Top oncology breakthroughs shared at ESMO 2021

Clarivate oncology experts share major takeaways from ESMO and their expected impact on the treatment landscape and patients.

As part of our Drugs to Watch™ series, which reviews therapies expected to have significant impact on healthcare markets, Clarivate oncology experts sifted through the more than 2,800 abstracts that were accepted for presentation at the ESMO 2021 Virtual Conference and selected their top picks. In the following article, we present our analysis of these abstracts and key takeaways for healthcare executives.

 

1. KEYNOTE-716 shows a clinical benefit with adjuvant immunotherapy in resected stage IIB-C malignant melanoma1

Introduced earlier in the treatment paradigm, Keytruda could substantially reduce risk of recurrence in high-risk early-stage melanoma patients.

Context: In August 2021, Merck & Co. announced that the KEYNOTE-716 trial evaluating Keytruda in resected high-risk stage IIB-C malignant melanoma patients met its primary endpoint of prolonged recurrence-free survival (RFS) compared to placebo.

What’s new from ESMO:  Interim efficacy and safety analysis from the randomized KEYNOTE-716 study showed that the trial met its primary endpoint of RFS, with patients receiving Keytruda presenting an RFS of 90.5% at 12-months compared to 83.1% in the placebo group. A 35% reduction in risk of recurrence or death (HR: 0.65; P = 0.006) was reported for Keytruda.

Treatment-related adverse events commonly associated with anti-PD-1 therapy occurred, with the vast majority being immune-related adverse events (endocrine toxicities). Overall, the trial showed a favorable benefit risk profile for an immunotherapy treatment in this high-risk, early-stage patient population.

What to expect: High-risk stage IIB-C melanoma patients who undergo resection and have no evidence of disease are a high unmet need group given the frequent incidences of recurrences and lack of approved treatment options other than observation alone.

For Keytruda, these results demonstrate, for the first-time, a role for an anti-PD-1 therapy in earlier stages of the melanoma treatment paradigm. Based on the KEYNOTE-716 data, it is anticipated that Keytruda will gain a label expansion in this patient setting, with FDA priority review status and a PDUFA date set for December 2021.

Competition is imminent as the CheckMate-76K trial evaluating Bristol-Myers Squibb’s Opdivo in stage IIB-C melanoma patients is also poised to enter this setting. Keytruda’s milestone of demonstrating an impact on post-surgical relapse is highly meaningful, as it could prevent more melanoma patients from advancing to uncontrolled stages of the disease, however overall survival (OS) data is yet to be reported from the study.

 

2. Enhertu demonstrates remarkable efficacy benefit in HER2-positive metastatic breast cancer2

Can Enhertu displace Kadcycla to become the new standard of care (SOC) in 2nd line metastatic HER2+ breast cancer patients?

Context: In August 2021, AstraZeneca and Daiichi Sankyo announced that their antibody-drug conjugate Enhertu (trastuzumab deruxtecan), showed a significant progression-free survival (PFS) benefit over Kadcycla (trastuzumab emtansine) among HER2+ unresectable and/or metastatic breast cancer patients in the Phase III DESTINY-Breast03 study.

What’s new from ESMO: Enhertu demonstrated a statistically significant and clinically meaningful improvement in PFS against Roche’s Kadcycla in patients with HER2-positive metastatic breast cancer that had been previously treated with trastuzumab and taxane. Enhertu reduced the risk of disease progression or death by 72% versus Kadcycla, and it more than doubled the objective response-rate (ORR) compared to Kadcycla (79.7% vs. 34.2%). The DESTINY-Breast03 trial also represents the first global Phase III head-to-head trial of Enhertu against an active control. against an active control.

What to expect: Based on these incredible data, we expect that Enhertu will rapidly become the SOC in second line metastatic HER2-positive disease and displace Kadcyla to later lines of treatment.

 

3. Kisqali in the battle of the CDK4/6 inhibitors3

Kisqali plus letrozole demonstrated a significant OS benefit, but is that enough to displace physician favorite Ibrance?

