatment-related adverse events of any grade, and grade 3 or 4 adverse events, occurred more frequently with sorafenib than with the combination in both high-risk and non–high-risk patients.
In both treatment groups, however, the incidence of serious adverse events was higher with the combination. Dr. Finn noted that the duration of therapy was longer with atezolizumab-bevacizumab than with sorafenib, which could account for the higher incidence of serious adverse events with the combination.
What’s next?
In her discussion, Dr. Knox noted that several other combinations are currently being explored for first-line treatment of HCC, including two trials with dual checkpoint inhibitors, and two comparing a tyrosine kinase inhibitor plus checkpoint inhibitor with tyrosine kinase inhibitors alone.
“There’s a lot of excitement about seeing these results, and I think when they read out in the next year or two, there will be a lot of cross-trial comparisons with patient groups and outcomes with the IMBRave150 data, which will be informative in choosing treatments for our patients,” she said.
“This abstract has shown that there is real benefit across both the high- and the lower-risk patients, and that clinicians need to be careful about the risk of hemorrhage in portal vein thrombosis,” Dr. Knox summarized.
The IMBRave150 trial is sponsored by F. Hoffmann–La Roche. Dr. Finn disclosed consulting activities for F. Hoffmann–La Roche, and institutional grant/research support from Roche and others. Dr. Knox disclosed grant/research support from F. Hoffmann–La Roche and others, and consulting for Merck, Pfizer, and Esai.
A version of this article first appeared on Medscape.com.
FROM AACR 2021
New data dim hopes for ‘triumph of drug discovery’
Hopes for a new category of agents recently hailed as “a triumph of drug discovery” have been dimmed somewhat by new data showing many types of acquired resistance.
KRAS is one of the most frequently mutated oncogenes in human cancer and has long been thought “undruggable” – but novel drugs acting specifically on the KRAS G12C mutation have shown promise in clinical trials.
Early results with the experimental KRAS inhibitors sotorasib and adagrasib were deemed promising, but new data presented at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract LB002) have splashed cold water on that enthusiasm.
The efficacy of these new drugs looks to be threatened by the development of resistance caused by a wide range of genomic and histologic mechanisms.
Mark M. Awad, MD, PhD, from the Dana-Farber Cancer Institute in Boston, reported data from 30 patients with non–small cell lung cancer (NSCLC) or colorectal cancer (CRC) bearing the KRAS G12C mutation who had disease progression while being treated with adagrasib in clinical trials. Investigators found multiple on-target KRAS alterations and off-target bypass mechanisms of acquired resistance to adagrasib in these patients.
“Diverse mechanisms confer resistance to the KRAS G12C inhibitors, including secondary KRAS mutations, MAP [mitogen-activated protein] kinase pathway alterations, acquired genomic rearrangements, and histologic transformation,” Dr. Awad said in a mini-symposium presentation.
“Several cases displayed multiple resistance mechanisms, and novel combinatorial strategies will be necessary to delay or overcome resistance in KRAS G12C-mutant cancers,” he said.
Inactivating KRAS
The KRAS G12C mutation is a glycine-to-cysteine substitution that results in the oncogene being switched on in its active form.
But the mutation has been considered too tough to target because of the KRAS gene’s strong binding affinity for guanosine triphosphate, an essential building block of RNA synthesis, and by a lack of accessible drug-binding sites.
Sotorasib and adagrasib are small-molecule, specific, and irreversible inhibitors of KRAS that interact with a “pocket” on the gene’s surface that is present only in an inactive conformation of KRAS. The drugs inhibit oncogenic signaling and tumorigenesis by preventing cycling of the oncogene into its active form.
Multiple mutations, histologic transformations
Dr. Awad and colleagues studied biopsy samples and circulating tumor DNA (ctDNA) from 30 patients both at baseline and after administration of adagrasib monotherapy. The patients all had initial responses to the drug but then experienced disease progression.
The investigators used mutagenesis screens to identify mechanisms of resistance to KRAS G12C inhibitors.
The 30 patients included 23 with NSCLC and 7 with CRC. Eighteen had unknown mechanisms of resistance, and putative resistance mechanisms were identified in the other 12 patients. Of this latter group, seven appeared to have single resistance mechanisms, and five had multiple mechanisms of resistance.
