ASCO 2019: Take-home messages from 10 disciplines

Central Nervous System Tumors

• The CATNON trial shows that in patients lower-grade gliomas without 1p/19q deletion, concurrent chemotherapy with temozolomide additionally with radiotherapy did not increase OS. However, in IDHmt tumors, there was a trend towards benefit of concurrent TMZ is present. Adjuvant TMZ increased OS in IDHmt but not in IDHwt tumors (Van Den Bent MJ et al. Abstract 2000).
• A phase I study shows CNS penetrance and lowering of 2-HG in patients with mutant IDH1 inhibitors AG-120 and AG-881 in recurrent IDH1 mutant, low-grade glioma (Melinghoff IK et al. Abstract 2003)
• A phase I study shows safety and promising responses of the mutant IDH1 inhibitor DS-1001b in patients with recurrent or progressive IDH1 mutant gliomas (Natsume A et al. Abstract 2004)
• A phase I study shows promising activity of the selective TRK inhibitor larotrectinib in TRK fusion cancer patients with brain metastases or primary central nervous system tumors (Drillon AE et al. Abstract 2006).

Gastrointestinal (nonpancreatic) cancer

• In patients with high risk stage II or stage III colorectal cancer patients receiving adjuvant FOLFOX or CAPOX chemotherapy, noninferiority of 3-month chemotherapy vs. the 6-month regimen could not be universally shown, the IDEA study shows. In contrast to patients receiving FOLFOX, three months might suffice for patients receiving CAPOX.
  (Sougklakos I et al. Abstract 3500).
• An update of the TRIBE-2 trial shows superiority of triple therapy with FOLFOXIRI+bevacizumab compared to sequential FOLFOX+bev followed by FOLFIRI+bev for patients with unresectable mCRC (Cremolini C et al. Abstract 3508).
• In the KEYNOTE-240 trial, pembrolizumab did not lead to improved PFS or OS compared to best supportive care in sorafenib-pretreated patients with hepatocellular carcinoma who were previously treated with systemic therapy (Finn RS et al. Abstract 4004).
• The KEYNOTE-062 trial reached its primary endpoint, showing that in patients with HER2-negative, advanced gastric or gastroesophageal junction (GEJ) cancer, first-line treatment with pembrolizumab resulted in noninferior OS compared to standard chemotherapy. Higher benefit was observed in patients with a CPS of ≥1%, the highest benefit was observed in patients with a CPS of ≥10%. No benefit was observed with additional chemotherapy to pembrolizumab treatment (Tabernero J et al. Abstract LBA4007).

Genitourinary cancers

• The update of the KEYNOTE-426 trial shows consistent benefit for the combination pembrolizumab + axitinib, especially for patients with the IMDC intermediate or poor risk, and in patients with tumors with sarcomatoid features. Patients with sarcomatoid features should receive nivolumab/ipilimumab or pembrolizumab/axitinib as firstline treatment (Rini B et al. Abstract 4500)
• The update of CARMENA on cytoreductive nephrectomy in metastatic renal carcinoma confirms last year’s findings that cytoreductive nephrectomy is not superior to sunitinib in the ITT population, but might be beneficial for patients with only one IMDC risk factor (Mejean A et al. Abstract 4508).
• A phase II trial shows that third-line treatment with enfortumab vedotin of locally advanced or metastatic urothelial cancer patients previously treated with platinum and immune checkpoint inhibitors results in high overall response rates (Petryak DP et al. Abstract LBA4505).
• The subgroup analysis of the JAVELIN Renal 101 trial shows that PD-L1 positive patients respond less to sunitinib and should receive a combination of TKI and immunotherapy. Tumors with many CD8-positive T cells responded well to immunotherapy, but less to a TKI monotherapy (Choueiri TK et al. Abstract 101).
• The E2810 trial shows pazopanib did not improve DFS in patients with metastatic RCC and low metastatic burden who had undergone metastasectomy (Appleman LJ et al. Abstract 4502).
• CheckMate 920 shows that patients with RCC and asymptomatic brain metastases had a good safety profile and promising responses to nivolumab/ipilimumab (Emamekhoo H et al. Abstract 4517).
• In RCC and urothelial carcinoma patients with controlled autoimmune disease or immunosuppression, checkpoint inhibitors were safe and effective (Chanza NM et al. Abstract 4571).
• Bevacizumab did not confer added benefit to standard first line therapy with gemcitabine/cisplatin in patients with metastatic urothelial carcinoma in the phase III CALGB 90601 (Alliance) trial (Rosenberg JE et al. Abstract 4503).
• The HCRN GU14-182 trial shows promising PFS for patients with metastatic urothelial cancer with pembrolizumab maintenance therapy after first-line chemotherapy (Galsky MD et al. Abstract 4504).

