Atezolizumab Shows Potential as Foundational Agent in the Treatment of Numerous Cancers

Attendees and poster presenters during Posters Sessions
Attendees and poster presenters during Posters Sessions at the American Society of Clinical Oncology (ASCO) | Courtesy: ? ASCO/David Eulitt 2017.

Data for?atezolizumab (Tecentriq?; Genentech/Roche) were presented during the 53rd annual meeting of the American Society of Clinical Oncology (ASCO), held June 2 – 6, 2017 in Chicago, Illinois. The data from phase I, II and Phase III studies suggested that atezolizumab has the potential to be used as a foundational combination partner with cancer immunotherapies, targeted medicines and various chemotherapies across a broad range of cancers.

Data from a study of atezolizumab plus bevacizumab (Avastin?; Genentech/Roche) in metastatic Renal Cell Carcinoma (mRCC) supports a scientific rationale for combining the two agents, including its potential to increase infiltration (trafficking) of T-cells into tumors and other immune-modulatory properties.

New data was also presented for atezolizumab as a monotherapy from the OAK trial, which represent the first treatment-beyond-progression data from a Phase III study of cancer immunotherapy in advanced lung cancer (NSCLC).

Updated data will also be presented from the Phase Ib study of atezolizumab in combination with chemotherapy for people with advanced NSCLC. Two Phase Ib studies in melanoma combining atezolizumab plus cobimetinib (Cotellic?; Genentech/Roche) and atezolizumab plus cobimetinib plus vemurafenib (Zelboraf?; Genentech/Roche) showed that the addition of vemurafenib and/or cobimetinib may alter the tumor micro environment, enhancing the anti-tumour activity of atezolizumab.

?By applying our seminal research in immune tumor profiling within the framework of the Roche-devised cancer immunity cycle, we are accelerating and expanding the transformative benefits with atezolizumab to a greater number of people living with cancer,? noted Sandra Horning, MD, Chief Medical Officer and Head of Global Product Development at Genentech/Roche.

?Our cancer immunotherapy development programme takes a comprehensive approach in pursuing the goal of restoring cancer immunity to improve outcomes for patients, and at ASCO 2017 we are presenting data from a range of medicines and combinations that we believe have this potential,? Horning added.

Clinical trials

Renal Cell Carcinoma (RCC)

The IMmotion150 clinical trial is a global, multicentre Phase II study that was designed to evaluate the efficacy and safety of atezolizumab plus bevacizumab, atezolizumab alone or sunitinib alone in 305 patients with previously untreated, locally advanced or mRCC. After progression on the sunitinib or atezolizumab arms of the study, 77% and 75% of patients crossed over to atezolizumab plus bevacizumab treatment, respectively. [1]

Clinical activity of atezolizumab plus bevacizumab was seen in crossover patients regardless of first line atezolizumab or sunitinib therapy or response to first line therapy, further supporting this combination as a potential treatment option. Specifically, atezolizumab plus bevacizumab resulted in an Overall Response Rate (ORR) of 26% in all-crossover patients (28% in crossover post-sunitinib; 24% in crossover post-atezolizumab patients) with a median Progression Free Survival (PFS) of 8.8 months in all-crossover patients. There were no new safety signals observed in the crossover treated patients.

Photo 1.0: General view of the 2017 ASCO annual meeting, held June 2 – 6, 2017 in Chicago, Ill.

A Phase III study, IMmotion151, in a similar population is expected to provide initial results in early 2018.

Lung cancer

In the primary analysis of the Phase III OAK trial? (N = 850), a study of atezolizumab vs docetaxel in 2L/3L NSCLC, Overall Survival favored atezolizumab (HR 0.73; 95% CI: 0.62, 0.87) despite similar PFS between arms (HR 0.95; 95% CI: 0.82, 1.10).

These results confirm the impact of atezolizumab treatment beyond radiologic disease progression (PD) and showed that a continuation of atezolizumab treatment after PD resulted in promising clinical benefit.

The study design allowed patients randomized to atezolizumabto continue treatment beyond PD, as assessed by Response Evaluation Criteria in Solid Tumours (RECIST) v1.1, if the patient was considered to be deriving clinical benefit from treatment. Atezolizumab could be continued until there was loss of clinical benefit according to the investigator?s clinical judgement.

Patients in the atezolizumab arm who continued atezolizumab therapy beyond PD had a prolonged clinical benefit, 12.7 months Overall Survival (OS) (95% CI 9.3?14.9) compared with 8.8 months OS (6.0 – 12.1) for those treated with other anti-cancer treatments post PD. Tumor target lesion responses and stabilization post-PD were seen across all subgroups of programmed death-ligand 1 (PD-L1) expression. These data support the treatment strategy of continuing atezolizumab beyond PD until loss of clinical benefit in patients, regardless of the level of PD-L1 expression.