One patient with NSCLC who had radiographic evidence of response followed by progression was found to have had a novel KRAS Y96C mutation, and three had novel KRAS mutations in other gene regions, with multiple concurrent alterations in genes implicated in other forms of cancer, such as PTEN, BRAF, and MAP2K1.
The investigators also identified amplifications of the KRAS G12C allele, and MET.
In two patients, NSCLC underwent histologic transformation from adenocarcinoma at baseline to squamous cell carcinoma at the time of acquired resistance to the drug. No genomic resistance mechanisms were detected in either of these patients, Dr. Awad said.
“In several cases, we see multiple mechanisms or co-occurring alterations in each individual patient, with the suggestion that perhaps the multiple mutations or resistance mechanism may be more common in the colorectal population, particularly with acquired gene fusions, than in the lung cancer population, although larger datasets will be needed to confirm this observation,” he said.
Does duration of response matter?
In the question-and-answer session following his presentation, Dr. Awad was asked about clinical responses in the patients who developed resistance.
“In this initial reporting of resistance mechanisms we did not overlay or report out the clinical outcomes, including the durations of response or the time to disease progression, in part because this is an ongoing clinical trial, and those data will be reported in full at a later time,” Dr. Awad replied. “But I think it will be really important to identify whether patients are more likely to develop resistance earlier versus later or have different resistance mechanisms.”
Dr. Awad commented further that the resistance to adagrasib appeared to be acquired. “These resistance mutations were not detected to the level of detection at the baseline samples. So presumably they may be present at some low levels at the time of initial diagnosis, or they emerge over the course of therapy,” he said.
“Many of the resistance mechanisms appear to be more subclonal, occurring at an allele fraction lower than the original KRAS G12C mutation, which we know is the clonal event in the entire population of the cancer, and I think when we’re seeing these multiple resistance mechanisms emerging, they are potentially each representing different subclones that can develop simultaneously,” he added.
Adagrasib trials are supported by Mirati Therapeutics. Dr. Awad disclosed consulting for Mirati and others, and institutional research support from several different companies.
A version of this article first appeared on Medscape.com.
Hopes for a new category of agents recently hailed as “a triumph of drug discovery” have been dimmed somewhat by new data showing many types of acquired resistance.
KRAS is one of the most frequently mutated oncogenes in human cancer and has long been thought “undruggable” – but novel drugs acting specifically on the KRAS G12C mutation have shown promise in clinical trials.
Early results with the experimental KRAS inhibitors sotorasib and adagrasib were deemed promising, but new data presented at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract LB002) have splashed cold water on that enthusiasm.
The efficacy of these new drugs looks to be threatened by the development of resistance caused by a wide range of genomic and histologic mechanisms.
Mark M. Awad, MD, PhD, from the Dana-Farber Cancer Institute in Boston, reported data from 30 patients with non–small cell lung cancer (NSCLC) or colorectal cancer (CRC) bearing the KRAS G12C mutation who had disease progression while being treated with adagrasib in clinical trials. Investigators found multiple on-target KRAS alterations and off-target bypass mechanisms of acquired resistance to adagrasib in these patients.
“Diverse mechanisms confer resistance to the KRAS G12C inhibitors, including secondary KRAS mutations, MAP [mitogen-activated protein] kinase pathway alterations, acquired genomic rearrangements, and histologic transformation,” Dr. Awad said in a mini-symposium presentation.
“Several cases displayed multiple resistance mechanisms, and novel combinatorial strategies will be necessary to delay or overcome resistance in KRAS G12C-mutant cancers,” he said.
Inactivating KRAS
The KRAS G12C mutation is a glycine-to-cysteine substitution that results in the oncogene being switched on in its active form.
But the mutation has been considered too tough to target because of the KRAS gene’s strong binding affinity for guanosine triphosphate, an essential building block of RNA synthesis, and by a lack of accessible drug-binding sites.
Sotorasib and adagrasib are small-molecule, specific, and irreversible inhibitors of KRAS that interact with a “pocket” on the gene’s surface that is present only in an inactive conformation of KRAS. The drugs inhibit oncogenic signaling and tumorigenesis by preventing cycling of the oncogene into its active form.
Multiple mutations, histologic transformations
Dr. Awad and colleagues studied biopsy samples and circulating tumor DNA (ctDNA) from 30 patients both at baseline and after administration of adagrasib monotherapy. The patients all had initial responses to the drug but then experienced disease progression.