Gynecologic cancers

• The PHAEDRA trial shows promising activity and safety of durvalumab in DNA mismatch repair deficient advanced endometrial cancer patients (Antill YC et al. Abstract 5501).
• A phase 2 study shows that avelumab is promising for patients with mutated recurrent/persistent endometrial microsatellite instable cancer, even in PD-L1 negative tumor (Konstantinopoulos PA et al. Abstract 5502).
• The EWOC-1 trial shows that also vulnerable elderly patients with ovarian cancer benefit from standard first line therapy with carboplatin/paclitaxel (Falandry C et al. Abstract 5508).
• The phase III SOLO3 trial shows that olaparib monotherapy is superior to chemotherapy in patients with platinum-sensitive relapsed ovarian cancer and germline BRCA mutations (Penson RT et al. Abstract 5506).
• AVANOVA2 shows that the combination of niraparib and bevacizumab, as well as niraparib alone, are active in patients with recurrent platinum-sensitive ovarian cancer. Combined treatment significantly improved PFS compared to niraparib alone (HR0.35). Particular benefit was shown for BRCA wild type patients (Mirza MR et al. Abstract 5505).

Head and Neck cancer

• Results of the KEYNOTE-048 trial support pembrolizumab or pembrolizumab + chemotherapy (platinum + 5-FU) as first-line therapy over the standard chemotherapy EXTREME (5FU+cisplatin+cetuximab, followed by cetuximab maintenance) in patients with a PD-L1 CPS≥1 or 20 (Rischin D et al. Abstract 6000).
• First-line TPEx (docetaxel+cisplatin+cetuximab, followed by cetuximab maintenance) shows comparable OS, but lower toxicity than the standard chemotherapy EXTREME (5FU+cisplatin+cetuximab, followed by cetuximab maintenance) in recurrent or metastatic HNSCC (Guigay J et al. Abstract 6002).
• Patients with salivary gland cancers and HER2 amplification benefit from therapy with ado-trastuzumab emtansine (D-TM1) (Li BT et al. Abstract 6001).

Lung cancer

• A five-year update of the KEYNOTE-001 trial shows that that patients with advanced NSCLC with high PD-L1 levels that are treated upfront with the PD-L1 antibody pembrolizumab have the highest chances to become long term survivors (Garon EB et al. Abstract LBA9015).
• The final survival update of the KEYNOTE-189 trial shows that first-line therapy of metastatic NSCLC with pembrolizumab in combination with pemetrexed and platinum leads to long-term substantial OS benefit, regardless of PD-L1 expression, and despite an ≥50% crossover rate into the immunotherapy arm (Gadgeel et al. Abstract 9013).
• The predictive potential of PD-L1 varies with respect to the tissue type of biopsy in NSCLC patients: Higher PD-L1 level in biopsies from lung or distant metastasis was associated with significantly higher clinical benefit, while PD-L1 expression from lymph node biopsies was not associated with either response or survival. Therefore, PD-L1 staining in lymph nodes might not be reliable (Hong L et al. Abstract 9017).
• An exploratory analysis of the MYSTIC trial suggests that tumor mutational burden and PD-L1 expression are not necessarily predictive for the same things: While tumor cell PD-L1 expression was predictive for OS with durvalumab versus chemotherapy, blood TMB was rather predictive for OS with durvalumab + tremelimumab in metastasized NSCLC (Rizvi NA et al. Abstract 339).
• A novel highly potent and selective RET inhibitor, BLU-667, has potent, durable and broad antitumor activity, and is well tolerated in patients with advanced RET-fusion+ NSCLC (Gainor JF et al. Abstract 9008).
• A phase I study shows that the ROS inhibitor repotrectinib is safe, and shows encouraging clinical activity in advanced NSCLC patients with ROS1 fusions (Cho BC et al. Abstract 9011).
• Two novel inhibitors, tepotinib and capmatinib, show promising activity and long duration of response across treatment lines in patients with NSCLC and MET exon 14 skipping mutations in phase II studies (Paik PK et al. Abstract 9005, and Wolf J et al. Abstract 9004).
• In advanced, previously treated NSCLC patients with EGFR/HER2 exon 20 insertions, TAK-788 shows promising results and a safety profile comparable to other EGFR TKIs in a phase 1 trial (Janne PA et al. Abstract 9007).
• Dual inhibition of EGFR and VEGFR with erlotinib and ramucirumab strongly improves PFS in the first line treatment of metastatic NSCLC with EGFR mutations compared to erlotinib alone at the cost of slightly increased toxicity (Nakagawa K et al. Abstract 9000).
• JNJ-372, a bispecific EGFR-cMet antibody, shows a manageable safety profile and promising tumor activity via antibody-dependent cellular cytotoxicity and receptor degradation in EGFR-driven advanced NSCLC, in a phase I trial (Haura B et al. Abstract 9009).
• Combination of gefitinib with pemetrexed-carboplatin chemotherapy as a first-line therapy of patients with advanced NSCLC improves PFS and OS in selected patients at the cost of increased toxicity (Noronha V et al. Abstract 9001).
• Pemetrexed/ cisplatin shows similar efficacy compared to vinorelbine/ cisplatin, with better tolerability, for adjuvant therapy of completely resected stage II-IIIA NSCLC (Kenmotsu H et al. Abstract 8501).
• Neoadjuvant atezolizumab was well tolerated in resectable NSCLC, and pCR and major pathologic response rates are encouraging (Kwiatkowski DJ et al. Abstract 8503).
• In the NEOSTAR trial, neoadjuvant nivolumab alone or in combination with ipilimumab was investigated for patients with resectable NSCLC. Major outcome was major pathological response rate, which was encouraging (Cascone T et al. Abstract 8504).
• Monotherapy with lurbinectedin, a selective inhibitor of trans-activated RNA polymerase II transcription shows similar efficacy compared to topotecan, with improved toxicity, as a second-line treatment for SCLC. Especially patients who responded well to prior chemotherapy benefitted (Paz-Ares LG et al. Abstract 8506).
• Response to checkpoint inhibition does not differ in patients with NSCLC and an autoimmune condition compared to non-autoimmune patients. There was no relevant increase in immune-mediated side effects (Khozin S et al. Abstract 110).