Context: The MONALEESA-2 study, previously reported that Kisqali (ribociclib) plus letrozole had achieved a statistically significant improvement in PFS versus placebo plus letrozole in first-line patients with HR-positive / HER2-negative advanced breast cancer.

What’s new from ESMO: Novartis presented OS data from the Phase III MONALESSA-2 study. Kisqali in combination with letrozole demonstrated a statistically significant and clinically meaningful OS benefit of over 12 months compared to letrozole plus placebo in postmenopausal women with HR-positive / HER2-negative advanced breast cancer (HR=0.76; p=0.004).

Kisqali is the first CDK4/6 inhibitor to show an OS improvement in this setting and is the only CDK4/6 inhibitor that has shown OS benefit across all Phase III trials of the MONALEESA program (MONALEESA-2, MONALEESA-3, and MONALEESA-7) with different endocrine therapy partners, regardless of menopausal status or line of therapy.

What to expect: Considering these findings, we expect that the use of Kisqali plus an aromatase inhibitor will increase and thus potentially limit the uptake of other CDK4/6 inhibitors, such as Ibrance, in the first-line HR-positive / HER2-negative advanced breast cancer population.

 

4. Keytruda wins again in triple-negative breast cancer4

Can the PD-1 inhibitor turn the tide for PD-L1 positive, triple-negative patients?

Context: In July 2021, Merck & Co. announced that the pivotal Phase III KEYNOTE-355 trial evaluating Keytruda (pembrolizumab), in combination with chemotherapy for the treatment of patients with metastatic triple-negative breast cancer (mTNBC), met its OS end point with statistical significance.

What’s new from ESMO: Keytruda plus chemotherapy reduced the risk of death by 27% in patients with metastatic triple-negative breast cancer whose tumors expressed PD-L1 (CPS ≥10), compared to chemotherapy alone.

The KEYNOTE-355 trial has now met both coprimary endpoints (PFS and OS), so there is very robust evidence that the use of Keytruda plus chemotherapy is appropriate for metastatic triple-negative breast cancer patients whose tumors express PD-L1 (~40% of cases).

What to expect: In the United States, Keytruda in combination with chemotherapy is already approved as a treatment for metastatic triple-negative breast cancer based on the KEYNOTE-355 study.

We expect that Keytruda’s use will significantly increase based on the reported OS data and because it will not face competition from any immune checkpoint inhibitor (as Roche voluntarily withdrew the U.S. accelerated approval of Tecentriq plus chemotherapy for the treatment for PD-L1-positive metastatic triple-negative breast cancer in August 2021). Keytruda plus chemotherapy has recently been approved in Japan for this indication and it has received a positive opinion from the Committee for Medicinal Products for Human Use (CHMP) based on the PFS and OS data in September 2021.

 

5. Trastuzumab duocarmazine offers potential for metastatic HER2+ breast cancer patients5

This novel antibody-drug conjugate (ADC)ADC faces much competition, should it be approved.

Context: In June 2021, Byondis announced that the Phase III TULIP study met its primary end point of PFS. This study compares the efficacy and safety of the ADC [vic-]trastuzumab duocarmazine (SYD985) to physician’s choice treatment in patients with pre-treated HER2-positive unresectable locally advanced or metastatic breast cancer (MBC).

What’s new from ESMO: Trastuzumab duocarmazine is an emerging therapy in breast cancer. The agent significantly improved PFS over physician’s choice of treatment in patients with pre-treated HER2-positive unresectable locally advanced or metastatic breast cancer, meeting the primary end point of the phase III TULIP trial (HR 0.64 [0.49-0.84]; p = 0.002).

What to expect: Based on these data, we expect that Byondis will seek approval in the United States before the end of this year, and later in Europe. The drug will become another treatment option for previously treated metastatic HER2-positive patients and it will be competing with other HER2-targeting that are currently approved in this patient population: Tukysa, Margenza and, most notably, the competing ADC Enhertu.

 

6. KRAS Inhibitors showing promise in colorectal cancer patients with unmet need6

Impressive results among heavily pre-treated patients hint at the potential for KRAS inhibitors among KRAS G12C mutated patients.