The investigators used mutagenesis screens to identify mechanisms of resistance to KRAS G12C inhibitors.
The 30 patients included 23 with NSCLC and 7 with CRC. Eighteen had unknown mechanisms of resistance, and putative resistance mechanisms were identified in the other 12 patients. Of this latter group, seven appeared to have single resistance mechanisms, and five had multiple mechanisms of resistance.
One patient with NSCLC who had radiographic evidence of response followed by progression was found to have had a novel KRAS Y96C mutation, and three had novel KRAS mutations in other gene regions, with multiple concurrent alterations in genes implicated in other forms of cancer, such as PTEN, BRAF, and MAP2K1.
The investigators also identified amplifications of the KRAS G12C allele, and MET.
In two patients, NSCLC underwent histologic transformation from adenocarcinoma at baseline to squamous cell carcinoma at the time of acquired resistance to the drug. No genomic resistance mechanisms were detected in either of these patients, Dr. Awad said.
“In several cases, we see multiple mechanisms or co-occurring alterations in each individual patient, with the suggestion that perhaps the multiple mutations or resistance mechanism may be more common in the colorectal population, particularly with acquired gene fusions, than in the lung cancer population, although larger datasets will be needed to confirm this observation,” he said.
Does duration of response matter?
In the question-and-answer session following his presentation, Dr. Awad was asked about clinical responses in the patients who developed resistance.
“In this initial reporting of resistance mechanisms we did not overlay or report out the clinical outcomes, including the durations of response or the time to disease progression, in part because this is an ongoing clinical trial, and those data will be reported in full at a later time,” Dr. Awad replied. “But I think it will be really important to identify whether patients are more likely to develop resistance earlier versus later or have different resistance mechanisms.”
Dr. Awad commented further that the resistance to adagrasib appeared to be acquired. “These resistance mutations were not detected to the level of detection at the baseline samples. So presumably they may be present at some low levels at the time of initial diagnosis, or they emerge over the course of therapy,” he said.
“Many of the resistance mechanisms appear to be more subclonal, occurring at an allele fraction lower than the original KRAS G12C mutation, which we know is the clonal event in the entire population of the cancer, and I think when we’re seeing these multiple resistance mechanisms emerging, they are potentially each representing different subclones that can develop simultaneously,” he added.
Adagrasib trials are supported by Mirati Therapeutics. Dr. Awad disclosed consulting for Mirati and others, and institutional research support from several different companies.
A version of this article first appeared on Medscape.com.
Hopes for a new category of agents recently hailed as “a triumph of drug discovery” have been dimmed somewhat by new data showing many types of acquired resistance.
KRAS is one of the most frequently mutated oncogenes in human cancer and has long been thought “undruggable” – but novel drugs acting specifically on the KRAS G12C mutation have shown promise in clinical trials.
Early results with the experimental KRAS inhibitors sotorasib and adagrasib were deemed promising, but new data presented at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract LB002) have splashed cold water on that enthusiasm.
The efficacy of these new drugs looks to be threatened by the development of resistance caused by a wide range of genomic and histologic mechanisms.
Mark M. Awad, MD, PhD, from the Dana-Farber Cancer Institute in Boston, reported data from 30 patients with non–small cell lung cancer (NSCLC) or colorectal cancer (CRC) bearing the KRAS G12C mutation who had disease progression while being treated with adagrasib in clinical trials. Investigators found multiple on-target KRAS alterations and off-target bypass mechanisms of acquired resistance to adagrasib in these patients.
“Diverse mechanisms confer resistance to the KRAS G12C inhibitors, including secondary KRAS mutations, MAP [mitogen-activated protein] kinase pathway alterations, acquired genomic rearrangements, and histologic transformation,” Dr. Awad said in a mini-symposium presentation.
“Several cases displayed multiple resistance mechanisms, and novel combinatorial strategies will be necessary to delay or overcome resistance in KRAS G12C-mutant cancers,” he said.
Inactivating KRAS
The KRAS G12C mutation is a glycine-to-cysteine substitution that results in the oncogene being switched on in its active form.