The study results show that among 332 patients receiving atezolizumab with PD, 51% (n = 168) continued atezolizumab TBP; 7% (12/168) achieved subsequent response in target lesions (? 30% reduction from new baseline at PD); 49% (83/168) had stable target lesions (best change between +20% and ?30%).

GP28328 Lung Cancer Trial

The updated efficacy and safety data for Arms C?E of our phase Ib GP28328 study are encouraging for atezolizumab in combination with various chemotherapies. The primary endpoint of the study was safety and atezolizumab was well tolerated when combined with various chemotherapies. [5][6]

The confirmed ORRs and mature OS data provide further evidence for a synergy between the anti-tumor activity of atezolizumab and chemotherapy. However, the researchers confirmed that PFS and OS data, while showing promising benefits, are limited by small numbers and wide confidence intervals.

Phase III studies that include chemotherapy and atezolizumab are currently ongoing.


Arm C
(carboplatin/
paclitaxel)
(n=25)
Arm D
(carboplatin/
pemetrexed)
(n=25)
Arm E
(carboplatin / nab-paclitaxel)
(n=26)
Confirmed Response rate
?ORR, n (%)?9 (36)?17 (68)?12 (46)
?CR, n (%)?0?1 (4)?4 (15)
?PR, n(%)?9 (36)?16 (64)?8 (31)
?SD, n (%)?12 (48)?4 (16)?9 (35)
?PD, n (%)?3 (12)?3 (12)?3 (12)
Median PFS (95% CI), months?7.1 (4.2-8.3)?8.4 (4.7-11.0)?5.7 (4.4-14.8)
Media OS (95% CI), months?12.9 (8.8-21.3)?18.9 (9.9-27.4)17.0 (12.7-NE)
?Updated efficacy and safety data table for atezolizumab in combination Arms C?E

Melanoma

The targeted inhibition of MEK with cobimetinib and BRAF with vemurafenib in BRAFV600-mutant melanoma can lead to both anticancer immune activation and direct tumor cell death. Atezolizumab inhibits PD-L1/PD-1 signaling. By combining cobimetinib + vemurafenib with atezolizumab may enhance antitumor activity, potentially leading to improved clinical responses and durability. Preliminary data from a phase Ib study (NCT01656642) showed that atezolizumab + cobimetinib + vemurafenib had a manageable safety profile and promising antitumor activity in patients with untreated BRAFV600-mutant unresectable/metastatic melanoma, with increases in CD8-positive T-cell infiltration observed after treatment withcobimetinib + vemurafenib. [8]

Updated study results from two Phase Ib studies combining atezolizumab plus cobimetinib and, atezolizumab plus cobimetinib plus vemurafenib showed improved ORR and PFS after a longer follow up. Both combination studies demonstrated a manageable safety profile.

Based on the results of the Phase Ib studies both combinations are now in Phase III clinical trials. The atezolizumab plus cobimetinib plus vemurafenib combination will be investigated in people with untreated BRAFV600?mutant unresectable metastatic melanoma while the atezolizumab plus cobimetinib combination will be studied in people with untreated, unresectable metastatic BRAF wild-type melanoma. [7][8][9][10]

Finally, data from two studies demonstrated the potential of atezolizumab in combination with novel cancer immunotherapies. These studies include a Phase I dose escalation study evaluating the T-cell bispecific (CEA- TCB) antibody as a single agent or in combination with atezolizumab in patients with metastatic colorectal cancer and a Phase Ib dose-escalation study evaluating the combined inhibition of atezolizumab plus IDO1 (GDC-0919) in patients with locally advanced or metastatic solid tumors and

Monotherapy data will also be presented from a Phase Ia study of atezolizumab in advanced/recurrent endometrial cancer (rEC), a patient population for whom the prognosis remains poor. The study is evaluating clinical activity and safety. Results show that atezolizumab has a favourable safety profile in rEC, with durable clinical benefit seen in some patients. Clinical benefit appeared to increase with higher PD-L1 expression, suggesting a link between PD-L1 status and response.[9][10]


Last editorial review: June 5, 2017

Featured Image: Poster area during 2017 ASCO annual meeting. Courtesy: ? 2017 ASCO/Scott Morgan. Used with permission. Photo 1.0: General view of the 2017 ASCO annual meeting, held June 2 – 6, 2017 in Chicago, Ill. Courtesy: ? 2017 ASCO/Scott Morgan. Used with permission.

Copyright ? 2017 Sunvalley Communication, LLC. All rights reserved. Republication or redistribution of Sunvalley Communication content, including by framing or similar means, is expressly prohibited without the prior written consent of Sunvalley Communication. Sunvalley Communication shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. Onco?Zine, Oncozine and The Onco?Zine Brief are registered trademarks and trademarks of Sunvalley Communication around the world.