Context: In March 2021, Mirati Therapeutics initiated the Phase III trial KRYSTAL-10, evaluating adagrasib plus Erbitux for the second-line treatment of metastatic colorectal cancer patients whose tumors harbor a KRAS G12C mutation.

The KRAS G12C mutation occurs in only around 3-4% of colorectal cancer patients, according to the Clarivate Disease Landscape and Forecast. However, patients with RAS mutations do not benefit from EGFR inhibitors, have fewer treatment options and represent a major unmet need.

What’s new from ESMO: Mirati Therapeutics presented updated data from the colorectal cancer cohort of the Phase I/II KRYSTAL-1 trial of adagrasib in KRAS G12C-mutant solid tumors. The monotherapy achieved a response rate of 22%, disease control rate of 87% and median PFS of 5.6 months.

Supporting the approach undertaken in the Phase III trial, the combination of adagrasib plus Erbitux showed a response rate of 43% and a disease control rate of 100%. These results are impressive considering patients had received a median of three prior lines of therapy.

What to expect: Amgen also presented positive Phase Ib data for their KRAS inhibitor (Lumakras) in combination with Vectibix in advanced KRAS G12C mutated colorectal cancer at ESMO 2021, based on which they plan to initiate a Phase III trial in the third-line setting. However, the positive data of the KRYSTAL-1 trial and the earlier initiation of the Phase III KRYSTAL-10 trial puts Mirati Therapeutics in the running to be the first company to have a KRAS inhibitor on the colorectal cancer market.

 

7. STAMPEDE and PEACE-1 data set to impact the prostate cancer treatment algorithm7,8

High-risk locally advanced prostate cancer patients can benefit from treatment intensification, and a triplet combination of SOC therapies widens first-line treatment options in mHSPC.

Context: Since 2005, the randomized STAMPEDE study has been challenging the standard of care for patients with locally advanced or metastatic prostate cancer who are starting long-term androgen deprivation therapy (ADT) by adding different agents (both as single agents and in combinations) and assessing the clinical outcomes.

The PEACE-1 study is investigating abiraterone plus docetaxel with or without radiation therapy. In an earlier analysis (presented at ASCO 2021), the addition of abiraterone to this standard of care showed a significant improvement in radiographic PFS in patients with metastatic hormone-sensitive prostate cancer (mHSPC). The OS data were immature (Fizazi K, 2021).

What’s new from ESMO: Additional results from the STAMPEDE study presented at ESMO 2021 for patients with high-risk locally advanced disease—the non-metastatic (M0) prostate cancer setting—show an improved six-year metastasis-free survival (MFS) (from 69% to 82%) and six-year OS (from 77% to 86%) with the addition of abiraterone to standard ADT.

Results reported at ESMO 2021 for PEACE-1 demonstrate improvements in median OS with the addition of abiraterone to docetaxel plus ADT (5.7 years vs. 4.7 years), underlining the notable efficacy of this triplet combination therapy for the treatment of de novo mHSPC, especially for patients with high-volume disease.

What to expect: The impressive survival results from STAMPEDE is likely to spur the use of abiraterone plus ADT earlier in the treatment algorithm, providing an effective regimen for this underserved population with high-risk locally advanced prostate cancer.

The efficacy results presented from the PEACE-1 study will likely shape clinical practice and encourage uptake of this triplet combination (abiraterone + ADT + docetaxel) as a standard treatment for de novo mHSPC, particularly as part of treatment intensification for patients with high-volume prostate cancer.

 

Clarivate Asia-Pacific oncology experts also identified the most ground-breaking abstracts from Mainland China, given the exciting developments in this fast-moving market:

 

1. Sugemalimab shows promise as a consolidation treatment for unresectable early-stage NSCLC9

Sugemalimab may become the first immune checkpoint inhibitor to be approved for unresectable stage III NSCLC patients irrespective of prior treatment with concurrent or sequential chemoradiotherapy (CRT).

Context: Concurrent or sequential CRT has been the SOC for unresectable stage III NSCLC in Mainland China for many years. As such, there is a high unmet need for novel targeted therapies in this patient population.