But the mutation has been considered too tough to target because of the KRAS gene’s strong binding affinity for guanosine triphosphate, an essential building block of RNA synthesis, and by a lack of accessible drug-binding sites.
Sotorasib and adagrasib are small-molecule, specific, and irreversible inhibitors of KRAS that interact with a “pocket” on the gene’s surface that is present only in an inactive conformation of KRAS. The drugs inhibit oncogenic signaling and tumorigenesis by preventing cycling of the oncogene into its active form.
Multiple mutations, histologic transformations
Dr. Awad and colleagues studied biopsy samples and circulating tumor DNA (ctDNA) from 30 patients both at baseline and after administration of adagrasib monotherapy. The patients all had initial responses to the drug but then experienced disease progression.
The investigators used mutagenesis screens to identify mechanisms of resistance to KRAS G12C inhibitors.
The 30 patients included 23 with NSCLC and 7 with CRC. Eighteen had unknown mechanisms of resistance, and putative resistance mechanisms were identified in the other 12 patients. Of this latter group, seven appeared to have single resistance mechanisms, and five had multiple mechanisms of resistance.
One patient with NSCLC who had radiographic evidence of response followed by progression was found to have had a novel KRAS Y96C mutation, and three had novel KRAS mutations in other gene regions, with multiple concurrent alterations in genes implicated in other forms of cancer, such as PTEN, BRAF, and MAP2K1.
The investigators also identified amplifications of the KRAS G12C allele, and MET.
In two patients, NSCLC underwent histologic transformation from adenocarcinoma at baseline to squamous cell carcinoma at the time of acquired resistance to the drug. No genomic resistance mechanisms were detected in either of these patients, Dr. Awad said.
“In several cases, we see multiple mechanisms or co-occurring alterations in each individual patient, with the suggestion that perhaps the multiple mutations or resistance mechanism may be more common in the colorectal population, particularly with acquired gene fusions, than in the lung cancer population, although larger datasets will be needed to confirm this observation,” he said.
Does duration of response matter?
In the question-and-answer session following his presentation, Dr. Awad was asked about clinical responses in the patients who developed resistance.
“In this initial reporting of resistance mechanisms we did not overlay or report out the clinical outcomes, including the durations of response or the time to disease progression, in part because this is an ongoing clinical trial, and those data will be reported in full at a later time,” Dr. Awad replied. “But I think it will be really important to identify whether patients are more likely to develop resistance earlier versus later or have different resistance mechanisms.”
Dr. Awad commented further that the resistance to adagrasib appeared to be acquired. “These resistance mutations were not detected to the level of detection at the baseline samples. So presumably they may be present at some low levels at the time of initial diagnosis, or they emerge over the course of therapy,” he said.
“Many of the resistance mechanisms appear to be more subclonal, occurring at an allele fraction lower than the original KRAS G12C mutation, which we know is the clonal event in the entire population of the cancer, and I think when we’re seeing these multiple resistance mechanisms emerging, they are potentially each representing different subclones that can develop simultaneously,” he added.
Adagrasib trials are supported by Mirati Therapeutics. Dr. Awad disclosed consulting for Mirati and others, and institutional research support from several different companies.
A version of this article first appeared on Medscape.com.
FROM AACR 2021
Personalized cancer vaccine shows early promise across tumor types
The vaccine, PGV-001, was given to 13 patients with solid tumors or multiple myeloma who had a high risk of recurrence after surgery or autologous stem cell transplant.
At last follow-up, four patients were still alive without evidence of disease and had not received subsequent therapy, four were alive and receiving therapy, three had died, and two were lost to follow-up.
Thomas Marron, MD, PhD , of Mount Sinai in New York presented these results in a poster at the American Association for Cancer Research Annual Meeting 2021: Week 1 ( Abstract LB048 ). Data in the abstract differ from the data presented.
“While cancer immunotherapy has revolutionized the treatment of cancer, we know that the majority of patients fail to achieve significant clinical response,” Dr. Marron said during his presentation. “One reason for this may be due to lack of preexisting primed T-cell response needed for PD-1 blockade to have a significant effect. To address this, personalized neoantigen vaccines may help prime an improved immune response against tumor cells.”
With this in mind, Dr. Marron and colleagues developed PGV-001, a vaccine consisting of patient-specific synthetic neoantigen peptides given to patients in the adjuvant setting.