Melanoma

• High levels of serum IL-6 and CRP at baseline are negative prognostic factors in melanoma patients receiving single agent and combination checkpoint inhibition (Weber S et al. Abstract 100).
• Tumor mutational burden and inflammatory response are not directly connected in all tumors (Pires Da Silva IED et al. Abstract 9511).
• The combination nivolumab+ipilimumab shows durable intracranial responses in patients with asymptomatic and, to a lesser extent, also with symptomatic melanoma brain metastases (Tawbi HAH et al. Abstract 9501).
• The COMBI-I study shows encouraging response rates of a triple combination of immunotherapy and targeted therapies (spartalizumab + dabrafenib + trametinib) as frontline therapy in patients with advanced melanoma (Long GV et al. Abstract 9531).
• Patient-reported quality of life and symptoms in patients with advanced melanoma were maintained from baseline during extended therapy with nivolumab with or without ipilimumab (Schadendorf D et al. Abstract 9551).
• In the first prospective randomized neoadjuvant trial to date, monotherapy with the oncolytic virus T-VEC in resectable stage IIIB-IV melanoma, improved R0 surgical resections, 1-year-RFS, and OS (Dummer R et al. Abstract 9520).
• Antibody-mediated stimulation of GITR together with anti-PD-1 therapy with pembrolizumab seems promising in the frontline setting (Papadopoulos KP et al. Abstract 9509).

Pancreatic cancer

• The phase III POLO trial demonstrates that maintenance therapy with olaparib in patients with a germline BRCA mutation and metastatic pancreatic cancer following first-line platinum-based chemotherapy improves PFS compared to placebo treatment (Kindler HL et al. Abstract LBA4).
• The phase III APACT trial compared adjuvant nab-paclitaxel plus gemcitabine versus gemcitabine for surgically resected pancreatic adenocarcinoma. While the primary endpoint of independent reviewer-assessed disease-free survival was not reached, however, OS was longer in the nab-paclitaxel plus gemcitabine group (Tempero MA et al. Abstract 4000).

Prostate cancer

• In the phase III ENZAMET trial, addition of enzalutamide to standard-of-care therapy improved OS as well as PSA relapse-free survival in over 1,000 patients with metastatic hormone-sensitive prostate cancer (Sweeney C et al. Abstract LBA2).
• The phase III TITAN trial showed significant improvement of radiographic PFS and OS through apalutamide treatment in patients with metastatic castration-sensitive prostate cancer receiving androgen deprivation therapy, at a tolerable safety profile (Chi KN et al. Abstract 5006).
• The Alliance A031201 trial shows that enzalutamide and abiraterone is not useful for non-metastatic castration resistant prostate cancer (Morris MJ et al. Abstract 5008).

Sarcoma

• The phase III ANNOUNCE trial, interrogating olaratumab plus doxorubicin versus placebo plus doxorubicin for patients with advanced soft tissue sarcoma, was negative with respect to both endpoints of progression free and overall survival (Tap WD et al. Abstract LBA3).