What’s new from ESMO: CStone Pharmaceuticals presented results from the GEMSTONE-301 Phase III study that demonstrated a statistically significant and clinically meaningful improvement in PFS as a consolidation treatment for patients with unresectable stage IIIA–C NSCLC who have not progressed following concurrent chemoradiotherapy (cCRT) or sequential CRT (sCRT). In addition, consistent PFS benefit was observed regardless of whether patients received prior sCRT or cCRT.

What to expect: Based on these results, sugemalimab is likely to gain approval in the broader patient population (unresectable stage III NSCLC patients irrespective of prior treatment with sCRT or cCRT) compared with durvalumab (approved in December 2019 for unresectable stage III NSCLC patients), allowing sugemalimab to register robust patient uptake.

However, durvalumab is expected to remain the preferred therapy for patients undergoing concurrent chemoradiotherapy owing to its first-in-class five-year survival data, better PFS benefit (compared with sugemalimab), first-to-market status and anticipated inclusion in National reimbursement drug list (NRDL) later this year.

 

2. Lorlatinib proves effective in treating ALK-positive, first-line metastatic NSCLC10

Can data from the CROWN study enable lorlatinib to outcompete its existing rivals in the first-line treatment setting?

Context: Lorlatinib (Pfizer’s Lorbrena)—a third-generation ALK inhibitor—conferred a consistent and clinically meaningful improvement in PFS versus crizotinib in the first-line metastatic ALK-positive NSCLC patients in the global Phase III CROWN study.

What’s new from ESMO: Pfizer presented results from the Asian subgroup analysis of CROWN study, where loratinib showcased similar efficacy and safety versus crizotinib, which was consistent with the global population.

What to expect: Although the data is encouraging, lorlatinib’s significant prolonged PFS benefit over crizotinib is expected to be overshadowed by its late market entry and the growing preference for alectinib (Roche’s Alecensa) in the first-line treatment setting in Mainland China.

Alectinib is expected soon to become the SOC for the first-line treatment of ALK-positive NSCLC, due to its highly impressive clinical efficacy in comparison with crizotinib (proven in a head-to-head Phase III ALEX clinical study) and its recent NRDL inclusion (in December 2019).

Lorlatinib’s prospects of a meaningful market uptake in the first-line treatment setting will also be strongly challenged by the high physician comfort that the existing ALK inhibitors enjoy in Mainland China, the anticipated launch of several domestically developed ALK inhibitors and the expected entry of ceritinib’s cost-effective generics in the country.

 

3. Trastuzumab emtansine (T-DM1) shows superiority in previously treated HER2-positive breast cancer10

Is positive Phase III data enough for trastuzumab emtansine (Roche’s Kadcyla) to experience substantial uptake in the previously treated HER2-positive breast cancer?

Context: In February 2013, trastuzumab emtansine (Roche’s Kadcyla) became the first antibody-drug conjugate (ADC) in the United States to be approved for the previously treated metastatic HER2-positive breast cancer, based on the Phase III EMILIA study.

What’s new from ESMO: Roche reported results from the Asian subgroup analysis of the Phase III EMILIA study. T-DM1 showed a clinically meaningful benefit compared with capecitabine plus lapatinib in previously treated Asian (including Chinese) patients with HER2-positive metastatic breast cancer, consistent with its results in the global population.

What to expect: Approved in June 2021, T-DM1’s uptake in the previously treated HER2-positive metastatic breast cancer patients in Mainland China is expected to be largely restricted by the domestically developed HER2 inhibitor—pyrotinib (Jiangsu Hengrui Medicine’s Airuini)—owing to the latter’s impressive clinical efficacy and recent NRDL inclusion [in December 2019]).

Pyrotinib is expected to emerge as a new SOC for previously treated breast cancer patients in Mainland China, replacing trastuzumab (Roche’s Herceptin, biosimilars) plus chemotherapy in this setting. In addition, the anticipated approval of three additional novel HER2-targeted ADCs—one from a multinational manufacturer and two developed by domestic companies—will further limit the patient uptake of T-DM1 in the breast cancer market of Mainland China.