Creating a personalized vaccine
The researchers synthesized PGV-001 for 15 patients with advanced malignancies. The patients first underwent tumor and germline DNA sequencing as well as HLA typing. Bulk RNA sequencing was performed on patients’ tumors as well.
Then, the researchers used a computational pipeline called OpenVax to identify candidate neoantigens. This pipeline, developed at Mount Sinai, identified and prioritized candidate neoantigens using predicted MHC class I binding affinity and neoantigen abundance.
OpenVax identified an average of 71.5 neoantigens per patient (range, 7-193). The goal was to synthesize a maximum of 10 peptides per patient, but two patients did not have an adequate number of neoantigens.
Vaccine administration
The peptides were administered over the course of 27 weeks along with poly-ICLC and a tetanus helper peptide. Before receiving their vaccine doses, patients with solid tumors had undergone curative-intent surgery, and those with multiple myeloma had undergone autologous stem cell transplant.
“Most experimental personalized cancer vaccines are administered in the metastatic setting, but prior research indicates that immunotherapies tend to be more effective in patients who have less cancer spread,” principal investigator Nina Bhardwaj, MD, PhD , of Mount Sinai, explained in a press release .
“We have, therefore, developed a neoantigen vaccine that is administered after standard-of-care adjuvant therapy, such as surgery in solid tumors and bone marrow transplant in multiple myeloma, when patients have minimal, typically microscopic, residual disease.”
Feasibility, safety, and immunogenicity
PGV-001 was synthesized for 15 patients and administered to 13 of them. Six of the 13 patients had head and neck squamous cell carcinoma, three had multiple myeloma, two had non–small cell lung cancer, one had breast cancer, and one had urothelial carcinoma.
Eleven patients received all 10 intended doses, and two patients received at least 8 doses.
“The vaccine was well tolerated, with only half of patients experiencing mild, grade 1 adverse events,” Dr. Marron said.
Transient injection site reactions occurred in four patients, and grade 1 fever was reported in one patient.
Immune monitoring is ongoing, but an initial analysis in one patient showed “robust responses” in CD4 and CD8 T cells by intracellular cytokine staining for interferon-gamma, tumor necrosis factor–alpha, and interleukin-2 after in vitro expansion in the presence of vaccine antigens, according to the researchers.
Dr. Marron noted that robust T-cell reactivity was seen at the completion of all 10 doses but was not seen after the 6th dose, and this supports the need for a prolonged dosing schedule.
Survival and subsequent therapy
At a mean follow-up of 880 days, four patients had no evidence of disease and had not received subsequent therapy. This includes one patient with stage IIIA non–small cell lung cancer, one with stage IVA HER-2 positive breast cancer, one with stage II urothelial carcinoma, and one with multiple myeloma.
Four patients were alive and receiving subsequent lines of therapy. Two of these patients had significant responses to anti–PD-1 therapy.
Three patients have died, two of whom had documented recurrence of their malignancy. The last two patients were lost to follow-up without documented recurrence.
“Our results demonstrate that the OpenVax pipeline is a viable approach to generate a safe, personalized cancer vaccine, which could potentially be used to treat a range of tumor types,” Dr. Bhardwaj said.
Trials combining neoantigens identified with the OpenVax platform are ongoing in patients with urothelial carcinoma and glioblastoma multiforme, Dr. Marron said.
The current study ( NCT02721043 ) is sponsored by Dr. Bhardwaj. Dr. Marron and Dr. Bhardwaj reported having no disclosures. Their colleagues disclosed relationships with Bristol Myers Squibb, Sema4, and Related Sciences.
The vaccine, PGV-001, was given to 13 patients with solid tumors or multiple myeloma who had a high risk of recurrence after surgery or autologous stem cell transplant.
At last follow-up, four patients were still alive without evidence of disease and had not received subsequent therapy, four were alive and receiving therapy, three had died, and two were lost to follow-up.
Thomas Marron, MD, PhD , of Mount Sinai in New York presented these results in a poster at the American Association for Cancer Research Annual Meeting 2021: Week 1 ( Abstract LB048 ). Data in the abstract differ from the data presented.
“While cancer immunotherapy has revolutionized the treatment of cancer, we know that the majority of patients fail to achieve significant clinical response,” Dr. Marron said during his presentation. “One reason for this may be due to lack of preexisting primed T-cell response needed for PD-1 blockade to have a significant effect. To address this, personalized neoantigen vaccines may help prime an improved immune response against tumor cells.”
With this in mind, Dr. Marron and colleagues developed PGV-001, a vaccine consisting of patient-specific synthetic neoantigen peptides given to patients in the adjuvant setting.
Creating a personalized vaccine
The researchers synthesized PGV-001 for 15 patients with advanced malignancies. The patients first underwent tumor and germline DNA sequencing as well as HLA typing. Bulk RNA sequencing was performed on patients’ tumors as well.
Then, the researchers used a computational pipeline called OpenVax to identify candidate neoantigens. This pipeline, developed at Mount Sinai, identified and prioritized candidate neoantigens using predicted MHC class I binding affinity and neoantigen abundance.
OpenVax identified an average of 71.5 neoantigens per patient (range, 7-193). The goal was to synthesize a maximum of 10 peptides per patient, but two patients did not have an adequate number of neoantigens.
Vaccine administration
The peptides were administered over the course of 27 weeks along with poly-ICLC and a tetanus helper peptide. Before receiving their vaccine doses, patients with solid tumors had undergone curative-intent surgery, and those with multiple myeloma had undergone autologous stem cell transplant.
“Most experimental personalized cancer vaccines are administered in the metastatic setting, but prior research indicates that immunotherapies tend to be more effective in patients who have less cancer spread,” principal investigator Nina Bhardwaj, MD, PhD , of Mount Sinai, explained in a press release .
“We have, therefore, developed a neoantigen vaccine that is administered after standard-of-care adjuvant therapy, such as surgery in solid tumors and bone marrow transplant in multiple myeloma, when patients have minimal, typically microscopic, residual disease.”
Feasibility, safety, and immunogenicity
PGV-001 was synthesized for 15 patients and administered to 13 of them. Six of the 13 patients had head and neck squamous cell carcinoma, three had multiple myeloma, two had non–small cell lung cancer, one had breast cancer, and one had urothelial carcinoma.
Eleven patients received all 10 intended doses, and two patients received at least 8 doses.
“The vaccine was well tolerated, with only half of patients experiencing mild, grade 1 adverse events,” Dr. Marron said.
Transient injection site reactions occurred in four patients, and grade 1 fever was reported in one patient.
Immune monitoring is ongoing, but an initial analysis in one patient showed “robust responses” in CD4 and CD8 T cells by intracellular cytokine staining for interferon-gamma, tumor necrosis factor–alpha, and interleukin-2 after in vitro expansion in the presence of vaccine antigens, according to the researchers.
Dr. Marron noted that robust T-cell reactivity was seen at the completion of all 10 doses but was not seen after the 6th dose, and this supports the need for a prolonged dosing schedule.
Survival and subsequent therapy
At a mean follow-up of 880 days, four patients had no evidence of disease and had not received subsequent therapy. This includes one patient with stage IIIA non–small cell lung cancer, one with stage IVA HER-2 positive breast cancer, one with stage II urothelial carcinoma, and one with multiple myeloma.
Four patients were alive and receiving subsequent lines of therapy. Two of these patients had significant responses to anti–PD-1 therapy.
Three patients have died, two of whom had documented recurrence of their malignancy. The last two patients were lost to follow-up without documented recurrence.
“Our results demonstrate that the OpenVax pipeline is a viable approach to generate a safe, personalized cancer vaccine, which could potentially be used to treat a range of tumor types,” Dr. Bhardwaj said.
Trials combining neoantigens identified with the OpenVax platform are ongoing in patients with urothelial carcinoma and glioblastoma multiforme, Dr. Marron said.
The current study ( NCT02721043 ) is sponsored by Dr. Bhardwaj. Dr. Marron and Dr. Bhardwaj reported having no disclosures. Their colleagues disclosed relationships with Bristol Myers Squibb, Sema4, and Related Sciences.
The vaccine, PGV-001, was given to 13 patients with solid tumors or multiple myeloma who had a high risk of recurrence after surgery or autologous stem cell transplant.
At last follow-up, four patients were still alive without evidence of disease and had not received subsequent therapy, four were alive and receiving therapy, three had died, and two were lost to follow-up.