 

4. Sintilimab plus chemotherapy shows benefit as first-line therapy in patients with advanced or metastatic ESCC and gastric or GEJ adenocarcinoma11

Is sintilimab on its way to be the first domestic PD-1 inhibitor to be approved in the first-line treatment setting for gastric and esophageal cancer in Mainland China?

Context: Currently, nivolumab is the only PD-1 inhibitor approved in Mainland China for gastric and GEJ adenocarcinoma (in August 2021), while pembrolizumab is approved for esophageal and GEJ cancer (in June 2021), for first-line treatment. None of the six domestic PD-1 inhibitors marketed in Mainland China are yet approved for gastroesophageal cancer in this setting.

What’s new from ESMO: Innovent reported results from the Phase III studies Orient-15 and -16, in ESCC and gastric and GEJ adenocarcinoma patients, respectively.

In ESCC patients, treatment with sintilimab plus chemotherapy significantly prolonged median overall survival (mOS) compared [with placebo plus chemotherapy (16.7 vs. 12.5 months)] and reduced the risk of death by 37.2%. In patients with gastric and GEJ adenocarcinoma, sintilimab plus chemotherapy extended mOS by 5.5 months in people with CPS ≥ 5 (18.4 vs. 12.9 months) and by 2.9 months in the overall population (15.2 vs. 12.3 months), in comparison with placebo plus chemotherapy. Also, the combination significantly reduced the risk of death in people with CPS ≥ 5 as well as in the overall population and showed an acceptable safety profile.

What to expect: Interim results of sintilimab in both ESCC and gastric and GEJ adenocarcinoma are promising. If final results of the studies are consistent with these, sintilimab may become the first domestic PD-1 inhibitor to be approved in Mainland China for both ESCC and gastric and GEJ adenocarcinoma in the first line setting.

If approved, sintilimab’s clinical profile and affordability is expected to garner significant patient uptake in Mainland China, especially considering that it is reimbursable due to its NRDL (category B) status, as well as its lower price point in comparison with both nivolumab and pembrolizumab,

 

5. Adjuvant camrelizumab combined with apatinib treatment may become new treatment option for early-stage hepatocellular carcinoma patients12

Camrelizumab / apatinib (PD-1 inhibitor / angiogenesis inhibitor) combination shows promising results in early-stage hepatocellular carcinoma (HCC).

Context: Currently, no targeted therapy is approved for early-phase HCC in Mainland China. Positive results of the camrelizumab / apatinib combination in this setting are promising and warrant further investigation.

What’s new from ESMO: Jiangsu Hengrui Medicine reported Phase II results in 45 patients (25 of CNLC stage II and 20 of CNLC stage III HCC) who received camrelizumab and apatinib upon surgery.

The median relapse-free survival (RFS) was 11.7 months, the 1-year OS rate was 97.8%, and the 1-year RFS rate was 48.9. Also, the 2-year OS rate was 75.7% and 2-year RFS rate 41.0%, after surgery. A total of 12 (26.7%) patients experienced adverse events, with only one (2.2%) having experienced grade 3/4 adverse events (grade 3 thrombocytopenia and grade 4 leukopenia). The most frequent adverse event was liver dysfunction (n=11/45, 24.4%) while no treatment-related deaths were observed.

These results show a promising efficacy and safety of the camrelizumab plus apatinib combination in the adjuvant setting for HCC—a subpopulation with high unmet need for a targeted therapy in Mainland China.

What to expect: Positive results from the early-phase study warrant further investigation of the combination, through a larger Phase III study in the adjuvant setting—a highly underserved subpopulation for which no targeted therapy is approved in Mainland China.

The combination is promising in terms of clinical profile as well as market access, considering both camrelizumab and apatinib are domestically developed, cost-effective and are included in the NRDL. Therefore, the combination, if approved for early-stage HCC in Mainland China, would be easily accessible to most patients.