Thomas Marron, MD, PhD , of Mount Sinai in New York presented these results in a poster at the American Association for Cancer Research Annual Meeting 2021: Week 1 ( Abstract LB048 ). Data in the abstract differ from the data presented.
“While cancer immunotherapy has revolutionized the treatment of cancer, we know that the majority of patients fail to achieve significant clinical response,” Dr. Marron said during his presentation. “One reason for this may be due to lack of preexisting primed T-cell response needed for PD-1 blockade to have a significant effect. To address this, personalized neoantigen vaccines may help prime an improved immune response against tumor cells.”
With this in mind, Dr. Marron and colleagues developed PGV-001, a vaccine consisting of patient-specific synthetic neoantigen peptides given to patients in the adjuvant setting.
Creating a personalized vaccine
The researchers synthesized PGV-001 for 15 patients with advanced malignancies. The patients first underwent tumor and germline DNA sequencing as well as HLA typing. Bulk RNA sequencing was performed on patients’ tumors as well.
Then, the researchers used a computational pipeline called OpenVax to identify candidate neoantigens. This pipeline, developed at Mount Sinai, identified and prioritized candidate neoantigens using predicted MHC class I binding affinity and neoantigen abundance.
OpenVax identified an average of 71.5 neoantigens per patient (range, 7-193). The goal was to synthesize a maximum of 10 peptides per patient, but two patients did not have an adequate number of neoantigens.
Vaccine administration
The peptides were administered over the course of 27 weeks along with poly-ICLC and a tetanus helper peptide. Before receiving their vaccine doses, patients with solid tumors had undergone curative-intent surgery, and those with multiple myeloma had undergone autologous stem cell transplant.
“Most experimental personalized cancer vaccines are administered in the metastatic setting, but prior research indicates that immunotherapies tend to be more effective in patients who have less cancer spread,” principal investigator Nina Bhardwaj, MD, PhD , of Mount Sinai, explained in a press release .
“We have, therefore, developed a neoantigen vaccine that is administered after standard-of-care adjuvant therapy, such as surgery in solid tumors and bone marrow transplant in multiple myeloma, when patients have minimal, typically microscopic, residual disease.”
Feasibility, safety, and immunogenicity
PGV-001 was synthesized for 15 patients and administered to 13 of them. Six of the 13 patients had head and neck squamous cell carcinoma, three had multiple myeloma, two had non–small cell lung cancer, one had breast cancer, and one had urothelial carcinoma.
Eleven patients received all 10 intended doses, and two patients received at least 8 doses.
“The vaccine was well tolerated, with only half of patients experiencing mild, grade 1 adverse events,” Dr. Marron said.
Transient injection site reactions occurred in four patients, and grade 1 fever was reported in one patient.
Immune monitoring is ongoing, but an initial analysis in one patient showed “robust responses” in CD4 and CD8 T cells by intracellular cytokine staining for interferon-gamma, tumor necrosis factor–alpha, and interleukin-2 after in vitro expansion in the presence of vaccine antigens, according to the researchers.
Dr. Marron noted that robust T-cell reactivity was seen at the completion of all 10 doses but was not seen after the 6th dose, and this supports the need for a prolonged dosing schedule.
Survival and subsequent therapy
At a mean follow-up of 880 days, four patients had no evidence of disease and had not received subsequent therapy. This includes one patient with stage IIIA non–small cell lung cancer, one with stage IVA HER-2 positive breast cancer, one with stage II urothelial carcinoma, and one with multiple myeloma.
Four patients were alive and receiving subsequent lines of therapy. Two of these patients had significant responses to anti–PD-1 therapy.
Three patients have died, two of whom had documented recurrence of their malignancy. The last two patients were lost to follow-up without documented recurrence.
“Our results demonstrate that the OpenVax pipeline is a viable approach to generate a safe, personalized cancer vaccine, which could potentially be used to treat a range of tumor types,” Dr. Bhardwaj said.
Trials combining neoantigens identified with the OpenVax platform are ongoing in patients with urothelial carcinoma and glioblastoma multiforme, Dr. Marron said.
The current study ( NCT02721043 ) is sponsored by Dr. Bhardwaj. Dr. Marron and Dr. Bhardwaj reported having no disclosures. Their colleagues disclosed relationships with Bristol Myers Squibb, Sema4, and Related Sciences.
FROM AACR 2021