 

Authors

Clarivate oncology experts who contributed to this article include Liseth Parra PhD., Carolina Do Pazo M.Sc., Fiona Wiegert M.Sc., Laura Vinuesa D.V.M., M.Sc., Amardeep Singh, M.Pharm. and Akash Saini, PhD.

 

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References:
1. Luke JJ, et al. Pembrolizumab versus placebo after complete resection of high-risk stage II melanoma: Efficacy and safety results from the KEYNOTE-716 double-blind phase III trial. Annals of Oncology. 2021; 32(suppl5):LBA3.
2. Cortés J, et al., LBA1 – Trastuzumab deruxtecan (T-DXd) vs trastuzumab emtansine (T-DM1) in patients (Pts) with HER2+ metastatic breast cancer (mBC): Results of the randomized phase III DESTINY-Breast03 study. Annals of Oncology (2021) 32 (suppl_5): S1283-S1346. 10.1016/annonc/annonc741
3. Hortobagy GN, et al., LBA17_PR – OS results from the phase III MONALEESA-2 (ML-2) trial of postmenopausal patients (pts) with hormone receptor positive/human epidermal growth factor receptor 2 negative (HR+/HER2−) advanced breast cancer (ABC) treated with endocrine therapy (ET) ± ribociclib (RIB). Annals of Oncology (2021) 32 (suppl_5): S1283-S1346. 10.1016/annonc/annonc741
4. Rugo HS, et al., LBA16 – KEYNOTE-355: Final results from a randomized, double-blind phase III study of first-line pembrolizumab + chemotherapy vs placebo + chemotherapy for metastatic TNBC. Annals of Oncology (2021) 32 (suppl_5): S1283-S1346. 10.1016/annonc/annonc741
5. Saura Manich C et al., LBA15 – Primary outcome of the phase III SYD985.002/TULIP trial comparing [vic-]trastuzumab duocarmazine to physician’s choice treatment in patients with pre-treated HER2-positive locally advanced or metastatic breast cancer. Annals of Oncology (2021) 32 (suppl_5): S1283-S1346. 10.1016/annonc/annonc741
6. Weiss J, et al., LBA6 – KRYSTAL-1: Adagrasib (MRTX849) as monotherapy or combined with cetuximab (Cetux) in patients (Pts) with colorectal cancer (CRC) harboring a KRASG12C mutation. Annals of Oncology (2021) 32 (suppl_5): S1283-S1346. 10.1016/annonc/annonc741
7. Attard G, et al., LBA4_PR – Abiraterone acetate plus prednisolone (AAP) with or without enzalutamide (ENZ) added to androgen deprivation therapy (ADT) compared to ADT alone for men with high-risk non-metastatic (M0) prostate cancer (PCa): Combined analysis from two comparisons in the STAMPEDE platform protocol. Annals of Oncology (2021) 32 (suppl_5): S1283-S1346. 10.1016/annonc/annonc741
8. Fizazi K, et al., LBA5_PR – A phase III trial with a 2×2 factorial design in men with de novo metastatic castration-sensitive prostate cancer: Overall survival with abiraterone acetate plus prednisone in PEACE-1. Annals of Oncology (2021) 32 (suppl_5): S1283-S1346. 10.1016/annonc/annonc741
9. GEMSTONE-301: A randomized, double-blind, placebo-controlled, phase III study of sugemalimab in patients with unresectable stage III non-small cell lung cancer (NSCLC) who had not progressed after concurrent or sequential chemoradiotherapy (CRT). ESMO 2021. Abstract LBA43.
10. Trastuzumab emtansine (T-DM1) in Asian patients with previously treated HER2-positive locally advanced (LA) or metastatic breast cancer (MBC): Data from the phase III EMILIA study. ESMO 2021. Abstract 284P.
11. Sintilimab plus chemotherapy versus chemotherapy as first-line therapy in patients with advanced or metastatic esophageal squamous cell cancer: First results of the phase III ORIENT-15 study. ESMO 2021. Abstract LBA52.
12. Adjuvant camrelizumab combined with apatinib treatment after resection of hepatocellular carcinoma in CNLC II and III stage: A single-center prospective phase II trial. ESMO 2021. Abstract 944P.

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